Work

Microbial metabolites as modulators of gut–brain communication in neurodegeneration: from intestinal sensing to disease initiation and progression

Year: 2026

Type: article

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.

Source: Frontiers in Aging Neuroscience

DOI: 10.3389/fnagi.2026.1926883

Authors: Xi Liu, Sirui Wang, Wei Long, Xinyue Tan, Wanlin Li, LiChen Gao

Institutions: Changsha Central Hospital, University of South China, Hunan University of Science and Technology

Language: English

Topic: Gut microbiota and health

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,801