Maternal obesogenic diet exposure regulates the offspring gut liver axis and fibroinflammatory liver disease

Maternal obesogenic diet exposure (MODE) promotes fibroinflammatory liver disease in offspring via vertical transfer of an altered microbiome. The mechanism for how an altered offspring microbiome increases susceptibility to liver disease is not clear. A critical early life event termed the 'weaning reaction' is dependent on the early microbiome and when altered, results in worse pathologic inflammation. MODE attenuates the weaning reaction promoting worse liver disease in mice in an early microbiome-dependent manner. Using our MODE model and cross-fostering approaches we assessed the effect of MODE on neonatal gut-liver axis development. MODE shifts the bile acid (BA) profile, expression of intestinal barrier genes, and establishment of gut immune cell populations in the offspring. Among the BA changes, UDCA is decreased in MODE offspring and supplementation with UDCA at 2 weeks of age reestablishes the weaning reaction and gut immune cell development. MODE offspring exhibit worse hepatic inflammation and fibrosis during dextran sodium sulfate induced colitis. These findings identify that MODE alters early gut immune programming events in offspring intestine with modifications in BA metabolism. Supplementing MODE offspring with secondary BAs may be an approach to restore the weaning reaction and immune cell populations.