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

The gut microbiome plays crucial roles 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 Turicibacter-plasma cholic acid, were identified using systems genetics approaches. By integrating the human MiBioGen database, we prioritized PTPRD, PTGR1, and GABRB3 as candidate genes potentially regulating the corresponding gMxBs. The impacts of these candidates on metabolic health were demonstrated in human UK biobank, FinnGen, and million veteran program. Collectively, this study illustrates potential modulators regulating gMxBs and provides insights into gut microbiome-host communication.