Mechanistic Pathways Connecting the Gut-Brain Axis to Neurodegenerative Disease Pathogenesis

Neurodegenerative disease research increasingly indicates that intestinal physiology can influence neuronal vulnerability through metabolic, endocrine, neural, and barrier-mediated pathways. Beyond broad associations between dysbiosis and disease, emerging evidence suggests that gut-derived molecules may regulate neuronal energy metabolism, mitochondrial function, synaptic maintenance, proteostasis, and the processing or propagation of misfolded proteins. Studies in Alzheimer’s disease, Parkinson’s disease, and related proteinopathies have identified changes in intestinal metabolites, epithelial integrity, and gut-to-brain signaling before or during the development of neurological symptoms. Nevertheless, many findings remain correlative, and the mechanisms that determine whether peripheral alterations promote neuronal resilience or progressive degeneration are not fully established. In particular, the temporal sequence linking intestinal metabolic changes to mitochondrial damage, synaptic dysfunction, pathological protein accumulation, and neuronal loss requires further clarification. A focused investigation of these mechanisms is needed to distinguish disease-driving signals from secondary changes and to identify biologically meaningful therapeutic targets.This Research Topic aims to define the causal molecular pathways through which gut-derived signals influence neuronal homeostasis and neurodegenerative pathology. It will focus on how microbial and host-derived metabolites, intestinal barrier products, and gut-initiated neural or endocrine signals affect neuronal bioenergetics, mitochondrial quality control, synaptic function, autophagy, proteasomal degradation, and the formation or spread of pathological proteins. Particular attention will be given to the timing of gut alterations relative to disease initiation and progression, the cellular receptors and transport systems that mediate gut-to-brain communication, and the factors that confer individual susceptibility or resilience. The Research Topic also seeks to evaluate interventions that modify specific gut-derived molecules or signaling pathways to preserve neuronal function, rather than broadly addressing microbiota composition or neuroimmune disease mechanisms.To gather further insights into the metabolic and molecular mechanisms connecting the gut with neurodegenerative pathology, we welcome studies focused on Alzheimer’s disease, Parkinson’s disease, and related neurodegenerative proteinopathies. Studies centered primarily on multiple sclerosis, autoimmune neuroinflammation, neuropathic pain, general CNS inflammation, or descriptive microbiota profiling without a defined neuronal mechanism fall outside the scope. Themes include, but are not limited to:• Gut-derived metabolites regulating neuronal energy metabolism, mitochondrial quality control, and oxidative balance• Role of gut microbiome in development and progression of neurodegenerative diseases• Blood–brain barrier transport mechanisms mediating gut metabolite access to the CNS• Intestinal epithelial and barrier mechanisms controlling the release and transport of neuroactive molecules• Receptors, transporters, and cellular pathways mediating the effects of gut-derived signals on neurons and glial cells• Microbial and host metabolites influencing synaptic plasticity, neurotransmission, and neuronal resilience• Gut-related regulation of autophagy, proteasomal activity, and other protein quality-control systems• Mechanisms linking intestinal signals with amyloid, tau, α-synuclein, and other pathological protein accumulation• Gut-to-brain pathways influencing the initiation, trafficking, or propagation of misfolded proteins• Temporal relationships between intestinal metabolic changes and preclinical neurodegenerative pathology• Interactions between gut-derived signals, genetic risk, and individual susceptibility to neuronal degeneration• Multi-omics and systems biology approaches that identify causal gut–brain mechanisms• Mechanistically targeted interventions involving specific metabolites, receptors, transport pathways, or intestinal processes• Mechanistic biomarkers of gut-brain dysfunction predicting disease onset or progression• Potential of therapeutic targeting of gut microbiome in neurodegenerative diseases Topic editors: Vaibhavi Vijay Peshattiwar, Phillip R Zoladz, Dilshan Beligala Source: https://www.frontiersin.org/research-topics/83547/mechanistic-pathways-connecting-the-gut-brain-axis-to-neurodegenerative-disease-pathogenesis