结直肠癌发生过程中肠道菌群与Rig-I介导的免疫调控关系及机制研究

Retinoic acid-inducible gene-I (Rig-I) is an intracellular viral RNA receptor, which specifically recognizes double-stranded viral RNA initiating antiviral innate immunity. In addition to susceptible to various RNA viruses, Rig-I knock-out mice were also found to be susceptible to spontaneous infection with a commensal bacterium, S. xylosus. Furthermore, we found that Rig-I knock-out mice were susceptible to colitis, accompanied with serious intestinal flora disorder, which was similar with human inflammatory bowel disease (IBD). These studies revealed that Rig-I played an important role not only in antiviral responses but also in antibacterial immunity and regulating the balance of intestinal microbiota. The imbalance of intestinal microbial ecosystem will break the homeostasis between host and microbes, which promotes the occurrence of IBD and colorectal cancer (CRC). So far, the mechanisms of Rig-I in modulating intestinal microbiota and progression of CRC are still unknown. Thus, this project aims to further study the regulating role of Rig-I in gut flora through high-throughput sequencing. Besides, we will use spontaneous and induced intestinal tumor mice models to study the mechanisms of Rig-I and intestinal flora in the progression of CRC, illuminating the interdependent relationship between gut flora disturbance and CRC, providing theoretical basis for microbial diagnosis and intervention therapy of colorectal cancer.

Rig-I（Retinoic acid-inducible gene-I）能够特异性识别病毒RNA，在抗病毒先天免疫中发挥重要作用。课题组研究发现Rig-I剔除小鼠除易感各种RNA病毒之外，易感染条件性致病菌、易发生结肠炎并伴有明显的肠道菌群紊乱，与人类炎症性肠病（IBD）具有类似的临床表现。提示除抗病毒作用外，Rig-I在抗细菌免疫、调节肠道菌群平衡中亦具有重要作用。研究显示，肠道微生物生态系统失调会打破宿主与微生物的稳态，促进IBD及结直肠癌（CRC）的发生。迄今为止，Rig-I在调节肠道菌群平衡及其在CRC发生发展中的作用仍未可知。为此，本研究拟在已有基础上，通过对肠道菌群进行高通量测序，进一步研究Rig-I对肠道菌群的影响，并利用自发及诱发肠癌小鼠模型，研究Rig-I及肠道菌群在CRC发生中的作用机制，明确菌群紊乱与CRC之间的依存关系，为CRC的微生物诊断及干预治疗提供理论基础。

Rig-I（Retinoic acid-inducible gene-I）能够特异性识别病毒RNA，在抗病毒先天免疫中发挥重要作用。课题组先前的研究发现Rig-I剔除小鼠除易感各种RNA病毒之外，易感染条件性致病菌、易发生结肠炎并伴有明显的肠道菌群紊乱，与人类炎症性肠病（IBD）具有类似的临床表现。提示除抗病毒作用外，Rig-I在抗细菌免疫、调节肠道菌群平衡中亦具有重要作用。另有研究显示，肠道微生物生态系统失调会打破宿主与微生物的稳态，促进IBD及结直肠癌（CRC）的发生。迄今为止，Rig-I在调节肠道菌群平衡及其在CRC发生发展中的作用仍未可知。为此，本研究在已有基础上，通过对肠道菌群进行高通量测序，进一步研究Rig-I对肠道菌群的影响，并利用自发及诱发肠癌小鼠模型，研究Rig-I及肠道菌群在CRC发生中的作用机制。我们发现，Rig-I在结直肠癌病人样本及诱导小鼠结直肠癌样本中低表达，而且Rig-I敲除小鼠更容易在AOM-DSS诱导下发生结直肠癌。进一步研究发现，Rig-I敲除小鼠肠道菌群紊乱，其肠道黏膜IgA, Reg3γ和Pdcd1表达降低。STAT3磷酸化水平在Rig-I敲除小鼠肠道及Il6处理的Rig-I沉默的1B4B6细胞系中明显降低。这说明Rig-I可通过IgA和Reg3γ调节肠道菌群，并能够抑制结直肠癌发生。该研究明确了菌群紊乱与CRC之间的关系，为CRC的微生物诊断及干预治疗提供理论基础。