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 assess the postprandial cecal microbiome, BA levels, and colon transcriptome of male BXD mice fed with a chow or high-fat diet, and find that genetic and dietary factors shift microbiome composition and affect gMxB. Four diet-dependent co-mapping genetic loci associated with gMxB, including the interaction between Turicibacter sanguinis - plasma cholic acid, are identified using systems genetics approaches. By integrating human MiBioGen database, we prioritize PTGR1 and PTPRD as candidate genes potentially regulating identified gMxB. The human relevance of these candidates on metabolic health is investigated using data from the UK biobank, FinnGen, and million veteran program databases. Overall, this study illustrates potential modulators regulating gMxB and provides insights into gut microbiome-host communication.