Microbial metabolites as modulators of gut–brain communication in neurodegeneration: from intestinal sensing to disease initiation and progression
- 1School of Pharmaceutical Science, Department of Pharmacy, Phase I Clinical Trial Centre, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, Hunan, China
- 2School of Life Science, Hunan University of Science and Technology, Xiangtan, Hunan, China
Abstract
How heterogeneous gut metabolite alterations relate to Parkinson’s disease (PD) and Alzheimer’s disease (AD) remains unresolved. We propose a framework in which intestinal sensing of indole derivatives, short-chain fatty acids and bile acids links microbial function to barrier regulation and gut–brain communication. Integration denotes tissue-level convergence of aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR) and metabolite-responsive G-protein-coupled receptor responses across epithelial and neighbouring immune cells, rather than an established same-cell receptor complex. Tryptophan metabolism provides an analytical focus connecting microbial indole production with host kynurenine and serotonin pathways; metabolite concentrations alone do not establish pathway flux or receptor activity. We hypothesise that suppressed indole-associated epithelial signalling, barrier hyperpermeability and peripheral immune activation could form a shared gut-derived vulnerability state in subsets of PD and AD. Its co-occurrence and temporal relationship to CNS pathology have not been prospectively demonstrated. Neural, immune and vascular processes may overlap in both diseases, with genotype and cellular context modifying relative susceptibility rather than determining exclusive pathways. Human observational findings are distinguished from experimental mechanisms and proposed interactions. Receptor-directed treatments and metabolite-based biomarkers remain candidates requiring mechanism-specific, safety and clinical validation. Whether a gut-derived intervention window exists, is reversible, or favours earlier treatment requires longitudinal and controlled studies. The framework accommodates bidirectional communication and CNS-intrinsic disease, and generates separate tests of composite gut phenotyping and genotype–metabolite interactions.
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BibTeX
@article{liu2026microbial,
title = {{Microbial metabolites as modulators of gut–brain communication in neurodegeneration: from intestinal sensing to disease initiation and progression}},
author = {Xi Liu and Sirui Wang and Wei Long and Xinyue Tan and Xinyue Tan and Wanlin Li and LiChen Gao},
journal = {Frontiers in Aging Neuroscience},
year = {2026},
month = oct,
doi = {10.3389/fnagi.2026.1926883},
url = {https://doi.org/10.3389/fnagi.2026.1926883},
note = {CC BY},
}
RIS
TY - JOUR
TI - Microbial metabolites as modulators of gut–brain communication in neurodegeneration: from intestinal sensing to disease initiation and progression
AU - Xi Liu
AU - Sirui Wang
AU - Wei Long
AU - Xinyue Tan
AU - Xinyue Tan
AU - Wanlin Li
AU - LiChen Gao
PY - 2026
DA - 2026/10/23
JO - Frontiers in Aging Neuroscience
DO - 10.3389/fnagi.2026.1926883
UR - https://doi.org/10.3389/fnagi.2026.1926883
AB - How heterogeneous gut metabolite alterations relate to Parkinson’s disease (PD) and Alzheimer’s disease (AD) remains unresolved. We propose a framework in which intestinal sensing of indole derivatives, short-chain fatty acids and bile acids links microbial function to barrier regulation and gut–brain communication. Integration denotes tissue-level convergence of aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR) and metabolite-responsive G-protein-coupled receptor responses across epithelial and neighbouring immune cells, rather than an established same-cell receptor complex. Tryptophan metabolism provides an analytical focus connecting microbial indole production with host kynurenine and serotonin pathways; metabolite concentrations alone do not establish pathway flux or receptor activity. We hypothesise that suppressed indole-associated epithelial signalling, barrier hyperpermeability and peripheral immune activation could form a shared gut-derived vulnerability state in subsets of PD and AD. Its co-occurrence and temporal relationship to CNS pathology have not been prospectively demonstrated. Neural, immune and vascular processes may overlap in both diseases, with genotype and cellular context modifying relative susceptibility rather than determining exclusive pathways. Human observational findings are distinguished from experimental mechanisms and proposed interactions. Receptor-directed treatments and metabolite-based biomarkers remain candidates requiring mechanism-specific, safety and clinical validation. Whether a gut-derived intervention window exists, is reversible, or favours earlier treatment requires longitudinal and controlled studies. The framework accommodates bidirectional communication and CNS-intrinsic disease, and generates separate tests of composite gut phenotyping and genotype–metabolite interactions.
SN - 1663-4365
ER -