SAT018 Investigate If Sex Differences In Microbiota Is Sufficient To Promote Bile Acid-Mediated Hepatocellular Carcinoma In Mice

Abstract

Abstract Disclosure: A.E. Dean: None. S. Anakk: None. Liver cancer is one of the leading causes of cancer-related deaths with men having a higher prevalence than women. It is becoming clearer that changes in bile acid levels are seen in patients diagnosed with liver cancer. Although initially made in the liver, these primary bile acids can also be modified by bacteria in the intestines to form secondary bile acids. The secondary bile acids are more hydrophobic and cytotoxic and when in excess, can promote tumorigenesis. We, therefore, examined if microbial differences between males and females explain sex-dependent HCC development when bile acid metabolism is altered. In this study, we used a mouse model of bile acid excess and HCC, where the bile acid-related nuclear receptors, farnesoid X receptor (Fxr) and small heterodimer partner (Shp), are knocked out. This double knockout (DKO) model mimics the cancer incidence observed in humans, where male mice are more susceptible to spontaneous tumorigenesis than females at 12 months of age. The circulating bile acid profiles of the male DKO mice are more hydrophobic and have a greater proportion of secondary bile acids than the females. Since we observed changes in the bile acid composition, we next investigated if fecal and cecal microbial profiles of male and female DKO mice differed, along with their wild-type counterparts. 16s rRNA full-length sequencing was performed on fecal and cecal samples from 12-month-old mice, and analyses are currently ongoing. We expect that the microbes identified in the male DKO mice will reflect their bile acid compositions, as well as spontaneous tumorigenesis. Additionally, we are analyzing the 16s rRNA gene from mice treated with cholestyramine (CHR), a bile acid binding resin, that exhibit decreased tumorigenesis at 12 months of age. In this manner, we can correlate microbiota changes to the bile acid composition, as well as the extent of tumor burden. Thus, this study will be able to integrate how sex differences in liver cancer incidence can be secondary to microbial modification of bile acids. Presentation: Saturday, June 17, 2023