The mucosal-neural axis in chemotherapy-induced gastrointestinal toxicity

1 Introduction

Chemotherapy-induced gastrointestinal toxicity (CIGT) originates from epithelial damage caused by cytotoxic effects on rapidly dividing cells. However, the clinical manifestations of CIGT, including nausea, vomiting, abdominal pain, and diarrhea, likely reflect not only epithelial injury but also alterations in epithelial-to-neural signaling that regulate gastrointestinal function. This is supported by the efficacy of therapies targeting neuronal signaling in acute emesis, such as 5-HT3 receptor antagonists used to treat chemotherapy-induced nausea and vomiting (CINV). Despite this, delayed symptoms and non-emetic manifestations, including abdominal pain and diarrhea, remain incompletely managed, and these treatments do not address the underlying epithelial injury. Together, this suggests that epithelial-to-neural crosstalk may contribute to disease pathophysiology. However, the mechanisms linking epithelial damage to sustained activation of enteric and extrinsic sensory pathways, including DRG neurons involved in pain and hypersensitivity, remain incompletely defined. We also consider the possibility that sensitized neurons further amplify CIGT and discuss therapeutic strategies targeting epithelial mechanisms.

1.1 Clinical features of chemotherapy-induced gastrointestinal toxicity

Chemotherapy-induced gastrointestinal toxicity (CIGT) is a comprehensive term encompassing a spectrum of adverse effects occurring as a direct or indirect consequence of cytotoxic chemotherapy. It is a complex pathology where symptoms manifest along a distinct temporal scale. While acute nausea and vomiting often occur rapidly following drug administration due to immediate neurotransmitter release, other features emerge as the underlying pathobiology evolves. The most prominent pathological hallmark is gastrointestinal mucositis, characterized by inflammation and ulcerative lesions of the mucosal lining (1, 2) (Figure 1). Following this initial phase, progressive mucosal damage gives rise to a constellation of debilitating clinical manifestations, including diarrhea, anorexia, and constipation, often accompanied by abdominal pain and significant weight loss (3–5). While these symptoms were traditionally attributed solely to epithelial injury. The pathogenesis of CIGT is however now understood to involve a synergistic interplay of gut microbiota dysbiosis (6, 7), dysregulated inflammatory responses (1, 6), and oxidative stress (7). Notably, the unregulated release of serotonin from damaged enterochromaffin cells acts on enteric and extrinsic sensory circuits, driving the neural dysfunction that characterizes CIGT (8). While the role of the dorsal root ganglion (DRG), which also innervate the gut wall, is well-established in somatic neuropathy affecting the extremities, their specific contributions to abdominal pain and nausea in chemotherapy patients remains an important area for further exploration.

1.1.1 Prevalence and dose-dependency of CIGT

The prevalence of CIGT among patients undergoing chemotherapy is remarkably variable, affecting between 5% and 100% of individuals (2, 9–12). This wide range is not arbitrary but is directly dependent on several key factors, most notably the specific chemotherapeutic agent used, the administered dose, and the treatment regimen (9, 13–15) (Table 1). An estimated death rate of 7.5% has been reported as a result of non-selective toxicities that occur in chemotherapy patients (16), underscoring the severe impact these agents have on cancer treatment outcomes. Thus, better management of these side effects or the prevention of toxicities altogether will be essential to ensure therapeutic success.

TABLE 1. Incidence of commonly used chemotherapy agents and related CIGT symptoms.

Abbreviations: CINV, chemotherapy-induced nausea and vomiting; RA, receptor antagonist; CR, complete response; 5-HT, serotonin.

Certain classes of chemotherapeutic agents are particularly notorious for inducing severe gastrointestinal toxicities, such as Grade 3 and Grade 4 diarrhea. Although across clinical trials and regulatory reports, any-grade diarrhea is common, grade 3 or four diarrhea occurs in roughly 20%–36% depending on dose and schedule (17, 18). One such agent, causing severe diarrhea is irinotecan (CPT-11, a topoisomerase-I inhibitor), which is strongly associated with delayed diarrhea (19, 20). For instance, CPT-11 induced diarrhea occurs early in about 51% of patients, whereas late occurrences affect 88%. And 31% of the patients display severe diarrhea (21). Fluoropyrimidines are another class frequently implicated in chemotherapy-related diarrhea. For instance, randomized clinical trials comparing bolus 5-FU/LV with capecitabine reported that both arms showed clinically meaningful rates of diarrhea (22).

Other chemotherapeutic agents, such as cisplatin instead cause other GI distress symptoms. For instance, cisplatin is emetogenic, causing nausea and/or vomiting. In placebo-controlled or minimal-prophylaxis randomized trials, a majority of patients experienced these symptoms with cisplatin when antiemetics were omitted, underscoring its distinct emetogenic profile. This contrasts with diarrhea-inducing agents such as irinotecan or fluoropyrimidines, which primarily drive gastrointestinal mucosal injury rather than emetic pathway activation (23, 24).

1.1.2 Impact of CIGT on patient survival

The consequences of CIGT are severe and multifaceted, impacting patient wellbeing, the feasibility of treatment, and ultimately, survival outcomes. The persistent and distressing symptoms of pain, nausea, vomiting, and diarrhea lead to a cascade of secondary complications, including malnutrition, anorexia, and severe weight loss. More than 63% of cancer patients undergoing chemotherapy experience unintentional weight loss, a condition directly linked to the symptoms of CIGT (1, 4). This results in poor nutritional status and is associated with poorer survival outcomes (25). The physical and emotional burden of these symptoms can lead to functional impairment, social isolation, and psychological distress, further eroding quality of life (QoL) (26).

Perhaps the most critical clinical consequence of CIGT is its role as a primary dose-limiting toxicity (2, 27). The severity of symptoms frequently forces clinicians to make the difficult choice of interrupting or altering the planned chemotherapy regimen (28). This manifests as treatment delays or dose reductions, which are common strategies to manage acute toxicity (29). This practice, while necessary for patient safety in the short term, has grave implications for treatment efficacy and survival outcomes. The concept of Relative Dose Intensity (RDI), the ratio of the delivered dose to the planned dose over a specific period, is a critical metric in oncology. A substantial body of clinical evidence demonstrates a direct, dose-dependent relationship between RDI and treatment outcomes, including progression-free and overall survival (30). Maintaining a relative dose intensity (RDI) of ≥80–85% is widely regarded as clinically meaningful, since lower RDI has been associated with inferior survival outcomes (31, 32). However, delays and dose reductions remain common in practice: for example, in first-line platinum-based chemotherapy for advanced NSCLC, ∼32% of patients had ≥7-day delays, ∼50% had ≥15% dose reductions, and ∼40% had RDIs of <85% (33). Treatment-limiting toxicities (including gastrointestinal and other toxicities) often contribute to these modifications, thereby reducing the likelihood of achieving the target RDI.

This underscores a central paradox of chemotherapy: while intended to eradicate malignant cells, its toxic effects on healthy tissues can necessitate treatment modifications that ultimately limit the ability to deliver therapy at its full intended intensity. CIGT is therefore not a peripheral “side effect” but a direct antagonist to the primary therapeutic goal. A clear sequence of events emerges where the administration of chemotherapy leads to CIGT, which in turn necessitates dose modifications. These modifications result in a compromised RDI, which is directly linked to reduced treatment efficacy and poorer survival rates (34). This reframes the management of CIGT from a matter of palliative care to a critical component of effective cancer treatment (35). An intervention that could successfully mitigate CIGT would not only improve patient QoL but could also enhance cancer survival rates, simply by enabling the delivery of the full, planned therapeutic dose of chemotherapy.

In its most severe forms, CIGT can be life-threatening, such as in patients with acute myeloid leukemia (16, 36). Chemotherapy in these patients can lead to neutropenic enterocolitis, a bacterial infection that causes profound damage to the mucosal barrier leading to necrotizing perforations, uncontrolled bleeding, abdominal abscess. Breakdown of the epithelial barrier allows for the translocation of luminal bacteria and their toxins into the bloodstream, which can lead to systemic infections and sepsis (37). Furthermore, the treatment delays necessitated by CIGT are independently associated with an increased risk of death. A meta-analysis across several major cancer types found that for every 4-week delay in initiating adjuvant or neoadjuvant treatment, the risk of mortality increases significantly (38). Thus, CIGT can contribute to fatal outcomes both directly, through complications like sepsis, and indirectly, by compromising the effectiveness of the cancer treatment itself.

1.2 Chemotherapeutic agents induce intestinal epithelial damage through shared cytotoxic mechanisms

Chemotherapeutic agents induce gastrointestinal toxicity through distinct primary mechanisms. However, despite these differences, they converge on a limited set of cellular stress pathways that compromise epithelial integrity and mucosal barrier function. The initial insult arises from direct interactions between chemotherapeutic agents and the intestinal epithelium, a tissue characterized by rapid and continuous self-renewal. These drugs are designed to target proliferating cancer cells but lack tissue specificity, rendering the rapidly renewing gut epithelium an inevitable site of collateral damage (35). The gastrointestinal epithelium undergoes complete renewal every 4–5 days, driven by highly proliferative stem and progenitor cells located at the base of intestinal crypts (39), making this compartment particularly susceptible to cytotoxic injury. Although different classes of chemotherapeutic agents have distinct molecular targets, including DNA, DNA-associated enzymes, and microtubules, they functionally converge on disruption of the cell cycle, leading to impaired proliferation and cell death within intestinal crypts (40, 41) (Table 2). In parallel, many of these agents induce reactive oxygen species (ROS) and mitochondrial dysfunction, which amplify epithelial damage by promoting apoptosis, inflammatory signaling, and loss of barrier integrity (Figure 2) (42). Here we provide an overview of major chemotherapeutic classes and their contributions to mucosal damage, highlighting shared effects on epithelial proliferation, apoptosis, and oxidative stress.

TABLE 2. Chemotherapy effects on intestinal mucosa.

Abbreviations: CS, cisplatin; CB, carboplatin.

1.2.1 Microtubule-targeting agents

Microtubule-targeting agents, such as taxanes, have been well characterized with respect to their effects on cancer cells. They disrupt microtubule dynamics by stabilizing polymerized tubulin. Their cytotoxic effects are primarily attributed to interference with aberrant spindle formation and chromosome segregation defects (43–45). This triggers stress-response pathways leading to mitotic catastrophe and apoptosis (46–50). In the intestinal epithelium, which undergoes rapid and continuous renewal, these microtubule-modifying effects are expected to impact proliferation and self-renewal of epithelial cells within the crypt compartment. Consistently, histopathological analyses of gastrointestinal biopsies from patients treated with taxanes revealed characteristic microscopic features, including an accumulation of crypt cells in mitotic arrest and the formation of abnormal “ring mitoses”, providing direct evidence of drug effects on the epithelial cells (51).

The most prominent member of the taxane family, paclitaxel, induces mitotic inhibition and apoptosis in the intestinal epithelium (52, 53). Intravenous administration of paclitaxel in mice was shown to rapidly block mitotic divisions within 2–4 h, followed by apoptosis peaking at 6–8 h. Nevertheless, surviving crypt cells resumed proliferation after 24 h, indicating that crypt cells rapidly regenerate (52). Symptoms in patients manifest as nausea, vomiting, diarrhea, stomatitis (inflammation of the oral mucosa leading to mouth sores, pain, and eating difficulties) (54). Consistent with the fast regenerative capacity, paclitaxel causes mostly mild to moderate toxicity (grade 1-2), whereas docetaxel was found to be slightly more toxic, evoking grade 3 toxicity. Both paclitaxel and the semi-synthetic taxane, docetaxel (Taxotere), have been associated with diarrhea. It is estimated that ∼20–40% of patients treated with docetaxel suffer from diarrhea, with 5%–6% displaying severe symptoms (55). While diarrhea in paclitaxel treated patients is less common, it has been suggested that paclitaxel-based chemotherapy may predispose to severe Clostridium difficile-associated diarrhea (CDAD), particularly with prior antibiotic exposure and/or neutropenia (56). Microtubule disruption alone may not fully explain the broad epithelial phenotypes. In vitro studies using human intestinal epithelial cells demonstrated that besides cytoskeletal disruption, paclitaxel also induces the formation of ROS and mitochondrial damage together with downregulation of RhoGTPase (54). Thus, additional factors such as oxidative stress and inflammation are likely to play a role. Like taxanes, vinca alkaloids (vincristine, vinblastine) are anti-mitotic agents that target microtubules, however, these inhibit polymerization (57). This destabilizing action prevents the formation of a functional mitotic spindle and metaphase arrest (58). The cytocidal effect in the intestinal crypts was shown to be a cumulative result of interphase cell apoptosis and metaphase arrest of dividing cells (59). Taken together, microtubule-targeting agents converge on the disruption of crypt cell division as a central mechanism of gastrointestinal toxicity, but ROS and mitochondrial damage also play a role, which parallels its effects on cancer cells (60, 61).

1.2.2 Platinum drugs

Opposed to microtubule-modifying drugs, platinum drugs (cisplatin, carboplatin, oxaliplatin) function as powerful alkylating-like agents in the treatment of a wide variety of cancers, including neuroblastoma, bladder, head and neck, lung, cervical, ovarian, testis, advanced gastrointestinal cancers, and rectal cancers (62). Upon entering the cell and undergoing hydrolysis, they become highly reactive and form covalent bonds with the N7 position of purine bases (adenine and guanine) in the DNA (63). This results in the formation of DNA adducts, primarily intra-strand and, to a lesser extent, inter-strand crosslinks. These crosslinks create significant structural distortions in the DNA (64), which physically obstruct the processes of DNA replication and transcription. This platinum-induced DNA damage activates DNA-damage surveillance pathways. In cells with functional p53, this response includes p53-mediated cell-cycle arrest to allow repair (65, 66). However, many cancers harbor TP53 mutations; in these cases, an inability to mount an effective G1/S checkpoint causes cells to progress with unrepaired crosslinks, ultimately leading to replication collapse and mitotic catastrophe and cell death (67, 68). Given the high rate of DNA replication, the progenitor cells of the intestinal crypts are exquisitely sensitive to this mechanism of action. For instance, studies in rat models show that a single dose of cisplatin (5 mg/kg) increased apoptosis in the intestinal crypts by 4-fold within 24–48 h. This damage preceded “crypt hypoplasia” (thinning), leading to the breakdown of the mucosal barrier (69). Common symptoms include abdominal pain, nausea, and vomiting, mucositis, delayed gastric motility, anorexia, and weight loss, besides electrolyte imbalances due to mucosal barrier loss (70). Often, these symptoms are persistent following treatment discontinuation (71). Of platinum drugs, cisplatin is the most emetogenic, causing diarrhea and emesis at high doses in 67% and 70%–80%, respectively (72). In large retrospective study, 86 patients with platinum-based therapy were identified to have suffered from severe colitis and diarrhea (73). About half of these patients also developed abdominal pain and blood or mucus in stool within a median time of 66 days following treatment begin, which lasted for a median range of 20 days. Another 17% had to discontinue treatment due to severe GI symptoms. In a rat model, cisplatin-induced gastrointestinal symptoms were shown to correlate with increased ROS formation, lipid peroxidation, and epithelial apoptosis, leading to damage of mitochondrial DNA and the activation of various signal transduction pathways that culminate in the induction of apoptosis and necrosis (74). Together, these findings indicate that platinum compounds share key cellular stress responses with microtubule-modifying agents, reflecting common vulnerabilities of rapidly proliferating cells.

1.2.3 Anthracyclines

Anthracyclines (doxorubicin, idarubicin) were found to exhibit a multi-pronged cytotoxic mechanism. Their planar ring structure allows these compounds to intercalate between DNA base pairs, physically obstructing the action of enzymes involved in DNA replication and RNA transcription (75–77). They also act as potent “poisons” for the enzyme topoisomerase-II (78, 79). By stabilizing the complex formed between topoisomerase-II and DNA, they prevent the re-ligation of DNA strand breaks that the enzyme normally creates and resolves, leading to an accumulation of permanent DNA damage. Furthermore, the quinone moiety of the anthracycline molecule can undergo redox cycling, a process that generates large quantities of ROS (80, 81). This leads to severe oxidative stress, causing damage to DNA, proteins, and lipids, and further promoting apoptosis. This combination of direct DNA damage, enzyme inhibition, and oxidative stress makes anthracyclines toxic to rapidly dividing cells, including stem/progenitor cells of the intestinal epithelium. Mouse studies showed that although this intestinal population is initially diminished with anthracycline treatment, these cells promote cell lineage expansion upon completion of treatment (82), consistent with regeneration of the epithelium. In conclusion, the intestinal epithelium exhibits robust regenerative capacity following anthracycline treatment, similar to paclitaxel treatment.

1.2.4 Antimetabolites

Antimetabolite chemotherapeutic agents, including 5-fluorouracil (5-FU), the 5-FU prodrug capecitabine, and irinotecan, exert their anticancer effects by disrupting nucleotide metabolism and DNA replication. 5-FU acts through inhibition of thymidylate synthase and incorporation into RNA and DNA, whereas irinotecan inhibits topoisomerase I, thereby impairing proliferation and promoting cell death in rapidly dividing tumor cells (83). This class of chemotherapeutic agents is widely associated with gastrointestinal toxicities characterized by a spectrum of mucosal injury-driven symptoms. These include diarrhea, mucositis and stomatitis, abdominal pain, nausea, vomiting, and, in more severe cases, colitis, ileitis, malabsorption, and weight loss. Among these manifestations, diarrhea represents a frequent and clinically limiting toxicity. In a meta-analysis including 7458 patients treated with 5-FU, 12.6% suffered from grade 3–4 diarrhea, whereas this number was even higher for capecitabine (∼50%) (84). This phenotype was also observed in C57BL/6J mice following 5-FU intraperitoneal (i.p.) injection. Histopathological examinations in this model showed intestinal inflammation, marked by increased cytokines such as TNF-α, IL-1β, IL-6, IL-17A, and IL-22, as well as dysregulation of aquaporins (AQP1, 4, 8, 11) in the upper intestinal tract and colon (85). Use of the TNF inhibitor, etanercept, however suggested that the observed inflammatory response was uncoupled from AQP dysregulation and diarrhea since TNF inhibition did not rescue these phenotypes. Beside diarrhea, capecitabine is associated with abdominal pain, pancreatitis, colitis, ileitis. Histopathological features include epithelial cell apoptosis, crypt damage and loss, mucosal injury, and inflammation (86, 87). The antimetabolite, irinotecan, similarly induces diarrhea and causes weight loss in rodents. In this model, crypt apoptosis appeared within 6 h, and preceded the onset of overt mucosal damage (88). Irinotecan treatment in rats was further associated with reduced tight junction marker expression, suggesting that the mucosal barrier is compromised in this model (89). Besides these effects, antimetabolite drugs have also been linked to intestinal ROS production and mucositis. For instance, irinotecan was shown to induce ROS via the NADPH oxidase, Nox2, which activates caspase-1 and inflammation (90). Also 5-FU induces ROS formation in the small intestine of BALB/C mice (42). These findings underscore that antimetabolite-induced GI toxicity is a coordinated pathological process where early barrier disruption and oxidative stress trigger a range of damaging effects. The persistence of symptoms despite TNF inhibition suggests that effective intervention requires a multi-target approach addressing epithelial stability and ROS signaling rather than inflammation alone.

In conclusion, chemotherapy-induced intestinal toxicities arise from discrete upstream mechanisms but presents with similar phenotypes across multiple drug classes. These shared responses to chemotherapy stressors are examined below in more detail.

1.3 Mechanisms governing and amplifying chemotherapy-induced epithelial injury

1.3.1 Chemotherapy-induced epithelial damage extends beyond proliferating crypt cells

The non-specific nature of chemotherapeutic agents, which target proliferating cells, provides a common explanation for epithelial susceptibility. However, this alone does not fully account for the diversity of tissue responses observed across the intestinal tract. While highly proliferative cells, such as intestinal crypt progenitors, are particularly susceptible to chemotherapy-induced damage, accumulating evidence indicates that epithelial injury is not restricted to these cells and can extend to differentiated cell populations. Thus, chemotherapy-induced toxicity reflects not only proliferation-dependent susceptibility, but also context-dependent sensitivity across various epithelial cell states. Epithelial susceptibility, in particular, has been observed not only in the intestine, but also in the skin, which contributes to chemotherapy-induced peripheral neuropathy (CIPN) (91, 92). For example, when paclitaxel conjugated to fluorescein (tubulin tracker) was administered intravenously into larval zebrafish, it accumulated rapidly in skin cells but not neurons, which only selectively showed tubulin tracker fluorescence in some neuron cell bodies (91), hinting at enhanced uptake or retention mechanisms in the skin. Consistent with this, studies in mice further showed that paclitaxel-induced mechanical hypersensitivity is mediated by keratinocytes, whereas optogenetic or chemogenetic keratinocyte inhibition largely alleviated the symptoms during acute and long-term exposure (93). These findings indicate that epithelial cells are not merely passive targets of chemotherapy but actively contribute to the development of treatment-related toxicities. Importantly, the epithelial response to chemotherapeutic agents is not strictly limited to proliferating cells. In larval zebrafish, for instance, most epithelial cells are not actively proliferating, yet these cells rapidly take up paclitaxel and exhibit damage days before axon degeneration commences (91).

Also, vincristine and platinum drugs affect non-mitotic cells. Vincristine was shown to induce apoptosis in interphase cells of mouse small intestinal crypts (59), and cisplatin increases apoptosis not only in proliferating crypt cells but also in differentiated villus enterocytes in the jejunum by 2.3-fold (94). This apoptotic response was attenuated by folate, riboflavin, and a multivitamin mixture lacking α-tocopherol. Notably, unlike the other vitamins tested, α-tocopherol did not protect differentiated villus cells in the presence of cisplatin but reduced apoptosis in proliferating crypts, emphasizing that mitotic and differentiated epithelial compartments respond distinctly to antimitotic cues, with proliferative crypt cells being more amenable to interventional rescue than differentiated villus cells.

The effects of chemotherapeutic agents on non-proliferating cells extends beyond epithelial tissues. The best example is that of non-proliferating neurons, which show degenerate in culture and in vivo when exposed to chemotherapeutic agents (95–97). Cardiomyocytes, which have a highly limited proliferative capacity in adults, were shown to be particularly susceptible to anthracycline-induced damage. For example, doxorubicin induces mitochondrial dysfunction and DNA damage through ROS generation and topoisomerase IIβ–mediated mechanisms (98). In the intestine, lineage-tracing experiments using BrdU pulse-labeling demonstrated that antimetabolite chemotherapy drugs, like cytosine arabinoside, rapidly induce apoptosis in S-phase cells within the crypts, indicating that some progenitors die almost immediately after drug exposure rather than undergoing mitosis first (99).

Together, these findings support a model in which chemotherapy-induced epithelial injury occurs across multiple cellular states, affecting both proliferating and non-proliferating cells within the intestine. While proliferative cells remain highly susceptible to rapid damage, differentiated cells can also be damaged. Thus, chemotherapy-induced toxicity may be best understood not solely as a proliferation-dependent toxicity but one that is shaped by chemotherapy regimens, cell proliferation, cellular state, and the activation of stress response pathways, such as through ROS formation. Together, these factors collectively determine the extent and nature of tissue injury.

1.3.2 ROS-driven inflammatory signaling

A key mechanism by which chemotherapeutic agents inflict cellular damage is through the generation of ROS, such as superoxide radicals and hydrogen peroxide (H₂O₂). The overproduction of these molecules overwhelms the endogenous antioxidant defense systems of cells, leading to oxidative stress (100). This redox imbalance triggers lipid peroxidation, protein oxidation, and DNA damage. It also activates stress-responsive signaling pathways, such as p53, TNF, NF-κB, and MAPKs (101, 102). In the intestinal epithelium, oxidative stress contributes to crypt cell apoptosis and villus atrophy (94, 102, 103), as well as compromised tight-junction integrity, ultimately impairing the mucosal barrier (104), establishing oxidative stress as both an initiating stress signal and a key driver of injury propagation via inflammation.

The initial epithelial damage triggers intracellular inflammatory signaling pathways (105–107). This response is amplified by oxidative stress and microbial components that arise from barrier disruption. A central pathway in this response is the Nuclear Factor-kappa B (NF-κB) pathway (105, 108). Under normal conditions, NF-κB is held inactive in the cytoplasm. Upon stimulation by danger signals, a cascade is initiated that leads to the degradation of its inhibitor, allowing NF-κB to translocate to the nucleus. Once in the nucleus, NF-κB acts as a master transcription factor, binding to the promoter regions of a vast array of genes involved in the inflammatory response. This results in the rapid and robust production and secretion of pro-inflammatory cytokines (109). Whether oxidative stress acts as a primary driver of downstream pathology or reflects a secondary response to epithelial injury and inflammation remains to be fully resolved.

Within the context of CIGT, several cytokines are considered of central importance in mucositis induced by chemotherapy. These include Tumor Necrosis Factor-alpha (TNF-α), Interleukin-1 beta (IL-1β), and Interleukin-6 (IL-6) (110, 111). Assessment of intestinal mucositis in mice i.p. injected with 5-FU significantly induced these three cytokines in the small intestine and colon in comparison with a saline control group, whereby Streptococcus thermophilus ST4 treatment showed protective effects (112). Another study in a murine model of irinotecan (CPT-11)-induced intestinal mucositis showed the upregulation of Nrf2, NF-κB, TNF-α, IL-1β, IL-6, IL-17, IL-10 in the duodenum. This upregulation was reduced with antioxidants, such as glutathione and malvidin (111), suggesting ROS as an upstream regulator. Interestingly, particularly malvidin improved biochemical and gene expression profiles, but it failed to prevent CPT-11 induced weight loss or colonic tissue injury, indicating that targeting oxidative stress and cytokine pathways alone does not suffice to preserve mucosal integrity and that multiple pathways are activated and responsible for various symptoms. Cytokines are released by both damaged epithelial cells and activated resident immune cells, such as macrophages, creating a strong inflammatory milieu within the gut mucosa (16, 113), which is a key driver of apoptosis (114). TNF-α, for example, can directly induce apoptosis in intestinal epithelial cells together with IL-1β (115, 116), promoting breakdown of tight junctions that compromises barrier integrity (111, 117), further promoting a cycle of inflammation and tissue damage. It remains unclear to what extent inflammatory signaling contributes to symptom generation in acute versus delayed CIGT, and whether it acts as a primary driver or a secondary response to epithelial injury.

Inflammatory cytokines such as TNF-α and IL-1β also induce the expression and activation of matrix metalloproteinases (MMPs), which degrade extracellular matrix components and weaken epithelial barrier integrity. MMPs are zinc-dependent endopeptidases belonging to the gelatinase B family of enzymes, whose primary function is the degradation of components of the extracellular matrix (ECM), including type I, II, IV and V collagens, which are major constituents of basement membranes and ECM (118). MMPs are secreted in their inactive pro-form, primarily by infiltrating immune cells like neutrophils and macrophages, in response to inflammatory stimuli such as TNF-α and IL-1β (119, 120). However, also epithelial cells secrete MMPs. MMP expression is often increased under conditions of chemotherapy treatment (92, 121). In preclinical models of chemotherapy-induced GI toxicity, for instance, MMP-2, -3, -9 and -12 levels were associated with inflammatory infiltrate and maximum tissue damage in the jejunum and colon (122). In a rat model for irinotecan treatment, activation of MMP-9 significantly contributed to mucositis pathobiology by enzymatically dismantling the structural scaffold in the mucosa through the degradation of the basement membrane and other ECM components. MMP-9 activity was shown to exacerbate the loss of barrier integrity, facilitate the infiltration of more inflammatory cells, and contribute to the overall tissue remodeling and ulceration characteristics of severe mucositis (123).

While much of the focus has been placed on MMP-2 and MMP-9, emerging evidence highlights MMP-13 as a potentially critical mediator of intestinal injury in inflammatory contexts. Alongside MMP-9, MMP-13 has been identified as a critical mediator in inflammatory intestinal diseases that share pathological features with CIGT, such as inflammatory bowel disease (IBD) (124) and sepsis (124, 125). Like other MMPs, MMP-13 is a zinc-dependent enzyme capable of degrading extracellular matrix components, with a preference for cleaving type II collagen, but also acting on types I and III (118). Its expression is typically low under normal physiological conditions and upregulated during inflammatory conditions, including chemotherapy treatment (97, 126–128). A crucial pathogenic role for MMP-13 in gut injury stems from its ability to act as a “sheddase” for TNF-α. TNF-α is produced as an inactive membrane-bound precursor (pro-TNF), which must be cleaved to release the soluble, biologically active form that drives inflammation. While the enzyme TACE is the primary TNF sheddase, studies in animal models of sepsis and colitis have demonstrated that MMP-13 can also perform this cleavage (125). In these models, MMP-13-deficient mice were strongly protected from gut injury as they exhibited reduced intestinal permeability, less depletion of mucus-producing goblet cells, and decreased endoplasmic reticulum stress. This protection was directly linked to lower levels of active, soluble TNF in the gut, suggesting that MMP-13 is a key contributor to inflammation and barrier damage via TNF regulation. Intriguingly, MMP-13 was shown to play a critical role in promoting CIPN via epithelial upregulation (92, 121). Thus, MMP-13 may be a potential therapeutic target for CIGT should its mechanisms be conserved in the chemotherapy-exposed intestine.

1.3.3 The gut microbiome as a modifier and amplifier of toxicity

The gut microbiome, which resembles the complex community of microorganisms residing in the intestinal lumen, plays a critical role in both amplifying and being affected by CIGT. Chemotherapy itself induces profound shifts in the composition and function of this microbial community, a state known as dysbiosis. This shift is not a passive consequence but an active component of the pathogenic cascade. For instance, fecal sample analysis using 16S RNAseq in patients with non-Hodgkin’s lymphoma who received the same myeloablative conditioning regimen, which included high-dose Carmustine (Bis-chloroethylnitrosourea), Etoposide, Aracytine and Melphalan and no other concomitant therapy such as antibiotics, showed enrichment in proteobacteria at the expense of actinobacteria and firmicutes, indicating an increased inflammatory environment (129). How can a dysbiotic microbiome contribute to CIGT? A potential link is the observation that irinotecan promoted microbial components, such as lipopolysaccharide (LPS) to translocate across the intestinal epithelial barrier, which was dependent on the Toll-like receptor (TLR-4). In contrast, TLR-4 knockout mice were protected from irinotecan-induced barrier disruptions (130). Irinotecan treated mice also showed a marked expression of TNF-α, IL-1β, IL-6, and IL-10, suggesting a strong inflammatory response, which was muted in the knockout mice. Microbial components are potent pathogen-associated molecular patterns (PAMPs) that are recognized by pattern recognition receptors, such as TLRs on immune and epithelial cells (131). Their recognition has been shown to trigger the activation of the innate immune system, leading to NF-κB signaling and amplification of these cytokines (132). Thus, barrier disruption and microbial invasion may establish a destructive positive feedback loop, which may explain how an initial, discrete chemotherapy-induced injury may escalate into a more severe, widespread, and self-sustaining inflammatory condition that defines the clinical syndrome of CIGT. The combined effects of proliferation-dependent epithelial damage and ROS-driven stress responses likely contribute to a cascade of events involving inflammatory signaling, extracellular matrix remodeling, and microbiome dysbiosis, collectively driving the progression from localized injury to systemic gastrointestinal toxicity. However, the precise contributions of microbiome changes to CIGT remains incompletely defined and is worth further investigating. In particular, metabolic crosstalk between the gut microbiome and the nervous system in this context has not been clearly established, despite extensive evidence that the gut-brain axis can modulate neural functions through microbial metabolites and signaling pathways. For instance, microbiota can synthesize and respond to 5-HT, as well as other neurotransmitters such as GABA, which influence host neural functions (133). They also produce short-chain fatty acids and modulate tryptophan metabolism, both of which can influence gut-brain signaling. These metabolites have been shown to affect enteroendocrine cells, vagal afferent activity, and immune pathways, and have been implicated in the regulation of visceral pain and gut-brain communication. However, their direct contribution to nausea and vomiting in CIGT have not been established. Clarifying their contributions may reveal new therapeutic opportunities for CIGT.

1.4 The mucosal-neural axis: epithelial-to-neuron crosstalk in CIGT

The mucosal-neuronal axis refers to the bidirectional crosstalk between the intestinal epithelium and the nervous system, including DRG afferents, vagal afferents, and enteric neurons. It is well established that epithelial injury and barrier dysfunction activate sensory neurons, while neural signaling in turn modulates epithelial integrity, immune activation, and the local cytokine environment. However, the mechanisms linking epithelial damage to coordinated responses across enteric and extrinsic neural circuits remain incompletely defined in the context of CIGT. We propose that epithelial injury induces a broader metabolic stress response that engages both intrinsic and extrinsic neural pathways, contributing to gastrointestinal dysfunction. In addition, emerging evidence from peripheral neuropathy models suggests that DRG neurons can become intrinsically sensitized by chemotherapeutic agents, raising the possibility that altered DRG activity may also influence gut functions independently of local epithelial injury. This section focuses on the mechanisms linking epithelial injury to neural responses and the role of the immune system in modulating these processes.

The clinical presentation of CIGT, characterized by abdominal pain, nausea, and altered gut motility, cannot be explained by epithelial injury alone, particularly given the clinical efficacy of antiemetic therapies that target neurotransmitter signaling within peripheral and central neural circuits (134). Chemotherapeutic agents perturb neural circuits that regulate gastrointestinal function, implicating both the intrinsic enteric nervous system (ENS) and extrinsic sensory pathways in disease pathogenesis (Table 3). It has been demonstrated that chemotherapy induces structural and functional alterations in enteric neurons and glial cells in preclinical models, leading to impaired enteric neuronal control of gut motility and secretory function (135–137). In parallel, several CIPN models have demonstrated that DRG neurons (the cell bodies of primary spinal sensory afferents) become hyperexcitable and exhibit altered electrophysiological properties in response to chemotherapeutic agents, such as paclitaxel (97). Since DRG neurons innervate the intestinal wall, they could directly signal to the epithelium to reduce the inflammatory environment, such as during epithelial recovery. It is well established that DRG neurons communicate with epithelial cells, and exert protective effects. For instance, Nav1.8⁺ CGRP⁺ nociceptors innervating the gut direct goblet cells to increase mucus secretion, which provide protective effects to the mucosa (138). Direct evidence for DRG involvement in CIGT is however lacking. It is further possible that chemotherapy exposure induces DRG degeneration, which may compromise the recovery, which remains to be investigated. DRG neurons may also integrate pathological signals arising from intestinal injury and relay this aberrant sensory input to the central nervous system. This is has been shown in the context of CIPN where paclitaxel and related chemotherapeutics induce DRG neuron hyperexcitability and spontaneous firing. For instance, whole-cell patch-clamp recordings of DRG neurons in vitro showed that paclitaxel exposure for 24 or 48 h induced spontaneous depolarizing fluctuations (DSFs) and increased excitability without eliciting ectopic action potential activity. Evidence of oxidative stress and mitochondrial toxicity also emerged after 48 h of paclitaxel exposure (139). Therefore, studies that examine DRG signaling to the intestinal epithelium and to the brain in the context of CIGT will help establish their particular role in contributing to this condition.

TABLE 3. Key players involved in mucosal and neuronal damage.

1.4.1 Pathophysiology of chemotherapy-induced enteric neuron and visceral hypersensitivity

Multiple chemotherapeutic agents exert direct neurotoxic effects on the ENS. Oxaliplatin treatment in mice, for instance, induces a significant loss and the remodeling of myenteric neurons, accompanied by changes in neurochemical coding and disruption of colonic motility (137). Notably, these neuronal changes arise in parallel with epithelial injury but can be detected even in the absence of extensive epithelial damage. Thus chemotherapeutic stress may directly perturb enteric neural integrity while epithelial damage may further amplify dysfunction. Alternatively, subtle epithelial perturbations may be sufficient to drive neuronal dysfunction, consistent with observations in other epithelial-neuronal interfaces, such as the skin epithelium. Further studies demonstrated that oxaliplatin alters both neuronal and glial populations within the myenteric plexus, leading to reductions in nerve fiber density and enteric glial cells. These changes are associated with impaired neuromuscular transmission and dysregulated smooth muscle contractility (140). Together, these findings establish a direct mechanistic link between chemotherapy-induced enteric neurotoxicity and the motility disturbances that define CIGT.

Preclinical studies further demonstrated that acute paclitaxel administration elicits visceral pain (nociception), as well as mechanical and thermal hypersensitivity through TRPV1-dependent sensory pathways. In rodents, a single systemic dose of paclitaxel (1 mg/kg) induced rapid visceral nociceptive responses and acute hypersensitivity, effects that are markedly attenuated by pharmacological TRPV1 inhibition and in TRPV1-deficient mice (141). Population-based studies of cancer survivors indicate that exposure to chemotherapy is also linked to a higher burden of chronic gastrointestinal complaints, including abdominal discomfort and bloating, which are associated with reduced physical and mental wellbeing. Predominantly breast cancer survivors were included in this study, pointing to a potential contribution of taxane-based regimens, such as paclitaxel, to gut-brain axis disturbances (142).

Beyond direct neuronal injury, chemotherapy-induced epithelial stress dependent inflammatory and oxidative signaling within the gut wall can further modulate neuronal function. Oxaliplatin treatment, for instance, has been shown to induce local inflammatory responses and microbial alterations that coincide with enteric neuronal remodeling and functional deficits (140). This suggests that epithelial and microbial changes may influence neuronal remodeling. Such changes are consistent with, and may contribute to, sensitization gut-innervating sensory pathways, which has been proposed as a mechanistic basis for abdominal pain and cramping experienced during CIGT. This type of sensitization is reflected in colorectal distension models, where increased sensitivity of gut-innervating sensory neurons leads to exaggerated pain-related motor responses, indicating visceral hypersensitivity (143). In the context of chemotherapy-induced epithelial and enteric neuronal injury, such sensitization would be expected to render normally innocuous physiological stimuli painful, producing allodynia and hyperalgesia. In conclusion, chemotherapeutic agents disrupt epithelial integrity and also directly damage enteric neurons, while potentially promoting inflammatory and microbial crosstalk that further sensitizes neural pathways (Figure 3).

1.4.2 Serotonin is a key mediator of neuronal sensitization

The gut epithelium is the primary source of serotonin for the body, which is synthesized and stored in specialized enterochromaffin cells (144). Mucosal damage during CIGT leads to the release of 5-HT into the gut wall (5, 145, 146). Serotonin then acts on a wide variety of 5-HT receptor subtypes expressed on both enteric neurons and extrinsic sensory afferent nerves that project to the spinal cord (147). Mechanistically, docking studies suggest that certain antineoplastic agents, including cisplatin, dacarbazine and nitrogen mustard, may compete with serotonin to directly bind to the 5-HT3 receptor and stimulate an emetic response (148). This signaling ultimately affects gut motility, secretion, and the perception of pain, establishing 5-HT as a critical sensitizing agent in chemotherapy-induced distress (149, 150). A direct link between cisplatin and serotonin dependent vagal activation was demonstrated using electrophysiological recordings in rats where cisplatin administration triggered an immediate increase in vagal afferent firing. This response was abolished by the 5-HT3 receptor antagonist, Y-25130 (151). While serotonergic signaling is well established in acute CINV, its role in mediating sustained gastrointestinal dysfunction in CIGT remains less clearly defined.

1.4.3 Sensitization of DRG afferents

The primary sensory neurons that transmit information, including pain signals, from the gut to the central nervous system have their cell bodies located in the dorsal root ganglia (DRG), which lie just outside the spinal cord (152, 153) (Figure 3A). These neurons are a principal target of chemotherapy-induced neurotoxicity (154, 155). The damage occurs through two convergent pathways. First, chemotherapeutic agents like paclitaxel and cisplatin can cross the blood-nerve barrier (156, 157) and directly damage the DRG neurons. This could in principle influence the intestinal mucosa which is innervated by peripheral axons of some DRGs. Known effects on DRG neurons that have been elucidated in the context of CIPN are mitochondrial dysfunction (158, 159), pathological alterations in ion channel expression and function (160, 161), including dysregulation of intracellular Ca²⁺ release channels and calcium homeostasis, and axonal degeneration (162, 163). Second, the inflammatory and neuro-sensitizing mediators released from the damaged gut (TNF-α, IL-6, 5-HT) enter the systemic circulation and may reach the DRG (164–166), leading to a secondary inflammatory response within the ganglia themselves, characterized by the infiltration of immune cells like macrophages (155). The combination of direct cytotoxic insult and indirect inflammatory sensitization renders the DRG neurons hyperexcitable (161). This state of central sensitization within the DRG is a crucial mechanism that underlies the chronic, burning pain and hypersensitivity in the extremities known for CIPN (155, 161) and may act similarly in the gut leading to CIGT. In addition, the skin epithelium has been shown to overexpress MMP-13 and produce excessive ROS in the presence of chemotherapeutic agents like paclitaxel, which contributes to axon degeneration in CIPN. The intestinal mucosa upregulates MMP-13 in response to inflammatory cues like LPS (124), and thus MMP-13 or other MMPs may contribute to CIGT via DRG axon damage. The extent to which this mechanism is involved in abdominal pain and visceral hypersensitivity or nausea and vomiting following chemotherapy remains to be explored.

1.4.4 Evidence for an integrated neuro-epithelial axis

Although no single study presented explicitly connects DRG sensitization to chemotherapy-induced intestinal injury, a DRG-to-neuron crosstalk hypothesis in CIGT is a robust and compelling inference drawn from the convergence of strong evidence from highly analogous and mechanistically overlapping fields. 1) Inflammatory gut models replicate a state of intense gut inflammation similar to CIGT, directly demonstrating that inflammatory mediators like TNF-α sensitize colon-innervating DRG neurons via modulation of ATP-sensitive P2X3 receptors ((165–167). Research on irritable bowel syndrome (IBS) has established a firm role for epithelial-derived serotonin in driving visceral pain and hypersensitivity through its action on sensory afferents (168–170). Finally, studies focusing on the somatic (non-visceral) neurotoxicity of chemotherapy have implicated epithelial damage as a key driver of DRG axon degeneration and pain (97, 171, 172). Based on the pathophysiology of CIGT, we hypothesize that a similar environment exists in the gut mucosa, characterized by epithelial damage, inflammation, and neurotoxicity, in which serotonin is released from ECs and exerts its sensitizing effects on sensory neurons. This crosstalk hypothesis is a logical consequence from the provided evidence of mechanisms leading to intestinal pathology.

This integrated view also suggests that CIGT and CIPN may not represent entirely separate toxicities. Instead, they appear to be mechanistic cousins, representing the visceral and somatic manifestations of a common underlying pathology: chemotherapy-induced neuroinflammation. The process begins with direct damage to both the gut epithelium (initiating CIGT) and the DRG neurons (initiating CIPN). The subsequent “leaky gut” caused in CIGT (104, 173, 174) then can become a systemic source of pro-inflammatory and pro-nociceptive signals produced by altered gut microbes. These signals then travel to the DRG leading to neuropathic pain (175, 176). Together, these observations suggest that gut-specific effects of chemotherapeutic agents may not only participate in visceral pain and nausea and vomiting, but may also amplify neuronal sensitization and drive CIPN symptoms (177, 178). This model may help explain the frequent and debilitating clinical overlap in patients who suffer from both severe gastrointestinal distress and peripheral neuropathy. It also raises the intriguing therapeutic possibility that interventions aimed at restoring gut barrier integrity could have beneficial effects on the symptoms of peripheral neuropathy and vice versa.

1.4.5 Future research on mucosal-neural crosstalk

Although serotonin has long been recognized as a central mediator of gut-neural communication, its precise role in chemotherapy-induced gastrointestinal toxicity (CIGT) remains incompletely defined. In vivo studies that directly link EC-derived serotonin to changes in visceral afferent firing during chemotherapy are still limited. While serotonin is well established as a driver of visceral sensory signaling in IBS, where it contributes to hypersensitivity, nausea, and motility changes via 5-HT₃ and 5-HT₄ receptors (179, 180), its causal contribution and mechanistic positioning in chemotherapy-induced mucosal injury may differ in magnitude, timing, and downstream integration.

A major unresolved question is how serotonergic signaling interfaces with other candidate epithelial- or immune-linked mediators that can sensitize sensory neurons in gastrointestinal inflammation more broadly. For example, purinergic ATP-P2X3 signaling and NGF-dependent mechanisms have been implicated in neuronal sensitization in diverse pain and inflammatory models, but their relevance, temporal recruitment, and symptom-specific contributions in CIGT remain to be established. Determining whether these pathways act independently of serotonin, converge on shared excitability pathways, or operate in a hierarchical manner to drive distinct outcomes such as visceral pain, nausea, and dysmotility would help to clarify the underlying mechanisms of chemotherapy-induced vomiting and nausea. Chemotherapy induces the expression of various MMPs, including MMP2, MMP3, and MMP9 (181) in the oral mucosa, presumably mediating remodeling of the mucosal microenvironment via changes in the extracellular matrix and barrier properties. Defining the relative contributions and mechanistic integration of these MMPs and others, such as MMP-13 in neuronal damage could be useful in determining mechanisms that underlie neuronal activation. Peripheral sensory afferents with origin in the DRG arborize within the mucosa and closely appose epithelial and ECs, positioning them to respond dynamically to local microenvironmental changes (Figure 3) (182). It is conceivable that chemotherapy-induced epithelial stress alters this neuroepithelial interface through mechanisms that include extracellular matrix remodeling, and this could influence DRG terminal accessibility, branching architecture, or local receptor exposure. Such remodeling might also indirectly shape serotonergic signaling by altering the diffusion, concentration gradients, or receptor microdomains associated with 5-HT₃ and 5-HT₄ pathways. Whether extracellular matrix remodeling functions upstream of serotonergic activation, operates in parallel, or independently regulates afferent sensitization in CIGT remains unknown. Direct in vivo studies examining DRG terminal structure, neuronal firing, and mucosal MMP activity and their involvement will be required to define the contribution of these interactions to symptoms such as nausea, visceral pain, and dysmotility. A critical next step is therefore to analyze these potential links. Other approaches could involve preclinical studies that use specific pharmacological tools, such as P2X3 receptor antagonists, or anti-NGF neutralizing antibodies, to determine if blocking these individual pathways can alleviate specific CIGT symptoms like visceral pain, nausea, or dysmotility. Furthermore, the communication is likely bidirectional; the nervous system can also influence mucosal inflammation and repair given the evidence from cancer studies (183–185). Investigating chemotherapy-induced enteric neuropathy and axon degeneration and how this might contribute to the mucosal ability to heal or regulate local inflammation is another important and underexplored area of research. A deeper understanding of this complex crosstalk is essential for developing novel therapies that can target the neurological symptoms of CIGT at their source.

1.5 Current management of CIGT and its limitations

In light of the mechanisms described above, current management strategies for CIGT remain largely supportive and do not directly target the underlying drivers of epithelial injury, inflammation, and neuro-epithelial signaling. These aim at symptom management rather than preventing the underlying pathology, and are often insufficient to prevent dose-limiting toxicities.

1.5.1 Symptom-specific CIGT management

The approach to treatment is typically tailored to the specific symptoms of the patient but follows specific regimens (Table 4). Nausea and Vomiting (CINV): This is the most successfully managed aspect of CIGT, largely due to the development of mechanism-based therapies. The understanding that chemotherapy triggers serotonin release from enterochromaffin cells in the gut led to the design of 5-HT3 receptor antagonists (e.g., ondansetron) (5, 24). These are the cornerstone of CINV prevention and are highly effective, especially for acute emesis. Prophylactic regimens for moderate-to-high risk chemotherapy now typically involve a multi-drug approach, combining a 5-HT3 antagonist with a neurokinin-1 (NK-1) receptor antagonist (e.g., aprepitant) and a corticosteroid (e.g., dexamethasone) (134, 186). Diarrhea (CID): Standard management focuses on fluid and electrolyte replacement to prevent dehydration, along with the use of anti-motility agents, with loperamide being the first-line therapy. For diarrhea that is severe or refractory to loperamide, the somatostatin analog octreotide may be used to reduce gastrointestinal secretions (187, 188). In irinotecan-associated diarrhea, budesonide has shown activity in some refractory-treatment reports, though randomized prevention data have been negative (189, 190). Mucositis (oral and intestinal): Treatment for mucositis is primarily palliative. For oral mucositis, care focuses on maintaining oral hygiene with gentle brushing and saline rinses, managing pain with topical anesthetics (“magic mouthwash”) and systemic analgesics, and maintaining nutrition with a soft, bland diet. Cryotherapy (sucking on ice chips during infusion of certain chemotherapies) can reduce the severity of oral mucositis (191). Photobiomodulation (low-level laser therapy) is used in specific settings to prevent oral mucositis and can reduce mucositis-associated pain (191). To date, palifermin (keratinocyte growth factor) is FDA-approved to decrease the incidence and duration of severe oral mucositis in patients with hematologic malignancies receiving myelotoxic therapy with autologous hematopoietic stem cell support (192). Management of intestinal mucositis involves treating the symptoms it causes, such as diarrhea and abdominal pain. Abdominal pain: Pain associated with CIGT is managed according to the general principles of cancer pain management, often following the World Health Organization (WHO) three-step analgesic ladder (193). This approach begins with non-opioid analgesics like acetaminophen and NSAIDs, escalating to weak and then strong opioids as needed. For neuropathic pain components, adjuvant medications such as anticonvulsants or antidepressants may be added.

TABLE 4. Antiemetic drug guidelines.

HEC/MEC/LEC: Highly/Moderately/Low emetogenic chemotherapy. Phases: acute (0–24 h), delayed (24–120 h), and overall (0–120 h).

1.5.2 Overall effectiveness, translational implications, and unmet needs

Current therapeutic strategies for CIGT remain largely symptom-based and predominantly target neural signaling pathways (Table 5). Antiemetic regimens, including 5-HT₃ receptor antagonists (e.g., ondansetron) and NK1 receptor inhibitors (e.g., aprepitant), represent a major success in supportive oncology care and effectively control acute nausea and vomiting in a substantial proportion of patients (194–196). Additional agents such as dexamethasone and olanzapine further enhance control of emesis through central mechanisms. However, within the framework of the mucosal-neural axis, these therapies primarily modulate downstream neural circuits and do not address the initiating epithelial injury or its downstream inflammatory and structural consequences. This disconnect has important clinical implications. While acute CINV is relatively well controlled, other manifestations of CIGT, including diarrhea, mucositis, abdominal pain, and dysmotility, remain inadequately managed. Current interventions for these symptoms are largely reactive and palliative. Loperamide is the standard first-line therapy for chemotherapy-induced diarrhea, and octreotide is used in severe or refractory cases, but these approaches aim to reduce stool output and secretion rather than restore epithelial barrier integrity or prevent mucosal injury (197, 198). For mucositis, most interventions remain supportive, focusing on oral hygiene, pain control, and nutritional maintenance, although palifermin provides proof of principle that epithelial-directed therapy is feasible in selected settings. Pain management similarly follows general analgesic principles and does not specifically target the mechanisms driving chemotherapy-induced mucosal and neural dysfunction. Emerging preclinical evidence suggests that epithelial injury is not merely a passive consequence of chemotherapy but an active driver of disease progression through barrier disruption, oxidative stress, and extracellular matrix remodeling. These processes may promote microbial translocation, sustain inflammatory signaling, and amplify neural sensitization. However, their clinical relevance remains incompletely established, and there are currently no approved therapies that directly target epithelial integrity, barrier restoration, or matrix remodeling in CIGT. From a translational perspective, this identifies several mechanistically defined therapeutic opportunities, which could be further explored.

TABLE 5. The effectiveness of antiemetics against CINV.

Acute control: Effectiveness of specified drug within the first 0–24 hours. Delayed control: Effectiveness of specified drug within 24–120 hours. (HEC/MEC), regimen (e.g., cisplatin, AC, carboplatin), and patient risk factors.

1.5.2.1 Epithelial barrier integrity and regeneration

Clinical use of palifermin demonstrates that epithelial-directed therapies are feasible. Additional approaches under investigation include glutamine supplementation, tight junction stabilizers, and microbiome-directed strategies (e.g., probiotics or fecal microbiota transplantation), although results remain variable and context-dependent.

1.5.2.2 Oxidative stress and mitochondrial injury

Reactive oxygen species are increasingly implicated in epithelial damage. Antioxidants such as N-acetylcysteine, mitochondrial-targeted ROS modulators, and superoxide dismutase mimetics show protective effects in preclinical models, but clinical validation is limited.

1.5.2.3 Extracellular matrix remodeling and barrier breakdown

Matrix metalloproteinases (e.g., MMP-2, -9, -13) contribute to structural degradation of the epithelial barrier and may represent a critical transition point from reversible injury to sustained pathology. While prior broad-spectrum MMP inhibitors were limited by toxicity, selective targeting of specific MMPs represents a promising but as yet unexplored strategy in CIGT.

1.5.2.4 Inflammatory amplification

Cytokine-driven pathways (e.g., TNF-α, IL-1β, IL-6) sustain mucosal inflammation. Biologic therapies targeting these pathways are effective in other inflammatory conditions but remain largely untested in CIGT and may be constrained by immunosuppressive risks in cancer patients.

1.5.2.5 Mucosal-neural signaling and visceral hypersensitivity

Current antiemetics effectively target central and peripheral neural pathways involved in nausea and vomiting. Additional neuromodulators, including gabapentinoids and tricyclic antidepressants, may alleviate pain and hypersensitivity but do not address upstream epithelial drivers.

Taken together, current clinical management is effective for downstream neural symptoms, while upstream epithelial damage, barrier dysfunction, and inflammatory amplification remain areas in which treatment could be improved. A key translational opportunity lies in combination strategies that integrate epithelial-protective or barrier-restoring therapies with established neuro-targeted regimens. Targeting critical upstream processes, particularly epithelial stress responses and extracellular matrix remodeling, as well as junction proteins may prevent the initiation and amplification of mucosal-neural signaling. However, progress in this area is limited by the lack of validated biomarkers linking epithelial injury to functional outcomes, and by a scarcity of clinical trials designed to test mechanism-based interventions in CIGT.

1.6 Discussion

The comprehensive analysis of the pathobiology of CIGT reveals a complex, multi-stage process that extends from initial molecular damage to systemic neuro-immune dysregulation. Integrating this knowledge into a cohesive model not only clarifies the disease process but also illuminates potential avenues for much-needed therapeutic intervention. The pathogenesis of CIGT can be conceptualized as a four-stage cascade, where each stage builds upon the last, creating an escalating cycle of injury and dysfunction. Initiation Phase (direct cytotoxicity): Systemic administration of chemotherapeutic agents inflicts direct cytotoxic damage on the highly proliferative stem and progenitor cells within the intestinal crypts due to the mechanism of chemotherapeutics targeting cell division. Breach phase (epithelial barrier breach). This initial insult leads to a wave of crypt cell apoptosis, resulting in a loss of intestinal regenerative capacity. The consequence is villus atrophy, crypt hypoplasia, and a physical and molecular breakdown of the epithelial barrier, characterized by the disruption of tight and adherens junction protein complexes. Immune response phase. The compromised barrier allows for the translocation of luminal microbial components, which, along with damage signals from dying cells, activates inflammatory pathways This triggers a positive feedback loop involving oxidative stress, lipid peroxidation, the release of pro-inflammatory cytokines, and the activation of matrix-degrading enzymes with concomitant downregulation of junction proteins that permit microbial invasion. This loop therefore drives sustained, widespread mucosal inflammation and microbial feedback. Neuro-sensory phase (mucosal-neural crosstalk). The inflamed and damaged mucosa releases serotonin and likely other neuroactive mediators. These molecules act on the local enteric nervous system to cause dysmotility (diarrhea, constipation) and sensitize the extrinsic primary sensory afferents in the dorsal root ganglia, leading to visceral hypersensitivity, abdominal pain, and possibly nausea, while this sensitization may also affect other peripheral tissues that are innervated by sensory afferents that also innervate the intestine. In the case of paclitaxel and anthracyclines, DRG neurons may promote recovery of the epithelium given its high regenerative potential for the intestinal epithelium when exposed to these chemotherapeutic agents (Figure 4).

Despite its profound impact on cancer treatment, the management of CIGT remains a significant, unmet clinical need. The current standard of care is largely limited to supportive measures and palliative symptom management, such as anti-emetics, anti-diarrhea medications, and analgesia. These approaches do not address the underlying pathobiology and dose reductions or treatment delays that may compromise therapeutic efficacy.

The integrated pathobiological model presented here reveals a multitude of potential targets for the development of novel, mechanism-based therapies. Interventions could be designed to act at each phase of the cascade. Strategies could focus on protecting the crypt stem cell population or inhibiting pro-apoptotic pathways specifically activated by chemotherapy in epithelial cells, by targeting the amplification loop by inhibiting key inflammatory cytokines (e.g., anti-TNF-α therapy), neutralizing ROS and preventing lipid peroxidation (antioxidants), restoring a healthy gut microbiome (probiotics, prebiotics, or fecal microbiota transplantation), or inhibiting the activity of MMPs. The symptoms of pain and dysmotility could be addressed by blocking the receptors for key neuro-sensitizing mediators, such as P2X3 receptor antagonists, therapies that target NGF or ATP, or exploring more specific serotonin receptor subtypes as therapeutic option, besides those already on the market targeting 5-HT3. The development of effective preventative and therapeutic strategies for CIGT is one of the most pressing challenges in supportive cancer care. A successful intervention would not only alleviate significant patient suffering but would also have the direct effect of enabling more patients to complete their planned chemotherapy regimens at the intended dose intensity. By preserving the efficacy of anticancer treatments, the effective management of CIGT holds the promise of improving overall cancer survival rates. Continued research into the intricate molecular and cellular interactions that drive this debilitating toxicity is therefore of paramount importance.

Generative AI statement

The author(s) declared that generative AI was used in the creation of this manuscript. AI was used to create the figures and for editing the manuscript text.

Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Footnotes

Edited by: Vivek Verma, University of Minnesota Twin Cities, United States

Reviewed by: Wojciech Michał Jankowski, Medical University of Lodz, Poland

Hao Guo, Xiamen University, China