Bile acids at the intersection of the gut microbiome and metabolome in metabolic health and disease

Bile acids are synthesized in the liver and act as detergents for dietary fat absorption. The intestinal microbiome metabolizes primary bile acids to secondary bile acids, which can impact host metabolism. Bile acids act in a variety of metabolic processes involving glucose, fat and energy homeostasis. The interplay of bile acids and metabolic diseases has gained importance in recent years, with a variety of studies investigating the relationship with sometimes diverging results. The knowledge obtained from our large cross-sectional study adds to the discussion of BA alterations in metabolic diseases. In our subset of the FoCus Cohort with 492 subjects, we compared nine BA species and total BAs in a comprehensive characterization of our participants regarding their phenotypes, lifestyle, medical history, biomarkers, microbiome and metabolome. We could show that both prediabetes and diabetes were associated with distinct alterations in BA concentration and composition, while obesity was not independently associated. Impaired glycemic control led to increased circulating bile acids, a shift toward more secondary bile acids, and an increase in the ratio of glycine to taurine conjugation. Additional analyses revealed that the ratio of glycine to taurine conjugation demonstrated variations between the single bile acids cholic acid, chenodeoxycholic acid and deoxycholic acid, regardless of the metabolic status, with C having a higher fraction of taurine conjugation. Furthermore, we observed correlations between bile acids and the waist-to-hip-ratio, inflammatory markers and triglycerides. In addition to diabetes mellitus, especially cardiac diseases and malignancies were associated with BAs in our cohort. High circulating BAs resulted in dysbiosis, while the analysis of the community metabolism allowed fascinating new insights into the interplay of BAs and the microbiome. We uncovered that processes involving bacterial membrane synthesis were upregulated in patients with high circulating BAs. There was high concordance between polyamine metabolism and BAs. Notably, our serum metabolome analysis mirrored several of the previously in silico predicted exchanged metabolites, especially branched chain amino acid metabolism. We could show that BAs are highly involved in metabolic diseases.