肠道菌群-TLR5-IL-6在肝癌中的作用及机制研究

Gut microbiota play a vital role in tumorigenesis and progression by influencing tumor microenvironment (TME), however, the detailed mechanisms and functions exerted by gut mucosal immunity, which always has the most convenient access to enteric bacteria, still need many more investigations. TLR5 is a crucial pattern recognition receptor in gut immunity, mainly distributed among dendritic cells, and can be specially activated by the commensal bacteria derived flagellin. In our previous research, RNomics data from TCGA suggested a positive correlation between Tlr5 and hepatocarcinogenesis and also a worse survival. Animal experiments further verified that hepatocellular carcinoma (HCC) progressed significantly faster in Tlr5 competent mice, with more MDSC mobilization in TME and peripheral circulation and systemic IL-6 elevation, compared with Tlr5 knockout mice, and IL-6 is an important factor to mobilize MDSC. What’s more, CD11c+MHCII+LPDCs (Lamina Propria Dendritic cells) are reported to specifically highly express TLR5, and secret plentiful IL-6 after activation. So, this project plans to validate the potentially positive significance of gut microbiota-TLR5 in HCC by Tlr5 conditional knockout mouse and multiple HCC models. Then the association with IL-6 and its mediated massive mobilization and activation of MDSCs are to be confirmed. Finally, the bridge role of CD11c+MHCII+LPDCs in the axis of gut microbiota-TLR5-IL-6 is to be explored. And our results are expected to achieve clinical translation, so as to provide novel scientific clues for efficiently controlling HCC development by interfering with flagellated bacteria.

肠道菌群能通过影响肿瘤微环境而参与肿瘤的发生发展，但具体机制及肠道免疫在其中的作用尚缺乏深入研究。TLR5是肠道免疫中的重要受体，主要分布于树突状细胞，能被菌群的鞭毛蛋白特异性激活。我们在前期研究中通过TCGA RNA组学数据证实Tlr5与肝癌的发生及患者更差的预后正相关。动物实验发现，Tlr5+/+小鼠肝癌生长更快，肿瘤微环境及外周MDSC数目更多，血清IL-6更高，而IL-6是募集激活MDSC的重要分子。此外，CD11c+MHCII+LPDC（肠道黏膜固有层树突状细胞）能特异性高表达TLR5，在鞭毛蛋白刺激下大量分泌IL-6。故本项目拟通过Tlr5条件性敲除小鼠及多种肝癌模型验证肠道菌群-TLR5在肝癌中的正性调控作用，明确其与IL-6升高、继而MDSC募集增加的相关性，探索LPDC在该通路中的桥梁作用。研究结果有望实现临床转化，为通过干预肠道菌群有效控制肝癌等策略提供新的科学依据。

肠道菌群能通过影响肿瘤微环境而参与肿瘤的发生发展，但具体机制及肠道免疫在其中的作用尚缺乏深入研究。TLR5是肠道免疫中的重要受体，主要分布于树突状细胞，能被菌群的鞭毛蛋白特异性激活。我们在前期研究中，通过TCGA RNA组学数据证实Tlr5与肝癌的发生及患者更差的预后正相关。并在动物实验中发现，Tlr5+/+小鼠肝癌生长更快，肿瘤微环境及外周MDSC数目更多，血清IL-6更高，而IL-6是募集激活MDSC的重要分子。此外，CD11c+MHCII+LPDC（肠道黏膜固有层树突状细胞）能特异性高表达TLR5，在鞭毛蛋白刺激下大量分泌IL-6。因此，本项目通过Tlr5条件性基因敲除小鼠及多种肝癌模型验证了肠道菌群-TLR5在肝癌中的正性调控作用，基本明确了其与IL-6升高、继而MDSC募集增加的相关性；并初步探索了LPDC在该通路中的桥梁作用，肠道菌群鞭毛蛋白通过刺激LPDCs分泌IL-6继而募集MDSC，鞭毛蛋白本身对MDSC没有直接作用；更进一步发现了TLR5对肠道稳态的维护可能是通过分泌抗菌肽RegIIIγ实现的。研究结果有望实现临床转化，为通过干预肠道菌群有效控制肝癌等策略提供新的科学依据。