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子/代谢物 可溶性纤维菊糖诱发小鼠肝细胞癌 缺乏Toll样受体5（TLR 5）。TLR 5是一种先天免疫受体， 细菌鞭毛蛋白在肠道微生物群稳态中起关键作用。TLR5 缺陷小鼠表现出代谢综合征的特征， 依赖。这项工作的目的是阐明如何一种天然的饮食成分， 使用的食品添加剂在先天性免疫缺陷小鼠中驱动HCC， 微生物过度生长提出了三个具体目标，每个目标都调查 肝细胞癌在肠道生态失调的小鼠中发展的机制。这三个目标是 相互关联、独立可实现，并解决以下方面的贡献：（i）结构 不同的天然可溶性纤维，（ii）肠道微生物群，和（iii）宿主肝脏 脂肪生成/脂肪分解对HCC的发展的影响。 这项建议对公共卫生有潜在的影响， 菊粉在食品工业中的过度使用。我们的工作将阐明 菊粉和/或SCFA的潜在有害作用。此外，人类HCC是第六个 是全球最常见的癌症和第三大癌症相关死亡原因。越高 HCC患者的死亡率是由于诊断不佳和晚期， 其异质性和无症状性。这证明了一种新的肝癌原 独立模型，以更好地了解人类HCC。该提案旨在实现这一目标。 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.