Gut microbiota metabolism linked to metabolic health and cardiovascular diseases

Abstract

Positioned at the interface of nutrition and host physiology, the gut microbiota produces bioactive metabolites that modulate host lipid and glucose metabolism as well as immune function. Many of these metabolites, although produced in the gut, exert influence on physiological processes in the whole body, with an impact on host cardiometabolic health. Despite increasing associations between individual microbiome features and disease reported, mechanistic insights and ecological understanding remain limited. This thesis aimed to explore the ecology of microbial functions and host interactions relevant to cardiometabolic disease using a combination of metagenomics, metabolomics, in vitro fermentation assays, and characterization of isolates. In Paper I, we show that the ismA gene, involved in microbial cholesterol reduction to coprostanol, robustly predicts fecal cholesterol conversion and characterizes a microbiome enriched in fermentative and anti-inflammatory features, linked to favorable cardiometabolic profiles in populations at risk. In Paper II we demonstrate that microbiota individuality drives short-chain fatty acid and bile acid profiles in vitro, with a larger impact than fiber type. These results may have implications for personalized nutrition. In Paper III, we characterize three strains initially classified as Desulfovibrio piger, revealing major phenotypic and metabolic differences. These results support the designation of a novel species Desulfovibrio aggregans sp. nov. and underscore the limitations of current species-level taxonomy. Paper IV highlights the predictive power of microbiota-associated circulating metabolites for type 2 diabetes, identifying specific microbe-metabolite-host interactions that are relevant for glucose control and can be modified through lifestyle interventions. These findings emphasize the importance of acknowledging and understanding the ecological complexity and metabolic impact of the gut microbiota in cardiometabolic disease, and point towards functional, context-dependent microbial signatures as targets for diagnosis, prevention or therapy.