BAAT gene knockout alters early life development and the gut microbiome and reveals unusual bile acids in mice.

Bile acids (BAs) are steroid detergents in bile that contribute to fat absorption, cell signaling, and microbiome interactions. The final step in their synthesis is amino acid conjugation with either glycine or taurine in the liver by the enzyme bile acid-CoA:amino acid N-acyltransferase (BAAT). Here, we describe the microbial, chemical, and physiological consequences of BAAT gene deletion in mice. BAAT mice were underweight after weaning but quickly exhibited catch-up growth. At 3-weeks-of-age, KO animals had increased phospholipid excretion and decreased subcutaneous fat pad mass, liver mass, glycogen staining in hepatocytes, and vitamin A stores in the liver, but these were less marked in adulthood. Additionally, KO mice had an altered microbiome, but mostly in early life. Their BA pool was highly enriched in cholic acid (CA) but not completely devoid of conjugated BAs. KO animals had 27-fold lower taurine-conjugated BAs than wildtype in their liver, but similar concentrations of glycine-conjugated BAs and higher microbially-conjugated BAs. Furthermore, the BA pool in BAAT was enriched in a variety of unusual bile acids that were putatively sourced from cysteamine conjugation with subsequent oxidation and methylation of the sulfur group to mimic taurine. Antibiotic treatment of KO mice indicated the microbiome was not the likely source of the unusual conjugations, instead, the unique BAs in KO animals were likely derived from the peroxisomal acyltransferases ACNAT1 and ACNAT2, which are duplications of BAAT in the mouse genome, but inactivated in humans. This study demonstrates that BA conjugation is important for early life development of mice.