MSACL 2025 Abstract

Microbial Bile Acids Impair Memory via the Gut–Brain Axis: A Multi-Omics Perspective

Dakshat Trivedi (1), Laura Gallardo Nuell (2), Jose Manuel Fernandez-Real (2), Jordi Mayneris-Perxachs (2), Phil Burnet (3), Jonathan R Swann (1)
(1) School of Human Development and Health, Faculty of Medicine, University of Southampton, UK, (2) The Girona Biomedical Research Institute Dr. Josep Trueta (IDIBGI) (3) Department of Psychiatry, University of Oxford, UK

Dakshat Trivedi (Presenter) University of Southampton

Presenter Bio: As a research fellow at the Institute of Developmental Sciences at University of Southampton, Dakshat applies biological mass spectrometry led metabolomics approaches within the area of human development and health.
​
Dakshat has a PhD in Biological Chemistry from the University of Manchester. Dakshat also holds a postgraduate degree in Forensic Science from King’s College, London & a BSc in Biomedical Sciences from Middlesex University, London. Dakshat's latest research interests include metabolic diseases, personalised nutrition, precision medicine, and healthy ageing. He has experience in population studies, mass spectrometry and vibrational spectroscopic analyses, and large-scale data analysis. Dakshat is keen on promoting equality, diversity, and inclusion within academia.
Research Fellow, Human Health and Development, University of Southampton

Relevant Financial Disclosures (within past 24 months, reported on Jul 16, 2025) No relevant financial relationship(s) to disclose. Discussing Products? NO, presenter will NOT present educational content related to products/services of the ineligible company(ies) listed above. Conflict mitigation NOT REQUIRED.

INTRODUCTION:
Cognitive decline in ageing can occur in the absence of overt neurodegeneration, suggesting a role for systemic metabolic changes. Emerging evidence supports the gut–brain axis as a key regulator of brain health, with microbial metabolites—particularly bile acids—acting as potential neuromodulators. However, the specific bile acids and microbial pathways contributing to memory impairment during healthy ageing remain understudied.

OBJECTIVES:
To investigate whether specific plasma bile acids are associated with cognitive decline in older adults, determine the microbial contribution to their biosynthesis, and assess their mechanistic role in modulating brain function via the gut–brain axis.

METHODS:
Targeted LC-MS/MS quantified 45 bile acids in plasma from 976 older adults in the IMAGENOMICS cohort, alongside clinical, biochemical, dietary, and cognitive metadata. Metagenomic sequencing identified KEGG orthologues in bile acid biosynthesis pathways to assess microbial contributions to circulating bile acid levels.

Causality was tested in two murine models. In the first, faecal microbiota from human donors stratified by cognitive performance were transplanted into germ-free mice, followed by cognitive assessment via the Morris water maze. In the second, specific-pathogen-free mice received oral hyodeoxycholic acid (HDCA) or vehicle control by gavage. Cognition was tested using the Y-maze. Frontal cortex and hippocampus were harvested from these mice for transcriptomic profiling of bile acid receptors FXR and TGR5.

RESULTS:
Higher plasma HDCA levels were significantly associated with poorer short-term memory performance. Metagenomic pathway analysis revealed enrichment of microbial genes linked to secondary bile acid biosynthesis in individuals with elevated HDCA. KEGG orthologue abundance correlated with plasma HDCA concentrations, supporting a microbial origin. Mice receiving FMT from high-HDCA donors exhibited impaired spatial memory, with longer path lengths and reduced efficiency. Oral HDCA recapitulated these behavioural deficits, confirming a direct role for this metabolite. Transcriptomic profiling revealed HDCA-induced downregulation of FXR and TGR5 in the cortex and hippocampus, indicating disrupted bile acid signalling in brain regions involved in cognition.

CONCLUSION:
Using a targeted, hypothesis-driven multi-omics approach, we identify microbial-derived HDCA as a modifiable contributor to age-related cognitive decline. These findings establish a mechanistic link between gut microbial bile acid metabolism and brain dysfunction, highlighting bile acid signalling pathways as potential therapeutic targets for preserving cognitive health in ageing.