MON-251 Maternal Obesogenic Diet Exposure Programs Offspring Gut Liver Axis

Abstract Disclosure: H. Hinrichs: None. N. Ramavath: None. M. Young: None. F. Ramirez Victorino: None. T.M. Bigley: None. M.D. Thompson: None. Introduction/BackgroundMaternal obesogenic diet exposure (MODE) promotes worse steatotic liver disease (SLD) in offspring. One mechanism of transmission is via vertical transfer of an altered microbiome to offspring, but the mechanism for how an altered offspring microbiome increases susceptibility to SLD 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. We have shown that MODE attenuates the weaning reaction promoting worse SLD in mice in an early microbiome-dependent manner. We sought to define a potential intermediate between the early microbiome changes and attenuation of weaning reaction.Materials and MethodsBeginning at four weeks of age, female mice were fed either chow (CON) or high fat, fructose, cholesterol (HFFC) diet for 6 weeks before being bred with lean males. For cross-foster studies, offspring were switched between CON and HFFC dams within 24 hours of birth. Mice were gavaged with ursodeoxycholic acid (UDCA) daily between 2 and 3 weeks of age to assess the role of UDCA supplementation in the weaning reaction and immune cell development. Tissues were collected from offspring between 2 and 4 weeks of age. Ileal expression of Tnfa and Ifng was measured. Histology was performed on liver to assess inflammation and proliferation. BAs in liver and cecal contents were measured via mass spectrometry. Flow cytometry was performed on ileum at 4 weeks of age.ResultsBA profiling on 3-week-old cecal contents and liver identified an increase in abundance of tauro- and glycine- conjugated primary BAs and a decrease in the abundance of secondary BAs (UDCA) in HFFC offspring. Cross fostering shows that shifts in BAs are dependent on the fostering dam diet. HFFC offspring exhibit increased hepatocyte proliferation and hepatic inflammation in the perinatal period that is dependent on the fostering dam diet. HFFC offspring had a reduction in CD45+ lymphocytes and CD4+Foxp3+ regulatory T cells in the ileum. UDCA supplementation reestablished the weaning reaction and increased CD45+ lymphocytes and CD4+Foxp3+ regulatory T cells in the ileum of HFFC offspring.ConclusionsThese findings identify that that MODE alters early gut immune programming events in offspring intestine with modifications in BA metabolism. Supplementing MODE offspring with secondary BAs like UDCA may be an approach to restore the weaning reaction and immune cell populations. Presentation: Monday, July 14, 2025