The overall goal of our research is to identify the mechanisms and factors/metabolite(s) by which dietary soluble fiber inulin induces hepatocellular carcinoma (HCC) in mice lacking toll-like receptor 5 (TLR5). TLR5, an innate immune receptor that senses bacterial flagellin, plays a critical role in gut microbiota homeostasis. Accordingly, TLR5 deficient mice display hallmarks of metabolic syndrome, which is absolutely microbiota dependent. This work aims to elucidate how a natural dietary component and widely used food additive drives HCC in innate immune deficient mice coupled with gut microbiotal overgrowth.
Three specific aims are proposed, each of which investigates the mechanisms by which HCC develops in mice with gut dysbiosis. The three aims are interrelated, independently achievable and address the contributions of (i) structurally different natural soluble fibers, (ii) gut microbiota, and (iii) host hepatic lipogenesis/lipolysis to the development of HCC. This proposal has potential implications for public health, given the prevalent and overuse of inulin in the food industry. Our work would elucidate the underappreciated potential detrimental effects of inulin and/or SCFAs. Further, human HCC is the sixth most common cancer and third most cause of cancer related deaths globally. The higher mortality rates in patients with HCC are due to poor and late stage diagnosis because of its heterogeneous and asymptomatic nature. This warrants a novel, hepatocarcinogen independent model to better understand human HCC. This proposal seeks to fulfill this constraint.
The long-standing notion maintains that naturally occurring dietary fibers are critical components of the human diet and offer numerous beneficial effects on gut health. Dietary fibers serve as precursors for short chain fatty acids via gut microbiotal fermentation. In our study, we observed spontaneous development of hepatocellular carcinoma (HCC) in innate immune compromised mutant mice maintained on a soluble fiber diet. Using our unique diet-induced mouse model of HCC, we have obtained evidence to suggest that gut microbiota are drivers of HCC pathogenesis. This proposal seeks to further investigate this exciting novel observation, address the potential underlying mechanisms and identify microbiotal metabolite(s) that cause HCC. The translational significance of this study is that the completion of the proposed studies will provide the necessary basis for contemplation of personalized nutritional recommendations for innate immune-compromised subjects.
| 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 |
