Interplay between Dietary Fiber and Gut Microbiota in Hepatocellular Carcinoma

项目摘要 我们研究的总体目标是确定机制和因素/代谢物(S) 膳食中可溶性纤维菊粉诱导小鼠肝细胞癌的作用 缺乏Toll样受体5(TLR5)。TLR5，一种先天免疫受体，感觉 细菌鞭毛蛋白在肠道微生物区系动态平衡中起着关键作用。因此，TLR5 缺陷小鼠表现出代谢综合征的特征，这绝对是微生物区系 依附的。这项工作旨在阐明一种天然的饮食成分和广泛的 食品添加剂在先天性免疫缺陷小鼠肝细胞癌中的作用 微生物过度生长。提出了三个具体目标，每个目标都进行了调查 肠道生物失调小鼠发生肝细胞癌的机制。这三个目标是 相互关联、可独立实现，并在结构上解决(I)的贡献 不同的天然可溶性纤维，(Ii)肠道微生物区系，和(Iii)宿主肝脏 脂肪生成/脂解作用与肝细胞癌的发展 这项提议对公共卫生有潜在的影响，因为普遍存在和 食品工业中菊粉的过度使用。我们的工作将阐明那些被低估的人 菊粉和/或短链脂肪酸的潜在有害影响。此外，人类肝细胞癌是第六种 这是全球最常见的癌症，也是导致癌症相关死亡的第三大原因。越高 肝癌患者的死亡率是由于诊断不佳和晚期，因为 它的异质性和无症状的性质。这证明了一种新的致癌物质--肝癌 独立模型，以更好地了解人类肝细胞癌。这项建议旨在实现这一点 约束。

Project Summary 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.