F. prausnitzii在Treg介导的肝移植免疫调控中的作用及分子机制

Acute rejection(AR) remains a life-threatening complication after orthotopic liver transplantation (OLT). Regulatory T cells (Treg) play important role in the promotion of transplant tolerance after liver transplantation. Studies have shown that the dysbiosis of gut microbiota is closely associated with AR and intestinal microbial variation may predict AR in early phase. Faecalibacterium prausnitzii (F.prausnitzii) was proved have anti-inflammatory and immunomodulatory capacity, and it can induce Treg production and immunosuppressive function. Our previous preliminary studies also show that F.prausnitzii has the potential immunomodulatory and protective effects for intestinal barrier, and it decreased during AR. However, its specific role and mechanisms of immunomodulatory during AR remain unclear, whether it by regulating the expression of NFAT in Tregs and NFAT-mediated signaling transduction pathways are still unknown. The aim of our present study is to explore the effects of F.prausnitzii on the restoration of intestinal barrier and Treg mediated immunomodulatory in animal AR models after OLT. And we also try to understand the role of F. prausnitzii on the expression of key protein and inflammatory cytokines in the NFAT related signaling transduction pathways in Tregs. According to the study, we will understand the specific mechanisms of F. prausnitzii in the Treg mediated immunomodulatory during AR after OLT in a deeper level, which will reveal the role of F. prausnitzii in the development of AR and provide a scientific basis for the prevention and immune reconstruction of AR.

急性排斥反应(AR)是影响肝移植成功与否的重要因素，Treg在肝移植免疫耐受中发挥重要作用。证据显示肠道菌群失衡与移植后AR的发生发展密切相关，肠道菌群变化可预测AR的发生，普氏栖粪杆菌(Fp)具有显著抗炎活性及免疫调节活性，诱导Treg细胞生成并增强其免疫抑制功能，为AR发生发展中的潜在关键功能菌。本课题组预实验发现AR发生过程中Fp显著减少，Fp具有潜在肠道黏膜保护及免疫调节功能，但其在肝移植AR过程中的免疫调控作用及机制仍不明确，其是否通过调控Treg细胞NFAT信号转导通路发挥作用尚不可知。本课题拟采用Fp干预肝移植急性排斥大鼠模型，从肠道黏膜屏障和机体免疫方面观察Fp在Treg介导的肝移植免疫调控中的作用，观察Treg细胞NFAT相关信号通路调控因子和下游产物的表达差异，明确Fp在Treg介导的肝移植免疫调控中的分子机制。为重建肝移植后免疫、预防肝移植后急性排斥反应提供新思路。

普氏栖粪杆菌(Fp)具有显著抗炎活性及免疫调节活性，为AR发生发展中的潜在关键功能菌，在肝移植AR过程中的免疫调控作用及机制仍不明确。本课题拟采用Fp干预肝移植急性排斥大鼠模型，从肠道黏膜屏障和机体免疫方面观察Fp在肝移植免疫调控中的作用，明确Fp在Treg介导的肝移植免疫调控中的分子机制。方法：利用异基因肝移植大鼠构建急性排斥动物模型，应用Fp进行干预，观察肝移植后大鼠肠道菌群结构变化、肠道屏障功能、肝脏损伤及Treg相关免疫变化。结果：Fp菌体组肝脏炎性病变明显减轻，Fp 对肠道黏膜机械屏障具有保护作用，各组回肠结肠及粪便菌群各组组成及丰度有显著差异，但不同部位肠道菌群变化有所差异，而三组间外周血及肠道淋巴结Treg细胞及其下游炎症因子无明显差异。结论：Fp 对肝移植急性排斥大鼠肠道微生物屏障、机械屏障均有保护作用，是潜在的调节免疫排斥的菌株，Fp 可能通过其他通路发挥作用。