Metaorganismal perspective on cardiometabolic diseases

Abstract

The gut microbiota is increasingly recognized as an important factor affecting host health, with alterations linked to the development of cardiometabolic diseases. This thesis investigates how gut microbial composition and function relate to early stages of metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiovascular disease across multiple human cohorts. In paper I, we identified distinct gut microbiota profiles in individuals with liver steatosis from three independent cohorts, characterized by reduced microbial gene richness and depletion of butyrate-producing taxa, together with enrichment of oral and small-intestinal origin opportunistic pathogens such as Fusobacterium nucleatum and Klebsiella oxytoca. These alterations were intrinsic to early MASLD and not just a consequence of obesity. In paper II, we demonstrated, using fecal metagenomics and plasma metabolomics, that different gut microbiome compositions are linked to distinct epicardial adipose tissue (EAT) traits, with EAT volume (EATV) reflecting general adiposity-related microbes and EAT attenuation (EATA) showing independent associations with specific taxa and metabolites. Notably, low EATA, indicative of denser and inflamed EAT, was associated with microbiome signatures previously implicated in coronary artery disease and systemic inflammation. In paper III, we characterized the gut microbiome as a contributor to atherosclerosis progression through purine metabolism, via a conserved gene cluster. Colonization experiments in germ-free mice confirmed that these bacteria modulate systemic purine and uric acid levels, indicating that microbial purine degradation is a key pathway through which the gut microbiome can influence risk of atherosclerosis. These findings underscore a significant role of the gut microbiome in regulation of cardiometabolic health and thus can be potential targets for preventive strategies in cardiometabolic diseases.