Advanced Preventive Medical Sciences Research Center, Kanazawa University, Kanazawa, Japan.
Division of Health Sciences, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
J Endocrinol. 2020 Nov;247(2):169-181. doi: 10.1530/JOE-20-0105.
Intestinal mucosal barrier dysfunction is closely related to the pathogenesis of nonalcoholic steatohepatitis (NASH). Gut immunity has been recently demonstrated to regulate gut barrier function. The Lactobacillus pentosus strain S-PT84 activates helper T cells and natural killer/natural killer T cells. In this study, we examined the effect of S-PT84 on NASH progression induced by high-cholesterol/high-fat diet (CL), focusing on the immune responses involved in gut barrier function. C57BL/6 mice were fed a normal chow or CL diet with or without 1 × 1010 S-PT84 for 22 weeks. S-PT84 administration improved hepatic steatosis by decreasing triglyceride and free fatty acid levels by 34% and 37%, respectively. Furthermore, S-PT84 inhibited the development of hepatic inflammation and fibrosis, suppressed F4/80+ macrophage/Kupffer cell infiltration, and reduced liver hydroxyproline content. Administration of S-PT84 alleviated hyperinsulinemia and enhanced hepatic insulin signalling. Compared with mice fed CL diet, mice fed CL+S-PT84 had 71% more CD11c-CD206+ M2 macrophages, resulting in a significantly decreased M1/M2 macrophage ratio in the liver. Moreover, S-PT84 inhibited the CL diet-mediated increase in intestinal permeability. Additionally, S-PT84 reduced the recruitment of interleukin-17-producing T cells and increased the levels of intestinal tight junction proteins, including zonula occludens-1, occludin, claudin-3, and claudin-7. In conclusion, our findings suggest that S-PT84 attenuates diet-induced insulin resistance and subsequent NASH development by maintaining gut permeability. Thus, S-PT84 represents a feasible approach to prevent the development of NASH.
肠黏膜屏障功能障碍与非酒精性脂肪性肝炎（NASH）的发病机制密切相关。肠道免疫最近被证明可以调节肠道屏障功能。戊糖片球菌 S-PT84 株激活辅助性 T 细胞和自然杀伤细胞/自然杀伤 T 细胞。在这项研究中，我们研究了 S-PT84 对高胆固醇/高脂肪饮食（CL）诱导的 NASH 进展的影响，重点关注涉及肠道屏障功能的免疫反应。C57BL/6 小鼠喂食正常饲料或 CL 饲料，或在 CL 饲料中添加 1×1010 S-PT84，持续 22 周。S-PT84 给药通过降低甘油三酯和游离脂肪酸水平分别降低 34%和 37%，从而改善肝脂肪变性。此外，S-PT84 抑制肝炎症和纤维化的发展，抑制 F4/80+巨噬细胞/枯否细胞浸润，并降低肝羟脯氨酸含量。S-PT84 给药缓解高胰岛素血症并增强肝脏胰岛素信号。与喂食 CL 饮食的小鼠相比，喂食 CL+S-PT84 的小鼠的 CD11c-CD206+M2 巨噬细胞增加了 71%，导致肝脏中 M1/M2 巨噬细胞比值显著降低。此外，S-PT84 抑制 CL 饮食介导的肠道通透性增加。此外，S-PT84 减少了白细胞介素-17 产生 T 细胞的募集，并增加了肠道紧密连接蛋白的水平，包括紧密连接蛋白-1、occludin、claudin-3 和 claudin-7。总之，我们的研究结果表明，S-PT84 通过维持肠道通透性来减轻饮食诱导的胰岛素抵抗和随后的 NASH 发展。因此，S-PT84 代表了一种预防 NASH 发展的可行方法。
