Genetic and dietary determinants of gut microbiome-bile acid interactions in the BXD recombinant inbred mouse population

The gut microbiome is crucial in regulating overall physiology and communicates with the host through various microbial-derived metabolites, including secondary bile acids (BAs). However, mechanisms underlying the gut microbiome-BA crosstalk (gMxB) are still poorly understood. Here, we assessed the postprandial cecal microbiome, BA levels, and colon transcriptome of a genetically diverse population of 32 BXD mouse strains fed with a chow or high-fat diet, and found that genetic and dietary factors shift microbiome composition and gMxBs. Four diet-dependent co-mapping genetic loci associated with gMxBs, such as the interaction between Turicibacter -plasma cholic acid, were identified using systems genetics approaches. By integrating human MiBioGen database, we prioritized PTGR1 , PTPRD , and GABRB3 as candidate genes potentially regulating gMxBs. The human relevance of these candidates on metabolic health was demonstrated using the UK biobank, FinnGen, and million veteran program. Overall, this study illustrates potential modulators regulating gMxBs and provides insights into gut microbiome-host communication.