Beyond sweetness: rare sugars as next-generation functional food ingredients for metabolic health, food innovation, and sugar-reduction strategies

1 Introduction

Excessive dietary sugar intake has become an important public-health concern and a major challenge for food-product reformulation. Current evidence associates excessive sugar consumption with adverse health outcomes, including overweight and type 2 diabetes mellitus (T2DM), and the World Health Organization (WHO) issued guidelines in 2015 recommending reductions in free-sugar intake (Teysseire et al., 2024). This concern is echoed by the reviews on the obesity epidemic and the use of sweeteners by people with diabetes or obesity who are trying to manage their blood glucose and/or weight (Kossiva et al., 2024). Sugar reduction is also relevant to cardiometabolic health because excessive sugar intake contributes to dietary patterns associated with obesity, type 2 diabetes, and related cardiometabolic disorders (Lu et al., 2025a). A major challenge for the food industry is to reduce sucrose content without compromising sweetness, texture, processing performance, product stability, or consumer acceptance. Conventional sugar-replacement strategies address only part of this formulation challenge. Narrative evidence suggests that alternative sweeteners are not chemically or metabolically uniform and cannot be considered biologically inert (Kossiva et al., 2024). Their contributions to dietary energy and carbohydrate intake depend on the sweetener class: high-intensity non-nutritive sweeteners may contribute negligible energy at typical use levels, whereas rare sugars and polyols are carbohydrate-based compounds with compound-specific and, in several cases, non-zero energy values (Teysseire et al., 2024). Technological limitations are also evident at the product level. In ice cream, replacing sucrose with systems containing sucralose, stevioside, and erythritol altered the sensory profile, including the intensity and onset of sweetness. A blend containing 60% sucralose, 20% stevioside, and 20% erythritol performed comparatively well in a study involving 106 consumers (Long et al., 2024). Sweetener systems add further complexity because high-intensity non-nutritive sweeteners, rare monosaccharides, and polyols differ in chemical composition and technological function; their applications must therefore consider texture, sensory quality, aftertaste, bitterness, stability, blending, and, where appropriate, microencapsulation (Benucci et al., 2024). Therefore, sugar reduction is not simply a matter of replacing sucrose with another sweetener; it is a matrix-specific formulation challenge. In this context, rare sugars are more appropriately considered low- or reduced-energy carbohydrates with compound-specific caloric and glycemic properties, rather than uniformly calorie-free sweeteners. Alternative sweeteners differ in chemical class, digestibility, available energy, and potential interactions with the gut microbiome; therefore, artificial sweeteners, rare sugars, and polyols should not be treated as metabolically equivalent categories (Lee et al., 2024). Because rare sugars are carbohydrates, their relevance extends beyond sweetness to compound-specific physicochemical and biological functions. A review of the cardiometabolic literature reported both preclinical experimental and human clinical findings related to insulin sensitivity and glucose regulation; however, these evidence streams should be interpreted separately because findings from animal or mechanistic studies do not establish clinical efficacy (Lu et al., 2025a). Interest is also expanding toward less extensively studied compounds such as L-xylulose, an L-form rare sugar investigated for its low-energy characteristics, α-glucosidase inhibitory activity, and potential food and pharmaceutical applications (Li et al., 2026b). Its low natural abundance and the difficulty of chemical synthesis remain important barriers to wider utilization. Rare sugars are therefore more appropriately considered multifunctional ingredients rather than additives that provide sweetness alone. Improvements in production efficiency and validation in food applications will be essential for wider utilization of rare sugars. Lactose-rich whey has been advocated as a feedstock for the production of the rare monosaccharide D-tagatose together with other value-added carbohydrates such as lactosucrose, epilactose, and lactulose; however, production costs remain an important barrier to broader industrial implementation (Singh et al., 2025). Recent chemical and process innovations illustrate both progress and remaining limitations: although D-galactose was converted to D-tagatose at room temperature, CaO functioned as a stoichiometric reagent rather than a true catalyst, with the highest yields obtained after 40 min and a maximum selectivity of 73% (Zhao et al., 2025a). Microwave-assisted continuous-flow isomerization of D-galactose to D-tagatose in arginine solution achieved D-tagatose production of up to 14.9% and productivity of up to 254.4 g/L/h, although browning increased with increasing D-galactose concentration (Klinchongkon et al., 2026). In addition to the applications of D-tagatose itself, D-tagatose-based fatty-acid monoesters with hydrophilic–lipophilic balance values of 5.8–9.7 stabilized high-internal-phase emulsions containing a 75% oil fraction for more than 27 days (Xie et al., 2025). Although enzyme technology has been used for the synthesis of rare sugars for functional food innovation, there is still room for improvement in the understanding of the mechanisms in complex food matrices and scaling up to industrial processes (Yao et al., 2026). Accordingly, this critical narrative review integrates evidence concerning the structural chemistry, production, food applications, metabolic effects, safety, gastrointestinal tolerance, microbiota interactions, and regulatory aspects of rare sugars, with particular emphasis on their potential roles in metabolic health, functional-food development, and sugar-reduction strategies.

1.1 Literature search and evidence-selection approach

This article was designed as a critical narrative review rather than a systematic review or meta-analysis. Literature relevant to the chemistry, production, food functionality, metabolism, safety, gastrointestinal tolerance, gut-microbiota interactions, and regulatory aspects of rare sugars was identified through searches of Scopus, Web of Science, PubMed, and Google Scholar. The literature search was updated through 10 August 2026. Searches included the principal rare monosaccharides considered in this review: ‘D-allulose’, ‘D-psicose’, ‘D-tagatose’, ‘D-allose’, ‘L-arabinose’, ‘L-xylulose’, ‘L-ribose’, ‘D-sorbose’, ‘L-sorbose’, ‘D-talose’, and ‘D-altrose’. These names were combined with topic-specific terms related to production, biosynthesis, bioconversion, enzymes, fermentation, immobilization, food applications, sensory properties, glycemic response, metabolism, gastrointestinal tolerance, safety, gut microbiota, regulation, and consumer acceptance. Additional searches were performed using combinations of these terms when specific production technologies, physiological mechanisms, or food matrices were evaluated.

Peer-reviewed original research articles, clinical studies, animal studies, cellular and mechanistic investigations, analytical studies, process-engineering studies, and relevant review articles were considered when they directly addressed the scope of the review. Studies were included when they provided information on the structural chemistry, natural occurrence, production or purification, food-technological functionality, sensory performance, metabolic or physiological effects, gastrointestinal tolerance, microbiota interactions, safety, or regulatory relevance of the rare monosaccharides defined in Section 2.1. Studies addressing related polyols, disaccharides, or oligosaccharides were included only when they provided a relevant comparator, bioconversion relationship, analytical context, or food-matrix comparison and were not treated as evidence for rare monosaccharides themselves.

Articles were excluded when they did not provide sufficient methodological or experimental detail, were unrelated to food, nutritional, biochemical, biotechnological, or regulatory applications of the compounds under review, or duplicated evidence already represented by a more complete primary publication. Publications for which only an abstract was available were used cautiously and were explicitly identified as having limited evidential detail where relevant. Preprints were not included as primary evidence unless subsequently published as peer-reviewed articles. The review was limited to English-language publications.

Throughout the synthesis, human clinical, animal/preclinical, cellular/mechanistic, ex vivo/microbiological, food-formulation/technological, and process-engineering/production evidence were maintained as separate interpretive categories, and findings from one category were not treated as direct evidence for outcomes belonging to another category. Human randomized or controlled studies and systematic reviews/meta-analyses were given greater weight when evaluating clinical and metabolic outcomes. Animal studies were classified as animal/preclinical evidence and were not directly extrapolated to human efficacy. Cellular studies were classified as cellular/mechanistic evidence, whereas ex vivo and microbiological investigations were classified as ex vivo/microbiological evidence and were used primarily to support mechanistic interpretation. Food-matrix, formulation, sensory, physicochemical, and shelf-life studies were classified as food-formulation/technological evidence. Enzymatic conversion, fermentation, biocatalysis, immobilization, microbial production, purification, and scale-up studies were classified as process-engineering/production evidence and were evaluated according to reported conversion yield, productivity, selectivity, stability, processing conditions, purification requirements, and scale-up feasibility. This evidence hierarchy was applied throughout the review to prevent human clinical efficacy from being conflated with preclinical, mechanistic, ex vivo, technological, or production-related findings.

Reference lists of relevant reviews and primary studies were also examined to identify additional publications that might not have been retrieved through the initial keyword searches. Because this was a narrative review, no formal PRISMA flow diagram, preregistered protocol, or quantitative risk-of-bias meta-analysis was applied. Nevertheless, the search scope, inclusion criteria, study-type distinctions, and evidential limitations were explicitly considered to improve transparency and reduce overgeneralization across heterogeneous evidence.

2 The definition, classification and structural chemistry of rare sugars

2.1 Definition of rare sugars

Within this review, the term rare sugars is used operationally to refer to rare monosaccharides, namely, monosaccharides that are absent from nature or occur only in very low abundance, consistent with contemporary rare-sugar literature (Nakakita and Hirabayashi, 2025). The principal compounds considered under this definition include D-allulose, D-tagatose, D-allose, L-arabinose, L-xylulose, L-ribose, D-sorbose, L-sorbose, D-talose, and D-altrose. This operational definition is intentionally narrower than broader uses of terms such as ‘rare carbohydrates’ or ‘functional carbohydrates.’

Sugar alcohols, or polyols, are not classified as rare sugars in this review. Compounds such as allitol, galactitol, erythritol, xylitol, and D-sorbitol are chemically reduced derivatives of monosaccharides and are therefore treated as a separate carbohydrate class. They are discussed only where they occur within related bioconversion networks or provide relevant technological or physiological comparisons (Wen et al., 2025c; Matsuo et al., 2024). Likewise, uncommon disaccharides and oligosaccharides, including trehalulose, lactosucrose, epilactose, lactulose, and tagatose-derived oligosaccharides, fall outside the operational definition of rare sugars used here. When these compounds are mentioned, they are explicitly identified by their own chemical class and are included only to provide context concerning food-matrix transformations, fermentation, analytical chemistry, or formulation.

Rare monosaccharides are also distinguished from common dietary sugars such as glucose, fructose, galactose, and sucrose and from high-intensity sweeteners on the basis of molecular class rather than sweetness intensity or health-related claims. Their nutritional and technological behavior is influenced by stereochemistry, carbonyl-group position, transporter affinity, microbial utilization, available energy, glycemic response, and food-matrix behavior (Kishida et al., 2023). Modern chemical, enzymatic, and microbial production approaches have increased access to these low-abundance monosaccharides through isomerization, epimerization, redox pathways, phosphorylation/dephosphorylation pathways, and multienzyme cascades (Nakakita and Hirabayashi, 2025; Wen et al., 2025b).

2.2 Major rare sugars relevant to food science

Although carbohydrate stereochemistry permits many possible monosaccharides, food-science research has concentrated on a smaller group for which sensory behavior, metabolic fate, safety, and production feasibility are sufficiently characterized. D-allulose and D-tagatose are currently among the most extensively characterized candidates because they combine low-energy sweetening potential with an expanding evidence base for postprandial glycemic and cardiometabolic effects (Lu et al., 2025a; Zhang et al., 2021; Ortiz et al., 2024). Other rare sugars remain important because small stereochemical differences can alter enzyme recognition, intestinal transport, microbial utilization, and manufacturing difficulty (Wen et al., 2025c; Zhu et al., 2024). L-xylulose illustrates the production challenge: sequential co-immobilization of L-arabinitol 4-dehydrogenase and NADH oxidase on magnetic nanoparticles improved conversion stability and catalyst reusability, showing how process engineering can increase the feasibility of a naturally scarce sugar (Patel et al., 2024). Accordingly, the compounds discussed below should not be treated as interchangeable sugar substitutes, but as structurally related carbohydrates at different stages of technological and translational readiness.

2.2.1 D-allulose

Historically referred to as D-psicose, D-allulose is one of the most extensively studied rare sugars for sugar-reduction applications. Structurally, D-allulose is the C-3 epimer of D-fructose, a stereochemical difference that alters its energetic and metabolic behavior while allowing it to retain a sucrose-like sensory profile rather than an equivalent sweetness intensity (Zhang et al., 2021). Published evidence describes D-allulose as a low-calorie sucrose alternative with approximately 70% of the sweetness intensity of sucrose and a reported dietary energy value of approximately 0.4 kcal/g (Zhang et al., 2021). Jurisdiction-specific regulatory status, labeling requirements, and assigned energy values are summarized separately in Section 8.8 and Table 1. In addition to its metabolic relevance, D-allulose has demonstrated practical value in food applications. Acute studies in healthy adults have evaluated the effects of D-allulose on glucose, insulin, ghrelin, lipids, uric acid, and inflammatory markers (Teysseire et al., 2023). In contrast, short-term interventions involving individuals with type 2 diabetes or diabetes-oriented dietary designs have focused primarily on glucose homeostasis (Preechasuk et al., 2023; Fukunaga et al., 2023). Broader evidence syntheses indicate that D-allulose can produce glycemic and lipid responses distinct from those of common sugars, while emphasizing the need for larger, longer, and more diverse clinical studies (Lu et al., 2025b). Despite its structural relationship to D-fructose, D-allulose exhibits distinct intestinal transport and metabolic handling. In rats, D-allulose, D-sorbose, and D-tagatose were transported via GLUT5 but not SGLT1, suggesting that the stereochemistry of fructose isomers influences intestinal transporter recognition (Kishida et al., 2023). This does not necessarily rule out the potential for other interactions with the nutrient-handling systems, but it is consistent with the general structure-function principle that rare ketoses may have different interactions with the nutrient-handling systems as compared to glucose or sucrose. The distinct technological behavior of D-allulose is also evident in food-formulation studies. In bread formulations, D-allulose enabled reductions in free-sugar content but altered fermentation behavior compared with sucrose-containing controls (Hu et al., 2025). The use of the rare sugar D-allulose in ground pork sausages affected water-holding capacity, apparent viscosity, and texture, indicating that D-allulose contributes to water retention and protein interactions within the food matrix rather than functioning solely as a sweetening ingredient (Kim et al., 2024). Studies of yogurt and baked products further indicate that the sensory acceptance of D-allulose and D-tagatose is strongly dependent on the food matrix (Esparza et al., 2025; Gomez-Betancur et al., 2025). Production efficiency remains a major determinant of the commercial feasibility of D-allulose. Conventional biocatalytic production of D-allulose typically involves the conversion of D-fructose using D-allulose three-epimerase, D-psicose three-epimerase, or D-tagatose three-epimerase within the Izumoring framework (Tan et al., 2023). However, the same production literature also reveals problems, such as low equilibrium conversion and low thermotolerance of enzymes that have stimulated the application of protein engineering, enzyme immobilization and whole-cell approaches (Tan et al., 2023; Zhao et al., 2025a). The crystal structure of an L-ribulose three-epimerase complexed with D-allulose and D-fructose revealed that hydrophobic sites at the entrance of the active-site of the enzyme influence the recognition of its substrate (Watanabe et al., 2024). More recent pathway-engineering approaches extend beyond classical epimerases; for example, engineering L-rhamnulose-1-phosphate aldolase improved stereoselectivity toward D-allulose over the competing by-product D-sorbose, with the P188N and P188Y variants showing particularly favorable performance (Fei et al., 2026). Although scale, cost, and formulation performance remain product-dependent challenges, the combination of established structural chemistry, metabolic interest, food-matrix functionality, and continuing advances in production technology supports the comparatively advanced translational status of D-allulose. The structural features, metabolic fate, glycemic effects, and food-matrix functionality of D-allulose are summarized in Figure 1. The enzymatic conversion of D-fructose to D-allulose and its relationship to other rare-sugar interconversions are depicted in the Izumoring network in Figure 2.

TABLE 1. Comparative regulatory status, approved or intended food uses, labeling requirements, assigned caloric values, gastrointestinal-tolerance guidance, and health-claim status of selected rare sugars. Regulatory information verified on 10 August 2026.

2.2.2 D-tagatose

D-tagatose is a rare, naturally occurring ketohexose that has attracted considerable interest in food science because it combines substantial sweetness with a markedly lower energy contribution than conventional sucrose. D-tagatose provides approximately 1.5 kcal/g and has a relative sweetness of approximately 92% that of sucrose, whereas D-allulose provides approximately 0.4 kcal/g and has a relative sweetness of approximately 70% that of sucrose. This direct comparison highlights the nutritional distinction between the two major rare sugars discussed in this section and allows their potential value in sugar-reduction strategies to be evaluated without requiring conversion from relative caloric values (Zhang et al., 2021; Espinosa and Fogelfeld, 2010). D-tagatose has also been characterized by low digestibility, a low glycemic and insulinemic response, and potential antioxidant, prebiotic, and oral-health-related properties (Ortiz et al., 2024). Production-oriented studies further support its potential as a lower-calorie sugar substitute with physiological and technological applications (Chen et al., 2025; Fan et al., 2025; Tang et al., 2025a). The technological relevance of D-tagatose is closely linked to its potential production from D-galactose, lactose, and lactose-rich dairy side streams. Conventional D-galactose isomerization is constrained by thermodynamic equilibrium, which has encouraged the development of alternative redox, epimerase-based, and microbial-cell-factory routes (Fan et al., 2025; Zhang et al., 2021). Using the amino acid sequence of xylose reductase from S. graminis, a new enzyme with four times the D-galactose substrate specificity of the template enzyme was identified in S. gorwiae, and the gene encoding it was inserted into Saccharomyces cerevisiae. The transformant strain was able to convert 10 g/L D-galactose to 5.47 g/L D-tagatose in 48 h, with a yield of 54.7% in 48 h for a dual redox system (Zhang et al., 2023). A model-driven study of Sungouiella intermedia revealed that this yeast catabolises galactose via both the Leloir pathway and an oxidoreductive route, generates galactitol as a redox-balancing overflow metabolite, and has the potential to be engineered for galactitol-to-tagatose conversion using cheese whey permeate as a feedstock (Peri et al., 2026). Enzymatic pathway design has also been extended upstream through the use of UDP-glucose four-epimerase from Nostoc sp. In this pathway, sucrose synthase generated UDP-glucose, GalE converted UDP-glucose to UDP-galactose, subsequent hydrolysis released D-galactose, and L-arabinose isomerase converted D-galactose to D-tagatose (Huo et al., 2026). Both chemical and epimerase technologies have their own unique strengths and weaknesses. Both the CaO-to-D-galactose molar ratio and reaction time influenced the process: complete conversion was reported after 40 min at room temperature at CaO/D-galactose molar ratios of 1:1 or 2:1, although CaO behaved as a stoichiometric reagent rather than a catalyst and higher ratios promoted formation of gel-like complexes (Zhao et al., 2025a). Tagatose four-epimerase has therefore attracted interest because it enables direct conversion of D-fructose to D-tagatose. A Thermoprotei archaeon T4Ease was found to contain a conserved (beta/alpha)8 TIM-barrel and a common metal-binding site along with a unique helix/loop that covers the substrate-recognition pocket, substrate-recognition residues and catalytic residues (Chen et al., 2025). Protein engineering and immobilization have also been used to improve thermostability and whole-cell biocatalytic performance (Liu et al., 2025a). Thus, D-tagatose combines substantial food relevance with a diverse range of production routes, while its application in matrices such as yogurt and baked foods continues to expand (Esparza et al., 2025; Gomez-Betancur et al., 2025). Nevertheless, conversion yield, purification requirements, browning, production cost, and industrial scale-up remain important barriers to wider use. Representative enzymatic routes for D-tagatose production are summarized in Figure 3.

2.2.3 D-allose

D-allose is a comparatively less studied rare aldohexose whose food applications are substantially less developed than those of D-allulose and D-tagatose, although interest in its biological and technological properties is increasing. Structurally, it resembles the common hexoses but differs sufficiently in hydroxyl orientation to alter the recognition of the enzymes, the way it is handled by cells and the requirements for its production. D-allose and D-allulose are both rare natural monosaccharides found in meager amounts, and both are of great interest as low-calorie sucrose alternatives. D-allose is reported to be about 80% as sweet as sucrose and has been described as a zero-calorie rare sugar, corresponding to an approximate energy value of 0 kcal/g (Mahmood et al., 2023; Masuda et al., 2025). This evidence makes D-allose a good candidate for a functional carbohydrate, but its application to food is less broad than that of allulose and tagatose, as many of the studies focus on biocatalysis and biological activity instead of food. D-allose exhibits a distinct profile of biological activities in experimental studies. Production-oriented studies have reported anticancer, antitumor, anti-inflammatory, antioxidant and pharmaceutical properties of D-allose (Tang et al., 2025b). In a broader perspective, D-allose is a rare monosaccharide which could be of interest in anticancer research due to its epimeric relationship to glucose and its possible role in the alteration of glucose uptake and/or glycolytic metabolism in cancer models (McCallum and Najlah, 2024). While the results cannot be directly translated in claims for food products, they are interesting for the scientific value of D-allose as a structural probe to understand how small changes in the carbohydrate structure can affect biological recognition. This value can be applied in related synthetic chemistry to the design of ingredients. Performing intramolecular aglycone delivery, a novel non-reducing disaccharide functionality, similar to sucrose, but composed of D-allose and D-psicose, was synthesized, showcasing the ability to use rare monosaccharides in the creation of new functional architectures of sweetener molecules beyond replacement of sucrose molecule-for-molecule (Sano et al., 2024). The rate of progress of the production evidence has been quicker than that of product-level food evidence. D-allose can be produced by using two enzymes of Bacillus subtilis, D-allulose three-epimerase and L-rhamnose isomerase, which have been reported to be high-level one-pot biosynthesis from D-fructose (Tang et al., 2025b). D-allose was also characterized by a ribose-5-phosphate isomerase B from a bacterium (Curtobacterium flaccumfaciens) which allows a wider biocatalytic network to be built that also involves pentose-phosphate-pathway enzymes (Zheng et al., 2024). Another way is chemical catalysis, which yielded glucose through epimerization pathways and at 140 °C allose and altrose were each generated 24%, supported by isotope-labeling NMR results, with 1,2-carbon-shift pathways (Zhu et al., 2024). All of these studies are structurally and biologically interesting and promising for D-allose, but are not yet fully validated as a mainstream food ingredient. Sensory performance and sensory effects, regulatory evaluation and human metabolic effects, and stable formulation in real foods are far less advanced, while production chemistry and mechanistic biology are more fully developed. D-allose is detailed in the major production pathways and its biological relevance in Figure 3.

2.2.4 L-arabinose

Unlike D-allulose and D-tagatose, the principal nutritional interest of L-arabinose lies in its modulation of sucrose digestion rather than in its use as a direct bulk replacement for sucrose. It is a pentose which has been studied as a sucrase inhibitor that could inhibit the hydrolysis of sucrose and reduce the glycemic, insulinemic response to sucrose. L-arabinose was compared with a 550 mL sucrose drink and sucrose-rich meals/snacks in a randomized double blind crossover trial in adults with impaired fasting glucose, as it was thought that L-arabinose may decrease the glycemic response by interfering with sucrose metabolism instead of being a typical bulk sweeter (Pretorius et al., 2025). This mechanism provides a distinct formulation rationale for L-arabinose because it can be incorporated into sucrose-containing foods to modulate the postprandial response rather than completely replacing sucrose. Similar findings reported in the biological literature indicate that the effects of L-arabinose are context-dependent and are associated with food-matrix and microbiome-related factors. One mouse study has shown that dietary L-arabinose led to an increase in the number of Enterobacteriaceae, as well as a decrease in the diversity of microbiota, and a deterioration of the outcome of a systemic Salmonella infection in the presence of microbiota (Yu et al., 2024). Not that this is to say it does not have glycemic-modulation capabilities, but that a carbohydrate that can impact digestion in the host can also be a substrate or an ecological stressor on the microbes in the intestine. One study in a separate mouse model of functional constipation showed that 20 days of L-arabinose intervention restored outcomes related to defecation, and altered the gut microbiota and metabolites (Liu et al., 2025a). The different contexts highlight the importance of assessing L-arabinose in terms of the acute glucose curve as well as dose, host status, microbial ecology, food matrix, and intended population. The technological relevance of L-arabinose also extends beyond glycemic modulation. Performing in vitro fermentation assays using rare and new-to-nature disaccharides, it was found that the gut microbial responses were strongly influenced by the glycosidic linkage: L-arabinose glucoside strongly increased the ability of bifidobacteria in donor-derived inocula while other glycosidic linkages resulted in other microbial shifts (Onyango et al., 2023). L-arabinose units have also been used in synthetic chemistry to produce aroma precursors for flavour and fragrance applications, demonstrating that L-arabinose-containing disaccharides can serve as precursors for controlled aroma release in addition to providing sweetness. The challenge in practice is then not that the elements have no conceptual relevance but rather the need to design the product carefully. For food applications, such as beverages, bakery, confectionery and dairy, dose realism, sweetness contribution, potential sensory effects and carbohydrate-digestive modulation would need to be balanced. L-arabinose is a low-energy pentose for which reported metabolizable energy values range from approximately 1.36–2.30 kcal/g, depending on dietary inclusion, supporting its lower-energy potential relative to conventional digestible sugars (Schutte, 1990). Its principal functional interest, however, extends beyond sweetness to the modulation of sucrose digestion and associated metabolic responses.

2.2.5 Other rare sugars

In addition to D-allulose, D-tagatose, D-allose, and L-arabinose, several less extensively studied rare monosaccharides broaden the structural and biotechnological diversity of this group. One example is L-xylulose, for which its low natural abundance makes biocatalytic production more practical than direct recovery. A sequential co-immobilization system combining L-arabinitol 4-dehydrogenase with NADH oxidase on magnetic nanoparticles improved conversion performance, operational stability, storage stability, and reusability compared with free or mixed-enzyme systems (Patel et al., 2024). Similarly, L-ribose has been included among rare monosaccharides produced through modern biotechnological approaches involving isomerization/epimerization, redox chemistry, and phosphorylation/dephosphorylation pathways, although these routes may be limited by thermodynamic equilibrium or cofactor requirements (Wen et al., 2025a). D-sorbose represents another rare monosaccharide of biotechnological interest and may occur both as a target compound and as a competing product during rare-sugar synthesis. When the stereoselectivity of the aldolase reaction is low, D-sorbose can be formed as a byproduct during engineered D-allulose synthesis, emphasizing the need to improve the D-allulose/D-sorbose product ratio (Fei et al., 2026). L-sorbose has independently attracted biological and industrial interest. Its reported antitumor properties have been associated with inhibition of glucose metabolism (Xu et al., 2023)), while metabolic engineering approaches have enabled the production of rare L-sorbose from abundant D-glucose using Escherichia coli (Taylor et al., 2025). D-talose and D-altrose are less developed as food ingredients but remain relevant examples of rare aldohexose stereoisomers that can be generated through catalytic epimerization. Selective D-galactose epimerization to D-talose using molybdenum oxide in water at 120 °C for 30 min resulted in a reported yield of 25%, selectivity of 70%, and carbon balance of 98% Allose and altrose have also been generated through high-temperature epimerization using Mo/beta as a catalyst, further demonstrating how catalytic reaction pathways can expand the structural library of rare monosaccharides (Zhu et al., 2024). Overall, these less-studied rare monosaccharides expand the chemical and technological diversity of rare-sugar research. However, the available evidence remains more strongly developed for synthetic, enzymatic, and early biological studies than for human studies or validation in commercial food matrices.

2.2.6 Related sugar alcohols (polyols)

These compounds are outside the operational definition of ‘rare sugars’ adopted in this review and are discussed only as related reduced derivatives. Sugar alcohols, or polyols, constitute a chemically distinct category from rare monosaccharides and should therefore be considered separately, even when they occur within related rare-sugar bioconversion networks. Galactitol is a sugar alcohol with potential food and pharmaceutical applications, and optimized whole-cell catalysis using engineered S. cerevisiae expressing an Aspergillus niger xylose reductase produced 12.10 g/L galactitol from D-galactose (Wen et al., 2025b). Allitol is another polyol associated with rare-sugar chemistry and has been evaluated in combination with D-allulose in high-fat-diet rats, where both compounds affected body-fat accumulation and short-chain fatty acid production in the cecum (Matsuo et al., 2024). Galactitol and allitol are therefore discussed here as related sugar alcohols rather than rare monosaccharides. Their inclusion is relevant because they illustrate how reduction of monosaccharides can generate structurally related polyols with distinct physicochemical and physiological properties. Maintaining this distinction is important for avoiding taxonomic ambiguity between rare monosaccharides and sugar alcohols.

2.3 Structure-function relationships

Stereochemistry governs the functional behavior of rare sugars. The change of the hydroxyl orientation can have an impact on sweetness, enzyme binding, the choice of transporters, the uptake of microbes, browning behavior and caloric contribution. Both D-allulose and D-tagatose possess sugar-like sensory and bulk properties and their metabolic outcomes are different from that of abundant sugars, while D-allulose is the C-3 epimer of D-fructose and D-tagatose is the C-4 epimer of D-fructose (Ayoub, 2026; Zhang et al., 2021; Ortiz et al., 2024). In fact, the transport of these rare fructose isomers, D-allulose, D-sorbose, and D-tagatose, has been shown directly to be via GLUT5, but not via SGLT1, in rats, demonstrating that the rare fructose isomers can maintain fructose transporter access without acting as glucose substrates (Kishida et al., 2023). In mice, D-fructose, D-allulose, D-tagatose and D-sorbose stimulated GLP-1 secretion and suppressed food intake while the aldohexose tested did not, suggesting that the effect of both the carbonyl position and stereochemical class is important for the enteroendocrine response (Masuda et al., 2025). This is also the case with enzymes from production. In ketose three-epimerase, D-allulose and D-fructose binding was not only determined by the binding residues of the substrate, but by the conformational changes of the hydrophobic regions of the active site towards the bound substrate (Watanabe et al., 2024). The binding of the substrate in tagatose four-epimerase relies on a well-defined pockets containing catalytic, metal binding, phosphorylation and recognition residues that are embedded in a conserved TIM-barrel architecture (Chen et al., 2025). The poor selectivity for D-allulose/D-sorbose in P188-containing loop of L-rhamnulose-1-phosphate aldolase was improved to sharp or nearly exclusive D-allulose production by engineering the P188 containing loop, as an example of the ability to stereospecifically change the chiral product outcome due to steric hindrance (Wang et al., 2026). Similarly, rare allose and altrose were prepared by glucose epimerization over Mo/Beta catalysts, and the study of D-talose indicated that the stereoselectivity of the epimerization, the Mo valency, the Lewis acidity of the catalyst, oxygen vacancies, and carbon-shift chemistry of the Bilik type were correlated (Zhu et al., 2024; Devi et al., 2024). The functionality of food is also related to the molecular structure. Sucrose contributes sweetness, solids, crystallization, freezing-point depression, browning, and texture, and these functions are difficult to reproduce with a single alternative ingredient. Rare sugars are therefore not necessarily equivalent to sucrose in their bulk, water-binding, and Maillard-reactive properties. Previous formulation studies have demonstrated matrix-dependent technological effects of D-allulose in bread (Hu et al., 2025), and sausage systems (Kim et al., 2024). From a comparative structure–function perspective, however, D-allulose and D-tagatose produced distinct effects on water-holding and textural properties in different dough and biscuit matrices despite both being epimerically related ketohexoses (Gomez-Betancur et al., 2025). Processing chemistry can also create practical challenges because alkaline or microwave-assisted treatments may improve productivity while simultaneously increasing acid formation or browning, depending on substrate concentration and reaction conditions (Zhao et al., 2025b; Wen et al., 2025b). Rare sugars can therefore be interpreted most effectively through a structure–function framework based on their stereochemical characteristics. It accounts for the difference between D-allulose and fructose in terms of their metabolic fate, suggests possible routes for the production of D-tagatose (galactose, lactose, galactitol or fructose epimerization pathways), explains why D-allose is biologically interesting but not necessarily a good fructose replacement, and provides a rationale for considering L-arabinose as a sucrose-digestion modulator rather than just a sweetener replacement. This structure-first approach also provides a foundation for future directions: future production systems should overcome stereoselectivity and thermodynamic limitations; future nutrition research should address the importance of matrix-specific behavior beyond just sweetness; and food technologists should better understand matrix-specific behavior and its link to sweetness, digestion/absorption, microbiome, and future safety. Rare sugars thus are not a homogeneous group of low-calorie sweeteners, but rather a structurally diverse group of carbohydrates, whose utility is related to a match between sugar structure and the intended metabolic and technological role. The structural classification of the principal rare sugars discussed in this review and their relationships within the Izumoring interconversion network are shown in Figure 2. A summary of the principal rare sugars discussed in this review, their chemical classification, sweetness relative to sucrose, caloric value, and salient characteristics is provided in Table 2.

TABLE 2. Major rare monosaccharides discussed in this review, their chemical classification, relative sweetness, caloric value, and key references.

3 Natural occurrence and dietary sources

3.1 Occurrence in fruits, vegetables, grains, honey, and fermented foods

Rare sugars occur in a wide variety of foods, including fruits, vegetables, grains, honey, and fermented foods. Rare sugars may enter the human diet through two principal routes: as naturally occurring minor components of complex foods or as ingredients produced, enriched, or incorporated during food processing. Sugar composition of most plant foods is mostly composed of common sugars and structural polysaccharides, with rare or less abundant monosaccharides being minor components, thus making it difficult to use direct extraction from ordinary fruits, vegetables or grains as a feasible industrial route. The example of grape must will be helpful. The glucose and fructose content was measured in 82 true Italian grape musts along with eleven other minor sugars, and the sugars mannose, galactose and trehalose were found in significant amounts, while the other sugars mentioned were present in smaller amounts and with greater variability (Scettri et al., 2024). The pattern reflects one of the common issues in food matrices–that is, the absence is not synonymous with the lack of abundance, rather it makes food concentration, authentication and commercial recovery technically difficult. As a contextual example outside the core rare-monosaccharide scope of this review, several types of stingless bee honey contain unusually high concentrations of trehalulose, an uncommon glucose–fructose disaccharide. The 43 samples of Heterotrigona itama honey were collected from three regions of Malaysia, namely, the inland, west coast and east coast regions and trehalulose was always found and was described as predominant along with fructose and glucose (Ramlan et al., 2024). Although the matrix of Geniotrigona thoracica honey looks more like a trace source, a subsequent study of the recovery of this species of honey found that raw stingless bee honeys also contain over 65%–72% trehalulose. However, even in this case, recovery was still challenging: In 15 min, 50 °C, and 1000 g/L honey concentration, only 6.34% trehalulose was recovered while 32.51% glucose and 33.15% fructose were recovered as the product of the reaction, showing that it is not easy to separate these selectively (Ridzwan et al., 2025). The fermented foods widen the picture since the metabolism of the microorganisms may modify, enrich or break down the carbohydrate profile of the plant, besides just maintaining it. For the Korean fermented soybean products, the hydrolysates of the products contained oligosaccharides with degrees of polymerization ranging from 3 to 7, where the predominant monosaccharides formed were galactose, xylose, arabinose and rhamnose, indicating that the soybean carbohydrates were hydrolyzed and transformed during fermentation and processing (Song et al., 2023). When doing an intensive LC- MS/MS analysis of doenjang, 11 monosaccharides were found, and among them, the monosaccharides of galactose, glucose and arabinose were found in high amounts, while traditional doenjang showed more monosaccharide diversity than modified ones (Song et al., 2024). Similarly, Leuconostoc citreum SH12 efficiently utilized glucose, sucrose, fructose and maltose in the fermentation of plant based substrates and also in the fermentation of soymilk produced mannitol, alpha-glucans and also utilized xylose, arabinose, mannose and cellobiose (Dai et al., 2024). Long fermented Tongchuan Douchi exhibited significant change in the carbohydrate metabolism after 6, 12, 18 and 36 months, and galactose, and starch/sucrose were pointed out as having been metabolized, while raffinose and stachyose were suggested as the sources of released galactose (Li et al., 2026a). The same phenomenon can be seen in the case of apple and orange juices fermented for 18 h at 37 °C with fructophilic lactic acid bacteria, where the total amount of free sugar was reduced by over 40% and 50%, respectively, and sugars were determined by HPLC (Shigeoka et al., 2026). Heating also matters. The sugar model using tsukudani seasoning (rare sugar syrup) was found to give better browning at 420 nm and resulted in 1.1–4.5 times higher furan-type aroma compound level than the glucose-fructose sugar model and the white sugar model, demonstrating how the processing can cause rare sugars to become active participants in the formation of aroma compounds via the Maillard reaction (Miyoshi et al., 2024). Therefore, the process of natural occurrence, fermentation and heating processes must be considered as a continuum of the transformation of carbohydrates, and not a fixed list of “uncommon sugars.”

3.2 Rare sugars in traditional and modern diets

Natural dietary exposure to the rare monosaccharides considered in this review is generally low, intermittent, and matrix-specific. There are many minor sugars present in grape must, but none of them is present in significant amounts or in a consistent concentration as compared to glucose and fructose. (Scettri et al., 2024). The monosaccharides in fermented soybean products are not in large amounts of purified rare monosaccharides, but are rather contained in oligosaccharides, such as those that include arabinose, rhamnose, xylose and galactose (Song et al., 2023); while fermented soybean paste does contain a diverse profile of monosaccharides, but common monosaccharides like galactose and glucose still remain prominent (Song et al., 2024). Stingless bee honey provides a contrasting example of exposure to an uncommon carbohydrate outside the rare-monosaccharide category, because trehalulose was reported as a major sugar in H. itama honey and at high abundance in raw Geniotrigona thoracica honey in the cited recovery study (Ramlan et al., 2024; Ridzwan et al., 2025). This comparison illustrates why rare monosaccharides such as D-allulose and D-tagatose should not be taxonomically conflated with other uncommon carbohydrates such as trehalulose when dietary exposure, metabolic effects, and food applications are considered. Modern products are not only exposing the public to a different dose, but to a different context of exposure as well. Rare sugars have transitioned from an incidental food constituent to a purpose-designed sweetener and there is a close relationship between their industry value and their production via enzymatically and fermentatively-based processes. Recent work on microbial D-allulose synthesis shows that engineered cells can move beyond simple reversible fructose epimerization by integrating epimerization, redox, aldol, and phosphorylation-dephosphorylation modules and by using a wider range of carbon sources (Zhu et al., 2026). This change can be seen in the food systems as a reality. To use in fruit tea drinks, the immobilized glucose isomerase and D-allulose three-epimerase were used to convert D-glucose and D-fructose in the model system to D-allulose, which was achieved in the model system at a rate of 76 g/L D-allulose from 500 g/L D-glucose (Xiao et al., 2024). In fermented dairy systems, Streptococcus thermophilus has also been proposed as a food-grade chassis for engineering exopolysaccharides containing rare-sugar residues, linking rare-sugar biotechnology with texture, stability, and value-added functionality (Xiao et al., 2025b). Stability is also important as cultured milk products are also products in which living microorganisms and enzymes are present. Commercial nonfat Greek yogurts containing simple or complex microbial communities, with a D-tagatose content of 10% (w/w) showed no changes in D-tagatose during 6 weeks of refrigerated storage, whereas the pH slightly decreased (about 0.1 unit) (Sorensen et al., 2024). Bakery applications likewise show that exposure and functionality are matrix dependent. In sponge cake, replacing sucrose with D-allulose had little effect on the batter but substantially changed cake-specific volume, texture, microstructure, color, antioxidant activity, and the volatile profile, including greater formation of furans and pyrazines (Xie et al., 2024a). The formulation-based results suggest that exposure to industrial rare sugars will not only be a function of the sweetness equivalence, but also of the matrix, serving size, water activity, browning, texture and consumer acceptance. Other factors such as absorption and excretion should be taken into account when determining the meaning of a diet. In HPAEC-PAD analyses of tolerance tests, postprandial levels of glucose, fructose, tagatose and galactose rose within 60 min, and returned to basal levels at min, except for that of tagatose which was still elevated; only 3.7% of the ingested tagatose was excreted in the urine over 24 h (Klugel et al., 2026). Overall, it is not possible to control natural diets for background exposure, and it is possible to control and provide doses of nutrients in the modern reformulated diet that are nutritionally meaningful, but will require matrix specific exposure and tolerability testing.

3.3 Analytical challenges in detecting rare sugars

Analytical challenges arise from the close stereochemical similarity of rare sugars, which can produce compounds with very similar molecular masses, polarities, and chromatographic behavior. In the food matrices with low concentration of rare sugars, there is a need for separation from the abundant glucose, fructose, sucrose, polyols, organic acids, amino compounds and food fermentation metabolites. This was solved by using highly selective chemical-shift filters which were followed by Total Correlation Spectroscopy (TOCSY) and enabled the quantification of glucose, fructose and eleven minor sugars in 82 authentic grape musts (Scettri et al., 2024). This has great potential for authentication as it can describe the wide range of sugar profiles apart from just retention times, but it also demonstrates the need to use specialist methods to describe the very different sugar profiles of minor sugars like arabinose and rhamnose when they are analysed across a range of natural samples (Scettri et al., 2024). Chromatographic technologies are still the mainstays as they can be applied to complex food matrices. In order to provide rapid, simultaneous, monosaccharide profiling, 11 monosaccharides were identified and the fermentation of soybean paste was shown to be linear, sensitive and accurate by spiking experiments using LC-MS/MS (Song et al., 2024). Larger carbohydrate structures were analyzed by the application of mass spectrometry and gas chromatography which allowed for the oligosaccharide profiling of doenjang and ganjang, and found to contain galactose, xylose, arabinose, rhamnose, fucose, fructose, mannose, glucose, and N-acetylglucosamine (degree of polymerization three–7) (Song et al., 2023). In these studies, it is revealed that the selection of method is related to the kind of glycosidic compound to be analyzed, which is whether it is a free monosaccharide, an oligosaccharide, a glycosidic linkage or a mixture of carbohydrates produced by fermentation. HPLC continues to be particularly advantageous for formulated sweeteners. D-allulose, D-tagatose, D-mannitol, mycose, palatinose and erythritol were simultaneously determined by a validated HPLC- ELSD method using a Zorbax NH2 column and the mobile phase of acetonitrile:water that showed R2 values between 0.9985 and 0.9998, LOD from 0.02 to 0.06 mg/mL and linear range of 0.060–0.60 mg/mL (Liu et al., 2024). In the comparative HPLC study, six low-calorie or uncommon carbohydrate sweeteners were analyzed using both ELSD and RID. Depending on the analyte, the LODs were 0.02–0.06 mg/mL for ELSD and 0.1–1.0 mg/mL for RID. These results demonstrate that detector selection strongly influences analytical sensitivity and dynamic range (Luo et al., 2024). In addition, there is another uncertainty because of structural isomerism. Ridzwan et al. found the trehalulose confirmation in stingless bee honey by NMR and FTIR analysis of honey which revealed that trehalulose is an alpha-(1->1) glucose-fructose sucrose isomer with several hydroxy groups (Ridzwan et al., 2025). The chiral dimension in the problem was highlighted by the work of ribose, where the D/L-ribose was successfully conventional HPLC separated, but beta-cyclodextrin coated silver nanoparticles allowed the separation of D- and L-ribose to be achieved visually by colorimetry and by SERS based on chirality-dependent aggregation and hydrogen bonding (Zhang et al., 2023). Another challenge comes with the biological matrices. HPAEC-PAD was validated for glucose, fructose, tagatose and galactose in plasma, erythrocytes and urine (following oral tolerance tests) with the evaluation of linearity, LOD, LOQ, precision, and recovery and the method was sensitive enough to follow the absorption and excretion after the oral tolerance tests (Klugel et al., 2026). Multi-platform analysis was often used in fermentation and processing studies, for example, the combination of wet coffee fermentation, HS-SPME/GC-MS and microbial sequencing to correlate the formation of volatile compounds with the fermentation process (Marques Tenório Pereira et al., 2026), and the combination of GC-IMS, electronic nose, and untargeted metabolomics in the study of douchi fermentation (Li et al., 2026c). For carbohydrate remodeling and flavor development. Analytical reporting is required therefore to distinguish detection from quantification in the field, to identify whether the sugars have been resolved in the mixture being analysed and to validate each matrix and not take it for granted that one sugar method is applicable without change to any other matrix (beverage to honey, fermented pastes to dairy products to baked products).

4 Production technologies for rare sugars

4.1 Limitations of natural extraction

Because rare sugars occur only at trace levels in most natural materials, direct extraction generally has limited industrial value and imposes substantial purification burdens. Contemporary scale-up therefore emphasizes microbial cell factories, enzyme engineering, metabolic-pathway redesign, and fermentation optimization as more selective and environmentally compatible production platforms (Xu et al., 2026). Allulose is a good example of a scale gap. Can occur naturally in the processing of sucrose- and fructose-containing food and beverages, but estimated dietary exposure from Western style diet is < 500 mg/day; use as a sugar replacement may result in higher intakes of 10–30 g/day (Daniel et al., 2022). Natural recovery is thus not sufficient as a basis for production. The field has shifted towards the developed conversion systems, which utilize common sugars, dairy byproducts, starch hydrolysates, glycerol or other low-cost substrates for the generation of target rare sugars via chemical, enzymatic and microbial platforms.

4.2 Chemical production approaches

Chemical production is attractive when inexpensive substrates, simple reactors, and rapid conversion are priorities. However, these advantages must be balanced against stringent reaction conditions, by-product formation, and greater downstream purification requirements. Chemical synthesis of D-allulose has been reviewed as feasible but less selective than biosynthetic methods (Zhang et al., 2024). Galactose heated in hot compressed water in the presence of an eggshell catalyst was found to yield rare sugars along with organic acids, demonstrating a similar trade-off between catalyst simplicity and product selectivity (Futamata et al., 2024). A recent example of a chemical production process is the synthesis of D-tagatose from galactose obtained from lactose. Integrated with glucose hydrolysis, simulated moving bed separation, activated carbon and ion-exchange purification and process-economic modelling, a Ca(OH)2-driven process was able to obtain a yield of tagatose higher than 60% after 60 min at ambient temperature; however, glucose suppression of co-isomerization and CaSO4 precipitation after the neutralization created additional separation requirements (Wang et al., 2025c). Therefore, chemical routes may be quick and economically viable, but for food-grade utilization, the control of byproduct and salt management, coupled with strong purification is necessary.

4.3 Enzymatic production strategies

Enzymatic production is the more prevalent development route because it combines stereochemical control with milder processing conditions and fewer undesirable degradation products. Its lower energy demand and reduced environmental burden, together with the potential to achieve high-purity D-allulose, further support its industrial relevance (Zhang et al., 2024). Reaction architecture remains a central constraint. Direct isomerization or epimerization of fructose can generate mannose, allulose, or tagatose, but equilibrium limitations, enzyme selectivity, stability, and downstream separation determine whether these routes are industrially competitive (Yang et al., 2025). The strategies are increasingly focused on discovering enzymes, engineering them to the desired properties, and designing a cascade of enzymes and immobilizing them as a non-soluble catalyst.

4.3.1 Isomerases

Isomerases play a key role in the transformation of vast quantities of carbohydrates into scarce ketohexoses such as the production of D-tagatose from D-galactose or from streams obtained from lactose. L-arabinose isomerase from Lentilactobacillus parakefiri, together with commercial beta-galactosidase and xylose isomerase, was able to transform 95 g/L lactose into 23–24 g/L D-glucose, D-galactose, D-fructose and D-tagatose at pH 6.5, while at pH 4.5, the conversion was 100 g/L lactose to 46 g/L D-glucose, 22 g/L D-galactose and 23 g/L D-tagatose (Weber et al., 2025). Further enhancement in operational feasibility was achieved with immobilized L-arabinose isomerase/beta-galactosidase cascades, achieving 42.9% conversion of lactose after 24 h using a PVA/CNTs/ZnO- supported dual enzyme system, which is 3.25-fold more than the free-enzyme system (Lu et al., 2025a). These studies indicate that isomerase-based systems can achieve substantial conversion efficiencies, although their practical application remains constrained by pH requirements, metal cofactors, equilibrium limitations, and integration with lactose hydrolysis.

4.3.2 Epimerases

Epimerases can be used to create new stereochemical variations in rare sugars, providing a way to diversify the sugar library. The production of D-allulose is typically performed by D-allulose three-epimerase, D-psicose three- epimerase or D-tagatose three-epimerase to convert D-fructose to D-allulose, but the poor thermotolerance and low equilibrium conversion rate are still an important limitation (Xie et al., 2024a). A mined tagatose four-epimerase from Spirochaetia bacterium showed optimum activity at pH 10.5 °C and 65 °C, with a half-life of 6.9 h at 65 °C and a conversion rate of 25.3% of D-fructose to D-tagatose at 100 g/L D-fructose (Guo et al., 2026). Native limitations can partially be overcome by engineering the proteins. A mutant of Kosmotaga tagatose four- epimerase has been obtained by structure-based design and evolution that exhibits 5.6- and 9.6-fold higher specific activity and catalytic efficiency, respectively, over the wild type enzyme, and produces 28% D-tagatose from 500 g/L D-fructose in 12 h (Wang et al., 2026). These results indicate that epimerases have some industrial potential and yet they still need to be more stable, more active towards specific substrates and have better conversion efficiency.

4.3.3 Immobilized enzymes

One of the biggest drawbacks of the enzymatic production of rare sugars is the cost of enzyme replacement, which is being solved by immobilization. Optimal conditions for the secreted D-psicose three-epimerase (DPE) produced in Pichia pastoris were found to be pH 6.0 °C and 60 °C, with 17.03% D-psicose conversion from 10% D-fructose and 83.38% relative activity after five reuse cycles (Srila et al., 2025). Immobilization of L-arabinose isomerase in sodium alginate-silica hydrogel yielded 30.12% yield with 1 M D-galactose at 68 °C, and maintained >55% of activity after 20 cycles with a productivity of 6.78 g/L/h, while it produced 114.32 g/L of D-tagatose from guar gum hydrolysate after 10 cycles (Wen et al., 2025c). Enzyme-based bioconversion and microbial cell-factory strategies for rare-sugar production are summarized in Figure 4. The dual-enzyme hybrid nanoflowers (beta-galactosidase and L-arabinose isomerase) showed more than 77.99% of cascade activity after seven cycles (Zhang et al., 2026). The systems proposed indicate that immobilization will enhance reusability, stability, process continuity but mass transfer and support cost will still need to be optimised.

4.4 Microbial and fermentation-based production

Microbial systems move the production of rare sugars from individual enzymes to integrated cell factories, where it is possible to regenerate cofactors in the cell, balance pathways and utilize cheap feedstocks. Yield of D-allulose from D-xylose was enhanced by 35.1% when engineered E. coli cells were grown with antisense RNA to suppress flux through the pentose phosphate pathway and fed-batch fermentation achieved a yield of 0.615 mM/mM D-xylose and productivity of 0.969 mM/h (Guo et al., 2024). Hosts are also becoming available that can be used to host food items. The authors of the aforementioned study (Fei et al., 2025). Integrated the aldO, rhaD and yqaB genes into B. subtilis 168 and achieved 34.7% glycerol conversion yield to produce 27.66 g/L D-sorbose and 12.57 g/L D-allulose. After flux redirection, Corynebacterium glutamicum demonstrated the feasibility of D-allulose production in minimal medium, yielding approximately 3.6 g/L D-allulose from a D-glucose/D-fructose mixture with a yield of 9.1% (Lehnert et al., 2026). These findings demonstrate progress in microbial rare-sugar production, although pathway imbalance, by-product formation, strain safety, and downstream separation remain practical limitations.

4.5 Izumoring strategy and rare sugar bioconversion networks

The Izumoring concept is still significant since the rare sugars are not a series of independent reactions, but a series of convertible monosaccharides. The framework connects common sugars with rare sugars through enzymatic and chemical conversion to enable the selection of substrates, catalysis and reaction pathways for specific target structures and processes. According to recent reviews, practically any monosaccharide, including L-sugars, can now be obtained by a combination of chemical and enzymatic methods in a manner similar to that pioneered by Izumori and his collaborators (Xu et al., 2026). For D-allulose, the classical Izumoring route uses D-allulose three-epimerase, D-psicose three-epimerase or D-tagatose three-epimerase to convert D-fructose, whereas newer cascade routes use phosphorylation-dephosphorylation or redox logic to overcome equilibrium restrictions (Xie et al., 2024b). New wider bioconversion maps include isomerisation/epimerisation, reduction/oxidation and phosphorylation/dephosphorylation pathways together with the cofactors regeneration and immobilised enzyme systems (Yang et al., 2025). It is crucial for scalable production that this network view is established and connected to the molecular stereochemistry, feedstock selection, catalyst design and downstream purification.

4.6 Purification, crystallization, and downstream processing

Downstream processing is often the deciding factor for an industrially viable reaction for the rare sugar. High conversion is not enough as there may be residual substrates, common sugars, organic acids, salts, coloured degradation products, enzymes, immobilization supports, cells and closely related isomers in the reaction liquor. Whole-cell bioconversion using Dorea sp. Was used for D-allulose production. This is the flow of the major downstream processing steps, which are shown in Figure 5 for rare-sugar purification. CAG317 D-allulose three- epimerase converted 32.60% of the glucose which was then separated by chromatography and the optimized cooling crystallization yielded a 77.43% crystallization rate and 98.70% product purity (Sun et al., 2023). This is also true in the processing of chemical D-tagatose. The dairy-waste route called for front-end simulated moving bed separation to isolate galactose, activated-carbon, ion-exchange resins and sugar separation, and CaSO4 precipitation after the neutralisation, which all necessitated solid-liquid separation to avoid fouling (Wang et al., 2025b). Purification therefore cannot be regarded as a last-stage process, but must be assessed in conjunction with reaction chemistry in food grade production.

4.7 Sustainability and techno-economic considerations

The key factors for sustainable production of rare sugars are the cost of the substrate, the life of the catalyst, water and energy consumption, and burden of separation and food-grade acceptability. In particular, dairy streams offer great possibilities because the permeates contain a high amount of lactose, which can be enzymatically processed into sweeter permeates containing D-tagatose, providing another added value of a significant by-product (Weber et al., 2025). Other circular feedstocks are also promising with regard to repeated production of targets: guar gum hydrolysate was used to produce D-tagatose repeatedly using immobilized L-arabinose isomerase, and the glycerol was used to produce D-sorbose and D-allulose in engineered B. subtilis (Wen et al., 2025a). Techno-economic analysis is starting to provide some clarity as to which directions are likely to scale. The Ca(OH)2 process was modelled for 10,000 tons/year and its internal rate of return (IRR) was reported as 58.21% and net present value (NPV) of $234.64 million; however, the same study also highlighted the requirement of glucose removal and CaSO4 handling (Wang et al., 2025b). Other platforms will probably involve the use of inexpensive feedstocks, immobilized or secreted enzymes, and high-yield cascades and integrated purification, in addition to yield improvement. This is the flow of the major downstream processing steps, which are shown in Figure 5 for rare-sugar purification.

5 Physicochemical and technological properties in food systems

5.1 Sensory, physical, and shelf-life functionality of rare sugars in food matrices

Technologically rare sugars are attractive as they not only replace the sweetness on a numeric basis but also do more. The non-nutritive sweeteners are categorized into artificial and natural non-nutritive sweeteners (which are not made from carbohydrates and do not provide calories), and into rare sugars and polyols (which are compounds with properties more similar to carbohydrates) (Kossiva et al., 2024). It is significant in the case of formulated foods because the quality of sweetness, labelling requirements, texture and consumer acceptance are often dependent on one another. The online survey of 1290 consumers and acceptance test with 229 consumers found that allulose was the least preferred conceptually, but that taste was the primary factor influencing consumers to like the tasting yogurts, regardless of the sugar attribute (Crown et al., 2024). Evidence from the dairy beverage also indicates that iso-sweetness does not necessarily mean iso-flavor. Descriptive analysis and Temporal Dominance of Sensations (TDS) testing also indicated that some of the sweeteners added to the chocolate milk presented bitter and/or metallic flavors, but allulose syrup, mixed-sugar syrup, and sucralose did not produce a difference in liking when compared to the sucrose control, and people liked the sweetened chocolate milks as well as the sucrose control in both adults and children; however, the lactose hydrolysis reduced the amount of sweetener needed by approximately 1/3 and improved sweetener blends to be comparable to sucrose acceptance (Nakamura et al., 2025). In sponge cake, D-allulose functioned as more than a sweetener: it altered volume, texture, microstructure, color, and aroma chemistry, demonstrating that sucrose replacement can preserve bulk while substantially changing the baked matrix (Xie et al., 2024b). Rather than assigning rare sugars to fixed categories such as food additives, functional food components, or food biofortifiers, their technological performance in food matrices is more appropriately evaluated across three practical dimensions: sensory and consumer performance, physicochemical/process functionality, and matrix-dependent structural and storage behavior (Figure 6). These dimensions are used here as an organizing framework for the present review rather than as an established regulatory or chemical classification. Physicochemical and process functionality includes properties such as hygroscopicity, glass-transition behavior, powder formation, crystallization, particle characteristics, and flow behavior. For example, the hygroscopicity and low glass-transition behavior associated with D-allulose-containing systems can complicate spray drying, whereas resistant maltodextrin and maltodextrin DE 11 improved powder yield, with resistant maltodextrin yielding more than 50% even at allulose loadings exceeding 80% (Dejima et al., 2026). Similarly, in dark compound chocolate formulated with erythritol, mannitol, or tagatose, hygroscopicity, particle size, and sugar-crystal morphology were major determinants of appearance, texture, flow behavior, and melting characteristics (Wong et al., 2024). Matrix-dependent structural and storage behavior encompasses the effects of rare sugars on freezing behavior, water retention, viscosity, texture, and shelf-life stability. In frozen dairy systems, differential scanning calorimetry showed that tagatose behaved similarly to dextrose in water and model ice-cream mixes; although concentration affected the initial freezing temperature, tagatose did not produce a distinct freezing profile that would preclude its use in frozen formulations (Peck et al., 2025). In a meat-product system, replacement of 2% sucrose with allulose, kestose, and resistant maltodextrin improved water-holding capacity but reduced apparent viscosity and some texture parameters, illustrating the need to balance water retention with structural development during reformulation (Kim et al., 2024). Together with the sensory and consumer-acceptance evidence discussed above, these examples demonstrate that the technological suitability of rare sugars is matrix-dependent and should be assessed according to the specific functional requirements of the intended food system.

5.2 Processing behavior, browning chemistry, and interactions with food biopolymers

The processing behavior is highly dependent on the partitioning of water and interaction with starch and proteins of the rare sugars. In sponge cake, D-allulose substitution produced marked changes in specific volume, texture, microstructure, color, antioxidant activity, and aroma volatiles despite having relatively little effect on the batter, confirming that its technological behavior emerges strongly during heating (Xie et al., 2024b). The recrystallization of the retrograded gels, the gumminess and the hardness of the wheat starch system also increased with the increase in the ratio of D-allulose:starch from 1:1 to 1:0.5, which increased the pasting temperature and transition enthalpy of the wheat starch system (Wang et al., 2024). The outcome is that allulose can either have a positive or negative effect on texture, depending on the moisture content of the product and their thermal history. The reduced-sugar cookies prepared with a gelatinization-temperature-matching method had a relatively stable color, spread, and appearance as compared to sucrose cookies, while the appearance and color of the allulose cookies were darker and the spread was lower, and the texture of the cookies made from the various oligosaccharide systems was closer to sucrose (Woodbury and Mauer, 2024). In all potato and wheat starches, as well as tapioca, corn, and normal rice starches, allulose showed no significant effect on the gelatinization temperatures in comparison with glucose, fructose, and sucrose, and also significantly lowered the water activity in several starch gels, but its anti-recrystallization effect was most clearly observed in normal and glutinous rice starches during 14-day storage at 4 °C (Kwakye et al., 2024a). One of the easiest to understand scenarios that differentiates rare sugars from high intensity sugars is in Browning chemistry. Allulose and sucrose were involved in the formation of Maillard reaction intermediates, partly and not at all in the case of mogroside, respectively, whereas xylitol was only partially involved (Tu et al., 2025). In bread, allulose crust volatile profile was more similar to sucrose, with pathways related to aroma were also present in allulose; crust volatile profile was different in all the other sugars and sugar alcohols analyzed (Tu et al., 2025) When the high-solid gelatin-saccharide gels with allulose, fructose or fructo-oligosaccharides were heated for 0–60 min at pH about 5.5 and water activity 0.6–0.7, the gelling process caused rapid browning, and the extent of Maillard reactivity increased as allulose < fructose < fructo-oligosaccharides, with the presence of alpha-dicarbonyls, 5-hydroxymethylfurfural and advanced glycation end products (Wang et al., 2024). When these reactions are desired for the purpose of changing the crust color, roasted flavor and/or protein functionality, the reactions are beneficial but also increase the requirement for process control. In the case of pumpkin seed protein concentrate, the effect of glycation with fructose or allulose at a protein:sugar ratio of 1:1 and 3:1 on the various properties of the protein such as browning index, free amino groups, reducing sugars, amino acid profile, FTIR spectra, solubility, emulsion activity, foaming capacity, antioxidant activity and hydration behavior has been investigated (Tas et al., 2026). Allulose at 60% showed a higher peak viscosity of 7628 cP and 14-day retrogradation enthalpy of 3.18 J/g than the control, which was 1473 cP and 2.66 J/g respectively, thus highlighting the need to optimize the use of rare sugars in each biopolymer network as well as in sweetness and not just on that basis alone (Woodbury and Mauer, 2023). Rare sugars are shown to have an effect on the food processing and interactions with biopolymers in Figure 7.

6 Metabolism, absorption, and physiological fate

6.1 Digestion and intestinal absorption

Rare sugars should not be described as sharing a single pattern of digestion, absorption, or metabolism, because their physiological fate is strongly compound-specific. Their intestinal absorption, systemic metabolism, colonic fermentation, renal excretion, and available energy therefore need to be considered separately. For D-allulose, structural similarity to D-fructose permits intestinal transport, but the absorbed fraction is poorly metabolized by human catabolic pathways and is largely eliminated in the urine rather than undergoing extensive classical oxidation (Daniel et al., 2022). Consequently, D-allulose should be described as providing a low but non-zero energy contribution, consistent with the approximately 0.4 kcal/g value reported elsewhere in this review, rather than as producing ‘virtually no energetic yield.’ The fraction that is not absorbed may reach the lower intestine, making both renal elimination and colonic exposure relevant to its physiological fate. The digestive role of L-arabinose differs from that of D-allulose because its principal nutritional interest in the studies considered here concerns modulation of sucrose digestion and the subsequent appearance of glucose rather than direct replacement of sucrose as a bulk sweetener. In healthy adults, 7.5 g L-arabinose consumed with a 50 g sucrose drink attenuated the early glucose response and decreased early exogenous glucose appearance, indicating an effect at the intestinal digestion/absorption interface (Pasmans et al., 2022). L-arabinose was also evaluated with sucrose-rich beverages and foods in adults with impaired fasting glucose at 10% w/w relative to sucrose, further supporting the importance of food matrix, dose, and host metabolic status when interpreting its effects (Pretorius et al., 2025). D-tagatose has a different physiological fate again. It is a lower-energy bulk sugar with gastrointestinal fermentation and tolerance considerations, and its reported glycemic effects have been associated with intestinal disaccharidase inhibition, glucose transport, and hepatic carbohydrate metabolism (Espinosa and Fogelfeld, 2010). Its caloric contribution and gastrointestinal behavior should therefore not be inferred from D-allulose or L-arabinose. Overall, the available evidence does not support a metabolically homogeneous ‘rare-sugar’ model. Each compound should instead be evaluated according to its own absorption, metabolism, fermentation, excretion, available energy, dose, and food-matrix context.

6.2 Hepatic and systemic metabolism

Systemic metabolism differs substantially among individual rare sugars and should not be generalized from one compound to another. D-allulose provides a clear example of the dissociation between intestinal uptake and conventional energy metabolism because absorption is not followed by extensive entry into glycolytic, lipogenic, or glycogen-storage pathways. A substantial proportion of absorbed D-allulose is eliminated in the urine, whereas the unabsorbed fraction may reach the lower intestine (Daniel et al., 2022). Its physiological effects should therefore be interpreted in the context of low but non-zero available energy, together with potential contributions from intestinal sensing, renal clearance, hepatic signaling, and interactions with the gut microbiota. Preclinical animal evidence indicates systemic effects beyond caloric dilution. In diet-induced obesity and type 2 diabetes models, an allulose-rich diet decreased body-weight gain, food intake, insulin resistance, and liver triglyceride accumulation and increased circulating glucagon-like peptide-1 and mitochondrial uncoupling in adipose tissue (Cayabyab et al., 2024). In a separate fructose-induced insulin-resistance animal model, 5% D-allulose supplementation improved systemic and skeletal-muscle insulin resistance, insulin-stimulated AKT phosphorylation, and hepatic lipid metabolism (Kamal et al., 2025). At the cellular/mechanistic level, D-allulose and D-tagatose increased apolipoprotein A-I expression in HepG2 cells through insulin-responsive transcriptional elements; this cellular finding should not be interpreted as evidence of clinical lipid protection (Haas et al., 2022). Assessments of natural sugar substitutes indicate that D-allulose is rapidly absorbed and excreted in the urine and has been well tolerated in the short-term studies evaluated, whereas D-tagatose may present greater gastrointestinal-tolerance limitations despite its reported metabolic effects (Wang et al., 2025d). Accordingly, systemic metabolism should be interpreted in a sugar-specific and model-dependent manner, and long-term human evidence remains limited. Rare sugars may differ not only in sweetness and available energy but also in the extent of intestinal absorption, renal excretion, colonic fermentation, endocrine signaling, and effects on lipid and carbohydrate metabolism.

6.3 Effects on postprandial glucose and insulin response

Among the rare sugars currently investigated, D-allulose, D-tagatose, and L-arabinose have comparatively more developed evidence concerning physiological responses. A recent systematic review and meta-analysis of controlled adult intervention trials pooled together 1,033 adult participants – 12 allulose trials and eight tagatose trials. It concluded that allulose lowered postprandial glucose incremental AUC and insulin and tagatose decreased postprandial glucose and insulin and had a significant effect on HbA1c and fasting insulin, but no effects on blood lipids or body composition were observed (Osborn et al., 2026). This is relevant to the interpretation of manuscripts: rare sugars are more likely to be effective as acute glycemic modulators, rather than as broadly effective metabolic disease treatments. The mechanisms are not the same for the different compounds. The ability of d-allulose to lower glycemic spikes, when used in combination with sucrose, and the potential for d-allulose to exert an effect via GLP-1 release in the gut, are two mechanisms by which it could contribute to lowering blood glucose. The peak postprandial glucose and insulin were decreased in a dose-dependent manner in healthy Thai volunteers, suggesting a direct meal-context effect after consuming 50 g sucrose beverage supplemented with 2.5–10 g D-allulose (Buranapin et al., 2024). Further studies in 2026 demonstrated that, in addition to its insulin secretagogic action, gut-derived GLP- one released by D-allulose also functions in concert with insulin to activate the vagal afferents on the left side of the body and enhance insulin sensitivity (Ohbayashi et al., 2026). In addition to L-arabinose, a different pathway was observed that delayed the appearance of glucose from sucrose consistent with intestinal modulation rather than a classic incretin pathway (Pasmans et al., 2022). The various mechanisms suggested for the activity of D-tagatose–inhibition of disaccharidases, effect on glucose transport, and effect on carbohydrate metabolism in the liver–are less well supported, and much more prone to tolerance issues (Espinosa and Fogelfeld, 2010). In conclusion, the available evidence is more supportive of short-term reductions in postprandial glycemic excursions than of long-term diabetes prevention or sustained improvement in HbA1c. Therefore, the carbohydrate source used in the formulation, timing of glucose measurement, background glycemia, and if the unusual carbohydrate is used to replace sucrose or it is used as a metabolic modulator should be reported.

6.4 Effects on appetite, satiety, and energy intake

Rare sugars have been investigated for potential effects on appetite through low energy contribution, sweet-preference modulation, intestinal sensing, and endocrine signaling. However, the current evidence for appetite regulation is predominantly animal/preclinical and mechanistic, rather than derived from large or long-term free-living human trials. In a 12-week allulose-rich diet study it was observed that allulose decreased food intake and body-weight gain, and increased GLP-1, indicating appetite effects may be more than just a calorie-for-calorie replacement (Cayabyab et al., 2024). Luminal D-allulose was found to stimulate GLP-1 secretion in vivo male rats via an intestinal distension mechanism, suggesting that it is not sensed by glucose/fructose metabolism (Mizuma et al., 2025). The GLP-1 pathway is in synergy with neural communications. Ohbayashi et al. (2026) reported that D-allulose-induced intestinal GLP-1 release facilitated insulin action and activated left-sided vagal afferents, supporting a potential gut–brain mechanism linking D-allulose signaling with insulin action and feeding regulation. D-allulose reduced visceral fat accumulation and ameliorated glucose intolerance in sucrose-fed ovariectomized mice; these beneficial effects were markedly attenuated in GLP-1 receptor knockout mice, supporting an important role for GLP-1 receptor signaling in the metabolic effects of D-allulose (Iba et al., 2026). The other endocrine axis is liver FGF21. D-allulose, D-tagatose and D-sorbitol increased FGF21 and activated oxytocin neurons, and decreased sugar intake/preference in male mice (Efendi et al., 2025). A follow-up study on obesity prevention showed that rare sugars that increase FGF21 levels in the circulation of mice fed high fat and high sucrose diets decreased body weight gain and total calories consumed in the mice, but failed to reverse established obesity and insulin resistance (Efendi et al., 2026). These animal and mechanistic studies support biological plausibility for endocrine and neural pathways involved in appetite regulation, but they do not establish sustained reductions in appetite, energy intake, or body weight in humans. Claims concerning appetite or weight management should therefore remain proportional to the study duration, species, dose, feeding design, and absence or presence of controlled human evidence.

6.5 Gut microbiota interactions

The gut microbiota is an important, but non-deterministic, player in the physiology of rare sugars. Some of these rare sugars or similar carbohydrates may reach the colon where their potential effects, either beneficial or potentially harmful, depend upon the ability of bacteria to utilize the sugar or similar carbohydrate, fermentation products, the ecology of pathogens, and barrier response mechanisms. Human clinical evidence within the tested dose range is available from a 12-week randomized, double-blind, placebo-controlled trial, which found no significant differences in microbial diversity, selected enteric pathogens, or short-chain-fatty-acid production between D-allulose and the sucralose control (Park et al., 2024). These findings support microbiome tolerability at the tested human exposure but should not be interpreted as evidence of universal microbiome neutrality. At the microbiological/mechanistic level, Clostridium innocuum can metabolize D-allulose through D-allulose-6-phosphate three-epimerase (AlsE), while a bioinformatic analysis of 85,202 bacterial genomes indicated that this metabolic capacity is taxonomically restricted (Minabou Ndjite et al., 2025). The outcomes in disease models are more context dependent when mediated by microbiota. In mice, DSS-induced colitis was alleviated by 125–500 mg/kg/day of D-allulose, which showed to affect the symptoms of the colitis by changing gut microbiota and bile acid metabolism (Ye et al., 2025). D-tagatose prevented intestinal barrier deficiency and decreased the severity of DSS-induced ulcerative colitis, increased the amount of short-chain fatty acids, and changed the intestinal flora (Wang et al., 2025a). The cautionary side is exemplified by the use of L-arabinose which improved loperamide induced constipation via microbiota changes mediated by Lactobacillus but also L-arabinose-induced dysbiosis, increased Enterobacteriaceae and increased systemic infections in the presence of microbiota in a Salmonella infection model (Zheng et al., 2026). These conflicting findings reveal that the effects of microbiota are sugar specific, host dependent, pathogen dependent, and starting microbiota dependent. The evidence also highlights the need to not lump together all rare sugars and label them as prebiotics: in constipation or colitis models, using a substrate that is selectively fermented or is stimulatory to microbes might be desirable, but not under challenge with the pathogen or in a dysbiotic model.

6.6 Gastrointestinal tolerance

Gastrointestinal tolerability of rare sugars is compound-, dose-, matrix-, and host-dependent. Absorbed fraction, osmotic load, residual carbohydrate reaching the colon, fermentation rate, dose per serving, food matrix and individual microbiota composition are the factors that regulate tolerance. Very little of the absorbed dose of d-allulose is metabolized and the dose is excreted renally, and dietary exposure is estimated to be less than 500 mg/day; however, with replacement use, doses of 10–30 g/day may be reached depending on foods consumed, so that the dose is comparatively favorable with a relatively low estimated natural dietary exposure (Daniel et al., 2022). This increasing difference between the amount of exposure people have to a food product in their diet and the actual amounts of ingredients in a food product during the product development process is critical to serving-size realism. Short-term tolerability data in humans indicate tolerability when used under controlled conditions. The 15 g/day microbiota study showed no significant changes in the evaluated microbiome or pathogen-related outcomes after 12 weeks. In a separate randomized study, an allulose–amino acid hydration drink consumed at 1–3 packets/day for 4 weeks was generally well tolerated, although mild gastrointestinal symptoms such as bloating and cramping were reported and monitored as relevant endpoints (Park et al., 2024). Allulose is generally well tolerated short-term, and gastrointestinal intolerance is most commonly associated with D-tagatose, though metabolic benefits are observed with D-tagatose (Wang et al., 2025d). Another practical aspect of the study of L-arabinose is that it might be possible to achieve glucose appearance modulation in combination with the use of sucrose-rich foods, but not as a standalone bulk sweetener, and thus the tolerance should be evaluated in the food matrix in which it is incorporated (Pretorius et al., 2025). In practice, a high-sugar food is not a problem, it is the deliberate design of dose escalation, serving size, population, and food format that are the issues. The evidence for long-term tolerance is less developed than that for glycemic effects, particularly for frequent daily consumption, gastrointestinally sensitive populations, and children. Therefore, gradual dietary introduction, realistic serving-size design, and post-market monitoring are warranted because low caloric value does not necessarily ensure gastrointestinal acceptability. Figure 8 summarizes gut-microbiota interactions, gastrointestinal tolerance, serving-size determinants, and context-dependent effects of rare sugars. Table 3 summarizes the available evidence concerning health effects, food applications, production technologies, safety considerations, and future research priorities for rare sugars.

TABLE 3. Summary of current evidence regarding the health benefits, food applications, production technologies, safety, and future research priorities of rare sugars.

Polyols appearing in selected comparative studies are chemically distinct from the rare monosaccharides defined as rare sugars in this review and are explicitly identified as related compounds or comparators.

7 Human health outcomes and preclinical/mechanistic evidence

Rare sugars do not constitute a single therapeutic class, and their reported effects should therefore be interpreted according to both the individual compound and the level of evidence. To avoid extrapolating preliminary or mechanistic findings directly to clinical efficacy, the evidence in this section is organized hierarchically. The hierarchy includes systematic reviews and meta-analyses of human studies, randomized or controlled human trials, acute human physiological studies, animal/preclinical studies, and cellular, biochemical, or microbiological investigations.

7.1 Systematic reviews and meta-analyses of human studies

At the highest level of human evidence considered in this section, D-allulose has been evaluated in a meta-analysis of six randomized controlled trials involving 126 people with type 2 diabetes. The pooled analysis found a reduction in glucose AUC, whereas insulin AUC and fasting glucose were not significantly affected (Ayesh et al., 2024). These findings support a potential glycemic effect but do not establish broader effects on obesity, inflammation, disease prevention, or long-term cardiometabolic outcomes.

7.2 Randomized or controlled human trials

Controlled human evidence also supports short-term postprandial effects of D-allulose. In a randomized, double-blinded crossover study involving 30 healthy Thai volunteers, supplementation with 2.5–10 g D-allulose together with 50 g sucrose reduced peak postprandial glucose and insulin responses in a dose-dependent manner (Buranapin et al., 2024). The duration and acute meal-based design of this study should be considered when interpreting the findings, because reductions in postprandial responses do not demonstrate long-term effects on body weight, diabetes prevention, or chronic cardiometabolic disease.

7.3 Acute human physiological studies

Acute human physiological studies provide additional information concerning endocrine and postprandial responses. In a human meal study, D-allulose decreased postprandial glucose and insulin responses and increased plasma GLP-1 compared with a reference meal (Noh et al., 2026). These findings demonstrate an acute physiological response under the tested meal conditions but should not be interpreted as evidence of sustained appetite suppression, long-term weight reduction, or disease prevention.

7.4 Animal/preclinical evidence

Evidence concerning appetite regulation, obesity, inflammation, hepatic lipid metabolism, and intestinal disease remains predominantly preclinical. In male mice, D-allulose, D-tagatose, and the polyol comparator D-sorbitol increased hepatic FGF21 signaling, activated oxytocin neurons, and decreased sugar intake and preference (Efendi et al., 2025). In high-fat-fed rats, a 5% D-allulose diet and whole-body vibration each reduced fat accumulation, although their combination did not produce a demonstrable synergistic effect (Higaki et al., 2024). In diet-induced obese mice, D-allulose was associated with more sustained weight loss after treatment discontinuation than oral semaglutide in the same experimental model and inhibited ghrelin-responsive arcuate neurons (Rakhat et al., 2026). These observations provide preclinical evidence concerning appetite and energy-balance mechanisms but do not establish equivalent effects in humans. Additional animal studies have investigated cardiometabolic and inflammatory outcomes. D-allulose decreased adipose mass, plasma lipids, hepatic fibrosis, inflammatory-metabolic gene disruption, and increased liver mitochondrial respiration in high-fat-diet-fed mice (Shin et al., 2025). D-psicose supplied at 2.5% and 5% in drinking water reduced hepatic lipid deposition, dyslipidemia, oxidative stress, and inflammation in a high-fat-diet NAFLD model, with AGE/RAGE/NF-κB and gut-metabolomic pathways proposed as possible mechanisms (Tan et al., 2025). These findings are derived from experimental disease models and should therefore be regarded as hypothesis-generating rather than as evidence of clinical treatment or prevention. Preclinical disease models also provide evidence concerning inflammation and intestinal health. D-allose decreased tumor number, hemorrhage, inflammation scores, and macrophage infiltration in an AOM/DSS colitis-associated carcinogenesis model and affected endoplasmic-reticulum stress and mitochondrial dysfunction in macrophages (Li et al., 2026c). In DSS-induced colitis, D-allulose at 125–500 mg/kg/day improved intestinal-barrier-related and inflammatory outcomes and altered bile-acid and microbiota profiles (Ye et al., 2025). D-tagatose also showed protective effects in a DSS-induced ulcerative-colitis model, including changes in inflammatory indices, barrier function, and microbiota composition (Wang et al., 2025a). These animal disease-model findings should not be interpreted as evidence that the same sugars prevent or treat inflammatory bowel disease or cancer in humans.

7.5 Cellular, biochemical, and microbiological evidence

At the cellular level, D-allulose inhibited oleic-acid-induced lipid accumulation in HepG2 cells, with an IC50 of 0.45 ± 0.07 mM, and promoted PPARα-associated β-oxidation (Warda et al., 2025). This finding provides mechanistic support for further investigation of lipid metabolism but does not demonstrate a clinical lipid-lowering effect. Microbiological and in vitro studies provide additional mechanistic information concerning oral and intestinal microbial interactions. In oral-biofilm models, allulose reduced bacterial growth, acid production, biofilm biomass, and exopolysaccharide-rich architecture without altering saliva-derived microbial diversity (Han et al., 2025). Tagatose-derived oligosaccharides resisted hydrolysis by small-intestinal enzymes and showed bifidogenic activity in vitro (Hernandez-Hernandez et al., 2024). Selective microbial utilization of D-allulose has also been demonstrated, with D-allulose-metabolizing capacity restricted to particular bacterial taxa rather than being distributed uniformly across the microbial community (Minabou Ndjite et al., 2025). In an enterohemorrhagic E. coli model, an L-arabinose transporter contributed to competitive gut fitness, and L-arabinose metabolism was linked with virulence regulation and host-cell colonization (Cottam et al., 2024). These cellular and microbiological findings clarify potential mechanisms and microbial context but should not be interpreted as direct evidence of beneficial or harmful clinical outcomes in humans. Overall, the available evidence is strongest for selected short-term glycemic outcomes in humans, whereas evidence concerning appetite regulation, obesity, inflammation, lipid metabolism, gut-barrier effects, microbiota modulation, and disease prevention remains substantially dependent on animal, cellular, biochemical, or microbiological models. Claims concerning human health should therefore remain proportional to study design, model, dose, duration, and level of evidence. Table 4 summarizes representative studies according to these evidence categories.

TABLE 4. Representative human clinical, animal/preclinical, cellular/mechanistic, and ex vivo studies investigating the metabolism, absorption, physiological effects, gut-microbiota interactions, and safety profiles of major rare sugars.

Polyols included in comparative or mechanistic studies are not classified as rare sugars in this review; they are identified separately as related sugar alcohol.

8 Applications in functional foods and food reformulation

8.1 Beverages

Added sugar is one of the most obvious targets for reformulation, and beverages are among the most suitable applications for rare sugars because sweetness, acidity, aroma release, bulk, and glycemic positioning can be evaluated in a relatively simple matrix. In contrast to high-intensity sweeteners, D-allulose and D-tagatose have the potential to provide sweetness as well as solid soluble carbohydrate, and have a lower available energy and lower-glycemic value than conventional sugars (Mitchell, 2006). This is desirable for low-sugar soft drinks, flavored water, juices, sports drinks and functional beverages, but it also means that formulation can’t just be based on sweetness equivalence; how they will perform in terms of bulk, mouthfeel, sourness balance, aftertaste masking and stability in pasteurization or during storage will have to be evaluated on a case-by-case basis (Benucci et al., 2024). The human beverage studies are supportive of the notion that allulose would have a glycemic effect reduction when used at a nutritionally meaningful dose in a beverage containing sucrose. D-allulose (at doses of 0, 2.5, 5, 7.5, or 10 g in a drink with 50 g of sucrose) reduced peak postprandial glucose and insulin in a randomized, double-blinded crossover study with 30 healthy Thai volunteers in a dose-dependent manner (Buranapin et al., 2024). This is a very relevant type of evidence for sweetened beverages, since the sugar is immediately available, and the physiological effect can be assessed without the interference caused by the bakery/confectionery matrices. Acute beverage findings should not be interpreted as proof of long-term weight or lipid benefits. A separate meta-analysis of male-rat studies found lower body-weight gain with D-psicose but no significant pooled effects on total cholesterol or triglycerides, illustrating both the biological signal and the limits of translation (Zhou et al., 2025). Chocolate milk illustrates the complexity of beverage reformulation. In the school-lunch study, lactose hydrolysis reduced the amount of sweetener required by approximately one-third and helped sweetener blends approach sucrose acceptance in adults and children (Nakamura et al., 2025). Dairy carbohydrates can also serve as production feedstocks: a four-enzyme, one-pot process converted lactose to both D-allulose and D-tagatose, yielding approximately 9.9 and 10.7 mg/mL, respectively, after 24 h (Moss et al., 2024). Integrated design, therefore, is not just suggesting the removal of sucrose, but a combination of rare sugars to provide some bulk and glycemic control, with high-intensity sweeteners or fruit flavours rounding it out. In an exploratory study in humans, a reference meal containing allulose resulted in greater GLP-1 increases and lower glucose and insulin responses than did other low-digestible carbohydrates, each demonstrating distinct physiological responses (Noh et al., 2026). In a similar study, 15 g D-allulose reduced glucose and C-peptide levels at the end of the trial, but not to an extent that completely abated the initial glucose response, suggesting that evaluation of the performance of this ingredient should be conducted within a food matrix (Simpson et al., 2025).

8.2 Dairy and fermented products

The application space of dairy and fermented products is more complex than that of beverages due to the interaction between sweeteners and proteins, live cultures, acids, flavor compounds and networks that contribute to the product’s texture. In a dairy context, the reviews on natural sweeteners highlight the importance of more than just sweetness equivalence—taste and structure must also be considered, for example, in controlling the aftertaste and mixing, including with other ingredients (Benucci et al., 2024). Consumer acceptance of yogurts has been found to be not predictable based on an ingredient image study. While in the online survey, allulose was the least preferred concept, in the 229-person acceptance test, allulose-sweetened yogurts and allulose, stevia and sucrose sweetened yogurts were liked better than stevia-sweetened yogurts (Crown et al., 2024). The outcome here is significant for reduced sugar dairy: unfamiliarity could count as a disadvantage for allulose (as a label ingredient) but as a product ingredient it can help moderate the sensory drawbacks of high-intensity sweeteners. The other concern that fermented dairy products have but not shelf-stable products is their stability. Contrary to the desired nutritional benefit of rare sugars, yoghurt contains live and active cultures that contain enzymes which can break the intended sugars down by hydrolysis or isomerization (Sorensen et al., 2024). Sugars such as D-tagatose were introduced in commercial nonfat Greek yogurts with simple and complex probiotic cultures and measured on a weekly basis for a total of 14 weeks to determine their availability over the course of the refrigerated shelf life, directly testing the availability of sugars in live-culture dairy foods (Sorensen et al., 2024). Thus, chromatographic confirmation of the stability of the sugar and not assuming the added sweetener is stable during the storage of the rare-sugar dairy formulation should be included. Food-formulation and sensory evidence from dairy products indicates that rare sugars can influence palatability and product performance. In a school-lunch chocolate-milk study, allulose syrup achieved liking comparable to sucrose in unhydrolyzed milk, while lactose hydrolysis further reduced the amount of sweetener required to achieve comparable acceptance (Nakamura et al., 2025). Separately, cellular/mechanistic evidence from HepG2 cells showed lower insulin-resistance markers for a camel-milk formulation supplemented with a camel whey protein fraction and D-allulose, while the tested formulation also improved odor-related sensory characteristics (Liu et al., 2025b). These cellular and formulation findings support further investigation but do not establish clinical efficacy for diabetes management. The rare sugar could be used as a sweetener, a selective substrate or a part of a synbiotic system, which is important as rare sugars and polyols are metabolically and technologically different from non-nutritive sweetener (Kossiva et al., 2024). Preclinical animal evidence has also been reported for combinations of rare sugars and probiotics. D-tagatose combined with Lactobacillus rhamnosus GG was investigated in a Gallus model challenged with aflatoxin B1, with inflammatory markers, oxidative-stress markers, cecal microbiota, and metabolites assessed after 14 days (Lv et al., 2025). This animal evidence should not be extrapolated directly to food-product performance. For applications such as kefir, probiotic yogurt, or fermented beverages, food-formulation and technological studies should separately evaluate acidification capacity, viable cell counts, strain-specific carbohydrate utilization, product stability, and sensory properties.

8.3 Bakery and cereal-based foods

The bakery and cereal products are the current strongest sector in which a reformulation of sucrose in the food can be done using rare sugars, as sucrose is used for sweeteness, bulk, dough properties, browning, water mobility, and shelf-life. A compound improver that contained oligosaccharides, sodium carboxymethyl cellulose and D-allulose was used to increase the specific volume of sugar reduced breads by 50.14% and decrease the hardness by 66.69% compared to a 90% sugar reduced bread. The same study showed that the combination of allulose with hydrocolloids and oligosaccharides could be used to preserve the texture as it led to a decrease in relative crystallinity, starch retrogradation enthalpy and water loss by 45.31%, 49.96% and 50.04%, respectively (Xiao et al., 2025a). The reasons why such blends are necessary are explained by the dough level evidence. It was observed that the gas holding capacity of the composite improver (90.92%) was highest and the gluten network density was highest in sugar reduced dough with D-allulose + CGMP + Sodium CMC, which restored the viscoelastic balance and fermentation behavior in sugar reduced dough (Xiao et al., 2025a). In yeast-leavened bakery products, allulose promoted earlier starch gelatinization and slower retrogradation; burger buns containing allulose retained a softer crumb, higher moisture, and lower water activity during storage at both 20 °C and 4 °C than sucrose- or fructose-based comparators (Wittland et al., 2024). This comparison highlights that allulose is not a “one-size-fits-all” sugar substitute. The texture and browning of biscuits and cookies are different. In chemically leavened muffins, allulose lowered batter viscosity, increased high-temperature viscoelasticity, and intensified browning, whereas kestose more closely reproduced sucrose-like expansion, porosity, softness, and sensory properties when used as a partial replacement (Cho et al., 2024). Allulose resulted in darker cookies with less spread and cake-like texture for the wire-cut cookies, and a few oligosaccharide systems were able to better capture the sucrose-like appearance and geometry (Woodbury and Mauer, 2024). Browning can be technologically desirable or undesirable depending on the target product and processing conditions. Allulose and sucrose were fully involved in the formation of Maillard reaction intermediates and the aroma production in bread, whereas xylitol was only partially involved and mogroside was not involved at all (Tu et al., 2025). At the starch-gel level, D-allulose suppressed refrigerated hardening in glutinous-rice, corn-amylopectin, and corn-starch systems, with microstructural and spectroscopic evidence indicating changes in pore structure and hydrogen-bond organization (Kwakye et al., 2024b). In cakes, muffins, breakfast cereals, and bars, rare sugars can contribute bulk and browning; however, successful formulation requires simultaneous optimization of hydration, leavening, color, aroma, and texture.

8.4 Confectionery and chocolate products

Sugar is key to controlling the crystallization, glass transition, viscosity, mouthfeel, sweetness release, water activity and shelf stability of confectionery and chocolate, making it a challenging target for reformulation. While rare sugars are desirable for their bulk sweetening properties and not just for their high intensity of sweetness, they do have a different set of properties in low moisture systems, low fat systems and in both systems as compared to sucrose (Mitchell, 2006). Mixtures of erythritol, mannitol, tagatose with inulin or polydextrose exhibited that the hygroscopicity, particle size and crystal shape of the sugar had a significant effect on the physical properties (rheology, texture) of dark compound chocolate, whereas its melting characteristics and the fat crystallization were less affected. This chocolate evidence proves to be beneficial because it is associated with the actual technological issue of low sugar chocolate, which does not fail simply due to the lack of sweetness, but rather because of how the sweetener system affects the flow properties, particle packing and moisture sensitivity of the chocolate. However, tagatose can also be used as bulk and sweetness, but depending on the crystal morphology and hygroscopic properties of tagatose, its product may require different refining, conching or polymer blending options to ensure it meets the desired product specification (Wong et al., 2024). In general the natural sweetener reviews suggest that a mix of different sweeteners is often needed to rectify any one sweetener for its negative properties such as aftertaste, bitterness, instability or texture loss (Benucci et al., 2024). This is because biscuits and confectionery have a similar thermal chemistry, but differ in terms of water mobility and crystallization. In chemically leavened muffins, allulose intensified browning and altered batter rheology, whereas kestose more closely preserved sucrose-like pore structure and texture (Cho et al., 2024). These results suggest that, in the case of caramels, gummies, chewy sweets, etc., the evaluation of the rare sugars should not be limited to the intensity of sweetness but should also cover other parameters, such as hygroscopicity, glass transition, stickiness, graining, chewiness and flavor release. Gummies and hard candies are still under-studied in the literature compared with bakery and chocolate, so claims for the gummies and hard candies should continue to be formulated hypotheses until matrix specific tests are available. Many of the other uses of tagatose are also in their infancy, particularly those related to oral health that can be separated from the artificial sweeteners where they are used in the same product (Kossiva et al., 2024). Preclinical animal evidence extends this oral-health rationale: in a Streptococcus mutans-induced mouse model, tagatose reduced caries severity in a dose-dependent manner and altered oral microbial and inflammatory profiles, although human product trials remain necessary (Zhao et al., 2026). Separately, in vitro mechanistic evidence showed that allulose affected bacterial growth, acid production, biofilm biomass, and exopolysaccharide-rich biofilm architecture in a cariogenic model compared with common sugar (Han et al., 2025). These preclinical and in vitro findings justify further investigation of applications such as sugar-free gums and lozenges but do not establish human oral-health efficacy or substitute for product-specific sensory and shelf-life evaluation.

8.5 Nutraceuticals and dietary supplements

Rare sugars may have applications in nutraceuticals and dietary supplements, although these products present formulation challenges related to sweetness, flowability, stability, gastrointestinal tolerability, and appropriate health-related positioning. In the microbial nutraceutical literature, rare sugars (D-allulose), which are low caloric sweeteners, have been reported as products that can be obtained along with other bioactives, such as oligosaccharides, short chain fatty acids, peptides, polyphenols and pigments (Singh et al., 2025). It applies to concepts of products that contain rare sugars as well as fiber, probiotics, extracts from plants or polyphenols, amino acids, minerals or vitamins, but not “drugs” (unless backed by clinical trials) implies drug-like treatment (Lu et al., 2025b). The most useful application of rare sugars in supplements could be as multiple carriers. As a replacement for sucrose, allulose can be used in powders and sachets as a source of sweetness and a carbohydrate bulk, but handling powder is a real challenge. A complementary powder-based opportunity is the valorization of whey powder as a production substrate. A one-pot whole-cell process generated 29.11 g/L D-tagatose and 11.45 g/L D-allulose from 200 g/L whey powder, followed by yeast removal of residual common sugars and chromatographic purification to 97.5% and 95.0% purity, respectively (Wen et al., 2025c). This approach links rare-sugar manufacture with dairy-side-stream valorization, although the flowability, hygroscopicity, and stability of the final ingredient still require product-specific control. Stimulations of metabolism should be realistic as well. Preclinical evidence should also be described at the correct level. A systematic review and meta-analysis of male-rat studies found that D-psicose reduced body-weight gain, but did not significantly change pooled total cholesterol or triglycerides (Zhou et al., 2025). A meta-analysis of allulose in type 2 diabetes showed similar decreases in glucose AUC and time above range, although not in all cases, when compared to the control group (Ayesh et al., 2024). So, it is important for supplement labels to differentiate between ‘postprandial support’ from other statements regarding weight loss, lipid lowering and disease treatment. In addition to the concerns with gastrointestinal function, there are concerns about the microbiome in repeated use supplements. Human tolerance work proposed 0.4 g/kg body weight as a maximum single dose and 0.9 g/kg/day as a maximum daily intake in healthy young adults (Han et al., 2018). A separate 90-day dietary study of D-allulose produced by a novel one-step fermentation process reported no treatment-related toxicity in rats and established a no-observed-adverse- effect level of 8000 mg/kg body weight/day; this supports process-specific safety assessment but does not replace human tolerability data (Li et al., 2026b). In a 12-week human trial, 15 g/day D-allulose produced no major changes in microbial diversity, selected enteric pathogens, or short-chain-fatty-acid production (Park et al., 2024). In high-fat-fed mice, however, D-allulose at 300 mg/kg for 60 days reduced adipose-tissue inflammation, improved intestinal-barrier markers, and altered the gut microbiota, illustrating a mechanistic signal that still requires human confirmation (Zhao et al., 2024). Synbiotic formulation is another emerging direction. In hyperlipidemic mice, D-tagatose combined with Lacticaseibacillus casei ATCC 393 improved several lipid and inflammatory outcomes and selectively altered gut taxa, but the evidence remains preclinical and cannot yet support equivalent human claims (Cavdar et al., 2025).

8.6 Infant, elderly, and clinical nutrition products

Consumers of infant, older-adult, and clinical nutrition products may have immature or altered gastrointestinal, renal, hepatic, immune, or microbiome function, warranting more cautious safety and tolerability assessment than is required for healthy adult populations. Rare sugars may help reduce added sugar and postprandial glycemic exposure in diabetes-oriented formulas and oral nutrition products, but evidence for long-term weight and lipid outcomes remains limited. In male-rat studies, D-psicose reduced body-weight gain without significant pooled effects on total cholesterol or triglycerides, reinforcing the need for cautious translation to vulnerable human groups (Zhou et al., 2025). Human clinical evidence on long-term cardiometabolic outcomes remains insufficient to support disease-management claims for rare sugars, while available preclinical findings should be interpreted as hypothesis-generating rather than clinically confirmatory (Lu et al., 2025a). For clinical nutrition, the composition of the food matrix becomes particularly relevant as it can alter the absorption, tolerance and metabolism. 15 g D-allulose added to a standardized porridge breakfast in healthy young adults decreased the late postprandial blood glucose and C-peptide iAUC180, but did not affect iAUC180 of insulin or the initial postprandial hyperglycemic response (Simpson et al., 2025). This finding can be helpful in the production of oral nutritional supplements and breakfast products as it demonstrates that the addition of allulose to a food matrix is not the same as the provision of a free drink of allulose. The direct testing of the matrix viscosity, starch content, protein, fat and serving size are all required. In vulnerable groups, the tolerance should be understood without taking into account the evidence for adults’ metabolism. For adults, a non-randomized D-allulose tolerance study proposed 0.4 g/kg body weight as the maximum single dose and 0.9 g/kg/day as the maximum daily dose (Han et al., 2018). A 90-day rat study of fermentation-derived D-allulose found no treatment-related toxicity up to 8000 mg/kg body weight/day, but this preclinical NOAEL should not be converted directly into a clinical serving recommendation (Li et al., 2026b). A randomized double-blind controlled crossover study in young children showed that both doses (2.5 g/120 mL and 4.3 g/120 mL D-allulose) were non-serious and mild or moderate with no participants reporting Bristol stool type 6 or seven in the high dose group (Risso et al., 2024). These data support tolerability at the tested doses but do not establish safety for unrestricted use in infant foods or in populations at increased risk of illness. Proper safety monitoring is also essential for elderly and clinical products, which needs to be microbiota-aware. No significant effects on microbial diversity, selected enteric pathogens, or short-chain-fatty-acid production were observed with 15 g/day D-allulose in a 12-week human trial, supporting microbiome safety at the tested exposure (Park et al., 2024). Preclinical animal evidence nevertheless indicates that D-allulose can modify intestinal-barrier function, adipose-macrophage activation, and microbiota composition under high-fat feeding (Zhao et al., 2025a). These disease-model findings concern biological activity under experimental conditions and should not be interpreted as equivalent to human safety or clinical efficacy. In animal models of colitis, D-allulose has been associated with changes in inflammation, intestinal-barrier function, bile-acid metabolism, and microbiota composition (Ye et al., 2025). Accordingly, evidence of bioactivity in preclinical models should be distinguished from human tolerability and safety evidence when considering clinical-nutrition applications, renal and hepatic monitoring, and serving-size recommendations.

8.7 Clean-label and natural-positioned products

The other challenge with rare sugars is their ability to fit with clean-label and natural-product positioning, because consumer perception of an ingredient does not necessarily correspond to its sensory performance in the final food product. Rare sugars such as allulose and tagatose are bulk sweeteners that provide not only sweetness but also material functionality, distinguishing them from many high-intensity sweeteners that primarily contribute sweet taste (Kossiva et al., 2024). Their applications in bakery, dairy, confectionery, and beverages therefore require consideration of sensory properties, aftertaste, stability, blending, and structural effects (Benucci et al., 2024). This distinction between ingredient perception and actual sensory performance is illustrated in yogurt products. Consumers showed greater conceptual preference for familiar sweeteners such as honey, agave nectar, and cane sugar, whereas allulose was less preferred when evaluated as a named sweetener; however, allulose-sweetened yogurts and allulose-containing blends achieved more favorable liking than stevia-sweetened yogurts (Crown et al., 2024). These findings indicate that unfamiliarity with the name of a rare sugar may influence consumer expectations independently of the sensory quality of the formulated product. Consequently, product communication, consumer familiarity, and sensory performance should be considered together when rare sugars are used as bulk sweeteners in food reformulation. Consumer acceptance of technically produced ingredients should be evaluated empirically rather than assumed from product appearance or positioning. For the purposes of positioning in the context of nutrceuticals, literature regarding the production of microbial sugars also reveals that many of these sugars are sold in combination with peptides, oligosaccharides, polyphenols and other bioactives, therefore also requiring a distinction between the function of the ingredient and the therapeutic claims made (Singh et al., 2025). Another challenge for clean labelling is the industrial sector. Rare sugars are sugars that are found in low concentrations in the nature, but are generally produced commercially by enzymatic, microbial or chemical bioconversion instead of extraction from food. Enzymatic synthesis of rare sugars has been pinpointed as a component of functional food innovation and scale-up and food matrix translation issues were also reported (Yao et al., 2026). The same applies to tagatose: industrial routes derived from galactose (and other substrates) are being developed to enhance feasibility but, as with all labels, must meet the definitions of natural, novel, low calorie or added sugar as defined by different jurisdictions (Mitchell, 2006). Clean-label strategies need to focus on substantiated benefits, however, rather than over promising. Artificial sweeteners and rare sugars should not be promoted as having the same metabolic effect or being biologically inert; data on either sweetener class indicate that they have different effects on digestion, absorption and the gut microbiome (Lee et al., 2024). The scale-up, purification, and matrix-translation issues associated with the industrial enzyme technology also question the credibility of rare sugars produced by bioconversion, leading to a lack of transparency and making it difficult to truly understand the potential advantages and disadvantages of bioconversion-based rare sugars (Yao et al., 2026).

8.8 Regulatory status, labeling, and health-claim considerations

Regulatory treatment of rare sugars varies substantially among jurisdictions and should therefore be evaluated independently for each compound and target market. The regulatory information summarized in this section and Table 1 was verified against official regulatory sources on 10 August 2026. Particular attention was given to D-allulose and D-tagatose because these compounds currently have the most developed regulatory records among the rare monosaccharides discussed in this review. In the United States, D-allulose, also referred to as D-psicose in several regulatory submissions, has been the subject of multiple Generally Recognized as Safe (GRAS) notices. For example, GRN 1193 describes intended use of D-psicose as a sweetener at levels ranging from 2% to 100% in numerous food categories, including bakery products, non-alcoholic beverages, cereals, chewing gum, confectionery, frozen dairy desserts, yogurt, jams and jellies, sweet sauces and syrups, and cereal or protein bars; FDA responded that it had no questions regarding the notifier’s GRAS conclusion (U.S. Food and Drug Administration, 2024a). FDA labeling guidance further states that allulose should remain included in Total Carbohydrate, while the agency intends to exercise enforcement discretion for its exclusion from Total Sugars and Added Sugars and for the use of 0.4 kcal/g when calculating Calories (U.S. Food and Drug Administration, 2020). D-tagatose also has a U.S. GRAS-notice history. GRN 352 describes intended uses as a sweetener, texturizer, humectant, and stabilizer in products including ready-to-eat breakfast cereals, soft drinks, confectionery, meal-replacement products, bakery products, ice cream, frozen yogurt, yogurt, chewing gum, puddings, cookies, and cereal bars (U.S. Food and Drug Administration, 2011). A later notice, GRN 977, describes use of enzymatically produced D-tagatose as a nutritive sweetener, flavor enhancer, humectant, texturizer, and stabilizer at levels of 1%–100% in multiple food categories (U.S. Food and Drug Administration, 2021). Unlike allulose, D-tagatose must be declared as Added Sugars on the Nutrition Facts label. FDA has indicated that it does not object to use of 1.5 kcal/g when calculating Calories and intends to exercise enforcement discretion for calculation of the Added Sugars % Daily Value on the basis of this reduced energy contribution (U.S. Food and Drug Administration, 2023). Importantly, a qualified-health-claim petition concerning D-tagatose and reduced risk of type 2 diabetes was denied by FDA in February 2024, indicating that food-use status should not be interpreted as authorization of a disease-risk-reduction claim (U.S. Food and Drug Administration, 2024b). In the European Union, D-tagatose is included in the Union list of authorized novel foods. The specified food category and maximum level are listed as ‘not specified’; however, foods containing it must identify the ingredient as ‘D-Tagatose’. Products containing more than 15 g per serving, as well as beverages containing more than 1% D-tagatose as consumed, must bear the statement that excessive consumption may produce laxative effects (European Commission, 2017). For energy labeling, an EFSA scientific opinion concluded that 3 kcal/g (12.5 kJ/g) is an appropriate rounded metabolizable-energy conversion factor for D-tagatose based on the available evidence (EFSA, 2016). D-tagatose is also included among sugar replacers eligible, under specified conditions, for authorized EU health claims concerning a lower postprandial blood-glucose rise and maintenance of tooth mineralisation (European Commission, 2012). For D-allulose in the European Union, several novel-food applications have been submitted to the European Commission, including applications from CJ-Tereos Sweeteners Europe SAS, Petiva Europe SA, Samyang Corp., Tate & Lyle Ingredients France SAS, and SAVANNA Ingredients GmbH (European Commission, 2015). However, no D-allulose entry was identified in the Union list of authorized novel foods examined on 10 August 2026. This indicates that submitted applications should not be interpreted as equivalent to Union authorization. In Canada, Health Canada completed a novel-food safety assessment of enzymatically synthesized D-tagatose and indicated that it had no objection to its use as a food ingredient and sweetening ingredient to fully or partially replace existing added sugars (Health Canada, 2022a). For labeling, D-tagatose is declared as carbohydrate and sugars, and Health Canada considered an energy conversion factor of 3 kcal/g (12.5 kJ/g) to best reflect the available evidence. The same assessment notes that excessive intake, for example, approximately 30 g per serving, may cause bloating, belching, flatulence, and laxative effects, although these effects are generally described as mild and transient and vary among individuals (Health Canada, 2022a). Separate consumer guidance notes that gastrointestinal effects may become more likely at approximately 30 g per serving or 45 g/day (Health Canada, 2022b). Overall, these regulatory differences demonstrate that authorization status, intended food uses, use levels, labeling requirements, caloric values, gastrointestinal-tolerance guidance, and health-claim eligibility cannot be generalized across rare sugars or jurisdictions. Regulatory status in one country or region should therefore not be extrapolated to another, and current requirements should be verified with the relevant regulatory authority before commercial formulation, labeling, or health-claim development.

9 Future perspectives

Future rare-sugar research is likely to move beyond generalized sugar-replacement claims toward precision nutrition, matrix-specific formulation, and scalable biomanufacturing. The glycemic response, insulin sensitivity, gastrointestinal tolerance, age, metabolic status, and dietary habits of individual may have an impact on the effect of a particular rare sugar, making it beneficial, neutral or poorly tolerated. The direction is seen in metagenomic data which indicated that only 15.8% of 3079 healthy adult samples contained an enzyme, alsE, known to be utilized by microbes for D-allulose, and which could thus become relevant in personalized use of rare sugars in the future (Minabou Ndjite et al., 2025). Additionally, there is human acute evidence that a combination of noninterchangeability of low digestible carbohydrates between them, as allulose, 1-kestose, resistant maltodextrin and fructo-oligosaccharides generated different glucose, insulin, GLP-1 and satiety responses after postprandial use (Noh et al., 2026). Foods that target the gut microbiome are a very intriguing and yet a relatively new area of research. Rare sugars can be used in association with dietary fibres, prebiotics, probiotics, synbiotics, postbiotics and fermented ingredients and in the future, with the exception of general prebiotics claims, their use should be supported by evidence of response at the strain, dose, host and matrix levels. Combination products require equally careful validation. A D-tagatose–L. casei synbiotic improved lipid and inflammatory outcomes and selectively shifted gut taxa in hyperlipidemic mice, but strain, dose, matrix, and host dependence must be established before translating this result into human product claims (Cavdar et al., 2025). Careful communication is important when making a clean-label reformulation, as “naturally sweetened” positioning was most preferred by yogurt consumers, but sucrose was still the most preferred sweetener for tasting, and allulose was more liked than stevia alone (Crown et al., 2024). A challenge for the future is to use rare sugars as multifunctional ingredients and not just as a source of sweetener. Formulation objectives differ among bakery, dairy, beverage, confectionery, and functional-snack products. In each matrix, developers should balance sweetness, texture, moisture, color and appearance, microbial stability, consumer acceptability, realistic serving size, and gastrointestinal tolerability. A sugar-reduced bread system based on the combination of formulation strategies (oligosaccharides, CMCNa and D-allulose) resulted in an increase in specific volume (50.14%), a decrease in hardness (66.69%) and a delay in starch retrogradation, thus highlighting the importance of a combined formulation (Xiao et al., 2025a). Rare sugars may become more affordable and sustainable through advances in biotechnology. Semi-rational engineering and directed evolution of a Thermotogae tagatose four-epimerase produced a 2.8-fold improvement in catalytic activity and generated 42 g/L D-tagatose within 2 h, illustrating the value of combining structure, dynamics, and activityscreening (Wang et al., 2025d). The ribitol dehydrogenase was modified by computational means to carry out D-psicose-to-allitol conversion at 94.3% yields, with a drop in the requirement for NADH (Hu et al., 2026). Industrial-side-stream valorization is also feasible: Gluconobacter oxydans produced L-sorbose from D-sorbitol using industrial sweet water and hydrolyzed defatted soybean meal, reaching a 0.99 g/g yield while reducing estimated medium cost by 33.23% (Samant et al., 2026). Moreover, sustainable integration is crucial; tagatose can be produced from lactose-rich dairy waste, with efficiencies reported to be above 60% and the TE evaluation of the whey valorization process indicated benefits (Wang et al., 2025c). Trials that are long term, randomized controlled, real food, and dose optimization, safety evaluation in vulnerable populations, endpoints in the microbiome, and metabolic outcomes that are standardized are now needed to drive translational progress. Future clinical studies should therefore measure more than sweetness and glucose alone. A randomized, crossover, double-blind trial protocol is evaluating acute postprandial GLP-1 responses to allulose versus aspartame together with exploratory metabolic adaptation during a 4-week intake period, providing an example of the more rigorous designs now required (Busch et al., 2026). More safety studies in the product format, such as allulose hydration beverages, should be conducted in realistic multi-product exposures and longer exposure durations in product format (Bloomer et al., 2024). Representative food applications of D-allulose and D-tagatose across beverages, dairy and fermented products, bakery foods, confectionery, and nutraceuticals are summarized in Figure 9.

10 Conclusion

Rare sugars are no longer of interest solely as specialty sweeteners or unusual carbohydrate structures but are increasingly being investigated as multifunctional food ingredients that bridge carbohydrate chemistry, metabolic health, food reformulation, and sustainable biomanufacturing. Their potential value arises from their relatively low energy contribution, generally low glycemic impact, carbohydrate-like technological properties, and compound-specific physiological effects. D-allulose and D-tagatose currently have a more developed evidence base for food applications than the other rare monosaccharides discussed in this review, whereas D-allose, L-arabinose, L-xylulose, L-ribose, D-sorbose, and other less-studied rare monosaccharides provide opportunities for investigating targeted metabolic, microbiome, and formulation functions. Related polyols, disaccharides, and oligosaccharides are chemically distinct from the rare monosaccharides that define the principal scope of this review and should therefore be evaluated according to their own structural, metabolic, and technological characteristics. Rare monosaccharides should not be regarded as a homogeneous class with interchangeable properties. Their digestibility, bioavailability, microbial utilization, browning behavior, technological functionality, consumer acceptability, and regulatory status vary substantially among individual compounds and food matrices. Consequently, findings obtained for one rare monosaccharide should not be generalized to another without direct supporting evidence. To support future progress, research should move beyond studies of isolated ingredients toward real-food intervention studies, personalized nutrition approaches, long-term safety evaluation, and scalable production based on bioeconomy strategies such as enzymatic and microbial biomanufacturing. Rare monosaccharides may become important ingredients in healthier, sugar-reduced foods, but their successful application should be guided by compound-specific scientific evidence rather than by generalized claims about rare sugars.

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Footnotes

Edited by: Tatiana Colombo Pimentel, Federal Institute of Education, Science and Technology of Paraná, Brazil

Reviewed by: Elena Narcisa Pogurschi, University of Agronomic Sciences and Veterinary Medicine, Romania

Yuta Masuda, Kyoto Prefectural University, Japan