State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Jinan Microecological Biomedicine Shandong Laboratory, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China.
Gut Microbes. 2023 Jan-Dec;15(1):2221485. doi: 10.1080/19490976.2023.2221485.
Current evidence indicates that the next-generation probiotic () has therapeutic potential for nonalcoholic fatty liver disease (NAFLD), especially its inflammatory stage known as nonalcoholic steatohepatitis (NASH). However, the mechanisms of in NASH prevention remain unknown. Here, supplementation prevented hepatic inflammation in high-fat diet-induced NASH mice, characterized by reduced hepatic proinflammatory macrophages (M1) and γδT and γδT17 cells. Consistently, hepatic M1 and γδT cells were enriched in biopsy-proven NASH patients and high-fat/high-carbohydrate diet-induced NASH mice. Antibiotics reduced hepatic M1, γδT and γδT17 cells in NASH mice. Furthermore, inhibited intestinal barrier disruption and accordingly downregulated hepatic Toll-like receptor 2 (TLR2) expression in NASH mice. The activation of TLR2 by lipoteichoic acid enriched hepatic γδT17 cells (not M1) in normal diet-fed mice and neutralized the γδT cell-lowering and liver inflammation-protecting effects of in NASH mice. Additionally, activated γδT cells could promote macrophage polarization via IL-17. Our study first supported that prevented NASH by modulating TLR2-activated γδT17 cells and further macrophage polarization, facilitating clinical therapeutic applications.
目前的证据表明，新一代益生菌（）对非酒精性脂肪性肝病（NAFLD）具有治疗潜力，特别是对其炎症阶段，即非酒精性脂肪性肝炎（NASH）。然而，预防 NASH 中 作用的确切机制仍不清楚。在这里，补充 可预防高脂肪饮食诱导的 NASH 小鼠的肝炎症，其特征是肝促炎巨噬细胞（M1）和 γδT 和 γδT17 细胞减少。一致地，活检证实的 NASH 患者和高脂肪/高碳水化合物饮食诱导的 NASH 小鼠中富含肝 M1 和 γδT 细胞。抗生素可减少 NASH 小鼠的肝 M1、γδT 和 γδT17 细胞。此外，通过抑制肠道屏障破坏， 下调了 NASH 小鼠肝 Toll 样受体 2（TLR2）的表达。脂磷壁酸激活 TLR2 可在正常饮食喂养的小鼠中富集肝 γδT17 细胞（而非 M1），并中和 对 NASH 小鼠的 γδT 细胞减少和肝脏炎症保护作用。此外，激活的 γδT 细胞可通过 IL-17 促进巨噬细胞极化。我们的研究首次支持，通过调节 TLR2 激活的 γδT17 细胞和进一步的巨噬细胞极化， 可预防 NASH，从而促进临床治疗应用。
