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自身免疫性肝炎（AIH）是一种由针对肝细胞的自身免疫反应所介导的肝脏实质炎症，主要病理学特征为淋巴细胞、浆细胞浸润，高免疫球蛋白和自身抗体阳性等。AIH引起的急慢性肝损伤最终可导致肝纤维化、肝癌等高风险疾病从而严重威胁人类健康。因此，进一步探讨AIH发病机制，开发具有治疗AIH作用的药物及方案具有重要意义。刀豆蛋白A（ConA）是一种刀豆提取物和植物凝集素，它作为一种高效的有丝分裂原刺激物，可在小鼠中诱导AIH，是一种成熟的模型，模拟人类发生的病理变化。
FLA与AHCC的差异与相似
图1 离子色谱图
FLA提高小鼠免疫力
图3 FLA对小鼠血清指标及肝脏的影响
FLA通过BAX/BCL-2通路减轻ConA诱导的细胞凋亡
图4 FLA对ConA诱导AIH小鼠肝脏BAX和BCL-2表达的影响
图6 FLA通过Nrf2途径改善Con A诱导的小鼠肝损伤
根据各个物种在不同组别的丰度变化情况，筛选相关性大于0.1并进行斯皮尔曼相关分析构建的相关性网络图（图8a），其中排名前10的分别为Lactobacillus、unclassified_Muribaculaceae、Muribaculum、Bacteroides、Candidatus_Arthromitus、Oscillibacter、unclassified_Lachnospiraceae、Roseburia、28_4和Alloprevotella。该网络图表明小鼠肠道微生物中部分有益菌与致病菌之间存在负相关性，部分有益菌与有益菌之间存在正相关性。为进一步明确小鼠肠道微生物与肝损伤之间的关系，又分析了种水平相对丰度在前10的物种与相关因子之间的关系，结果见图8b-c，Muribaculum_intestinale的相对丰度与Nrf2、Ho-1、Bcl-2呈负相关，与S IL-6、S TNF-α、S AST、S ALT、Bax、Nf-κb、Tlr4、Traf6、Il-6、Tnf-α、Keap-1呈正相关。Lactobacillus_johnsonii、Ligilactobacillus_murinus的相对丰度与S IL-6、S TNF-α、S AST、S ALT、Bax、Nf-κb、Tlr4、Traf6、Il-6、Tnf-α、Keap-1呈负相关，与Nrf2、Ho-1、Bcl-2呈正相关。综上，FLA可能通过增加Lactobacillus_johnsonii、Ligilactobacillus_murinus的相对丰度来改善小鼠的肝脏损伤。
本研究通过液体深层发酵技术得到香菇发酵复合物（FLA），并通过Con A诱导小鼠免疫性肝损伤。在AIH的治疗研究表明，从一系列生物学指标分析，FLA具有肝保护作用。FLA保护的潜在机制可能与炎症反应的减少和肠道菌群调节的改变有关。因此，本研究的结果为开发抗AIH的有效药物提供了理论依据。
Fermented Lentinus edodes extract containing α-glucan ameliorates concanavalin A-induced autoimmune hepatitis in mice
Xin Hua,b, Dan Chengc, Yingxia Zhangc, Po Lic, Xiaoping Wua,b, Junsheng Fua,b,*
a College of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China
b Mycological Research Center, Fujian Agriculture and Forestry University, Fuzhou 350002, China
c Shanghai Lithy One-Health Group Technology Co., Ltd., Shanghai 200235, China
*Corresponding author.
Abstract
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease that threatens human health worldwide. The aim of this study was to detect the protective effect of a fermented Lentinus edodes extract containing α-glucan (FLA), in a concanavalin A (ConA)-induced AIH mouse model and to determine the underlying liver-protective mechanism. The results showed that compared with the model group, the level of proinflammatory cytokines in serum of FLA pretreated mice was significantly decreased, and the degree of inflammatory cell infiltration in liver, thymus and spleen was significantly reduced. Quantitative polymerase chain reaction, immunohistochemistry, and Western blotting showed that FLA pre-treatment inhibited the ConA-induced apoptosis of hepatocytes by down-regulating the expression of BAX and up-regulating the expression of BCL-2. Further research found that FLA may improve liver injury in mice by activating NRF2 signaling pathway and inhibiting TRAF6/NF-κB signaling pathway. Thus, FLA may improve liver injury in mice by shifting gut microbial composition to reduce the release of inflammatory cytokines in the serum and prevent the necrosis of hepatocytes. Up-regulation of NRF2 signaling pathway, down-regulation of TRAF6/NF-κB signaling pathway, and an increase in the relative abundance of Lactobacillus_johnsonii and Ligilactobacillus_murinus play a protective role in liver.
HU X, CHENG D, ZHANG Y X, et al. Fermented Lentinus edodes extract containing α-glucan ameliorates concanavalin A-induced autoimmune hepatitis in mice[J]. Food Science and Human Wellness, 2024, 13(4): 2102-2115. DOI:10.26599/FSHW.2022.9250175.
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