Parent R01 Abstract The parental R01 grant discussed the novel interplay among dietary fermentable fibers, host gut microbiota/metabolites, and host innate immunity in the progression of hepatocellular carcinoma (HCC; most common liver malignancy). Natural dietary fibers consist of fermentable fibers that are metabolized by the gut microbiota (GM) into short chain fatty acids (SCFAs) and insoluble fibers that aid in roughage. In particular, SCFAs have been attributed to alleviating metabolic syndrome (i.e. obesity), which has made dietary fermentable fibers (e.g. inulin, pectin) a target for food industries. This includes making them commercially available as both a prebiotic and a supplemental fiber source in processed foods. Based on this notion, we believed that supplementing a fermentable fiber diet could alleviate the metabolic syndrome exhibited in Toll- like receptor 5 deficient mice (Tlr5KO; innate immune receptor responsible in recognizing bacterial flagellin and maintaining GM homeostasis). Upon feeding an inulin-containing diet (ICD) diet, we observed that ~40% of Tlr5KO mice were protected from metabolic syndrome. Alarmingly, however, this subset of Tlr5KO mice developed indices of cholestasis such as hyperbilirubinemia and cholemia, which subsequently lead to the 100% guaranteed development of multinodular HCC, characterized by hepatic ballooning/adipoma, within 6 months (Singh et al., Cell 2018). Histological analysis of the livers in hyperbilirubinemic (H-bili) Tlr5KO mice further revealed hyperplasia, immune cell infiltration, necrosis and steatosis, which was absent in wild- type (WT) and low bilirubin (L-bili) Tlr5KO mice. Interestingly, Tlr5KO mice maintained on a 100% non-fermentable fiber diet (i.e. cellulose) were protected from HCC. To further determine the influence of fermentable fibers on HCC development, in specific aim 1 we will employ alternative fermentable fibers (i.e. guar guam, carrageenan) and monitor for HCC progression. Completion of this aim will further support our hypothesis that the beneficial effects of dietary fermentable fibers are contingent on the GM status of an organism. Alongside, due to the presence of hepatic steatosis in susceptible Tlr5KO mice, we strive in specific aim 3 to determine the role of lipogenic and lipolytic enzymes in the process of HCC development. In particular, we will target stearoyl- CoA desaturase-1 (SCD1) and phospholipase D1 (PLD1), where we believe that deletion of either enzyme will confer protection in Tlr5KO mice. Overall, completion of this proposal should not only unravel the contributory role of fermentable fibers in HCC development, but also provide therapeutic targets that can reduce the risk of liver cancer pathogenesis.
This project aims to delineate the role of dietary fermentable fibers and hepatic lipid metabolism in the development of hepatocellular carcinoma (HCC). The objectives of this proposal are consistent with the goals outlined in the funded parental R01 grant titled ?Interplay between Dietary Fiber and Gut Microbiota in Hepatocellular Carcinoma? and meet the requirements for Research Supplements to Promote Diversity in Health-Related Research (PA- 18-906). The data generated from this project will provide a better understanding in detail to the role of fermentable fibers in HCC development and provide potential therapeutic targets for its treatment.
|Singh, Vishal; Yeoh, Beng San; Chassaing, Benoit et al. (2018) Dysregulated Microbial Fermentation of Soluble Fiber Induces Cholestatic Liver Cancer. Cell 175:679-694.e22|