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Yuriko Sakai, Hideyuki Arie, Yinhua Ni, Fen Zhuge, Liang Xu, Guanliang Chen, Naoto Nagata, Takuya Suzuki, Shuichi Kaneko, Tsuguhito Ota, and Mayumi Nagashimada

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.