Molecular Insights to Gut–Brain Communication: Metabolomics Approach on Lifestyle Influences

Abstract

Alterations in the gut microbiota composition and function have been implicated in various human diseases. Gut–brain axis, a bidirectional communication network involving the neural, immune, and endocrine systems, facilitates the crosstalk between the gut microbiota and the central nervous system (CNS). Small molecules produced through host and microbial metabolism, known as metabolites, play a focal role in this signaling. Metabolomics, the comprehensive profiling of metabolites in biological samples, has been instrumental in identifying these active compounds. Applied to fecal and blood samples, metabolomics has revealed the significant influence of lifestyle factors, such as nutrition or substance use, on human metabolome. However, the connections between lifestyle factors and neuroactive metabolites remain poorly understood.

This doctoral thesis aimed to discover metabolites with neuroactive potential and provide insights on how lifestyle factors may influence them. The primary methodology across the included studies was nontargeted metabolic profiling using liquid chromatography–high-resolution mass spectrometry (LC-HRMS), enabling broad detection of chemically diverse metabolites in human clinical samples. These samples were collected from clinical interventions examining the effects of alcohol use and withdrawal in individuals with alcohol use disorder (AUD), inulin supplementation in individuals with AUD or obesity, and high-intensity interval training in individuals with metabolic-dysfunction associated steatotic liver disease (MASLD).

The findings show that AUD has a profound effect on plasma metabolome, particularly affecting lipid intermediates, bile acids, steroids, and diet- and microbiota-derived metabolites. Notably, many of these changes showed reversible trends following a three-week withdrawal period, underscoring the independent impact of AUD. Several diet- and microbiota-derived metabolites were inversely associated with psychological symptoms and were also detected in the brains of deceased individuals with a history of heavy alcohol use. Inulin supplementation during withdrawal had modest effects on fecal and plasma metabolites, with minor reductions in fecal secondary bile acids and amines and increases in plasma lipid species. These changes showed moderate correlations with gut microbiota composition. Overall, alcohol use, inulin supplementation and exercise each produced distinct effects on fecal and plasma metabolomes. The relationships between fecal and plasma metabolites were treatment- and time-specific, and not consistent across interventions.

This doctoral thesis uncovered several plasma metabolites with neuroactive potential and emphasized the role of diet and microbiota in shaping their abundance. It also demonstrated that microbiota-targeted interventions do not necessarily induce broad metabolic changes, as evidenced by the specific outcomes of inulin supplementation. Furthermore, the distinct metabolic effects of different lifestyle interventions, influenced by environmental and individual factors, may explain the inconsistent associations between fecal and plasma metabolomes. The findings highlight the importance of assessing and considering the individual variability in microbiota composition, diet, lifestyle, and health when investigating pivotal metabolites involved in the gut–brain axis communication.