Bofutsushosan Improves Gut Barrier Function with a Bloom of Akkermansia Muciniphila and Improves Glucose Metabolism in Diet-Induced Obese Mice

Abstract

Bofutsushosan (BFT), an oriental herbal medicine, has been clinically used for obese patients. To explore the impact of BFT on glucose metabolism, male C57BL6 mice were fed on high-fat diet (HFD) for 12 weeks and administered either BFT (25 mg /day) or saline for the last 8 weeks. Oral glucose tolerance test and insulin tolerance test revealed improved glucose metabolism with improved insulin sensitivity in BFT treated mice, which was associated with decreased inflammatory gene expressions and improved insulin signaling in the adipose tissue. Whereas the weight of liver and adipose tissue was not changed, cecum weight was significantly increased by BFT. 16S rRNA sequence analysis of fecal samples showed that microbial composition was markedly changed. BFT reduced the relative abundance of Bacteroidetes from 52% to 34%, whereas it increased Verrucomicrobia from 3.4% to 24%. An increase in Verrucomicrobia was mainly associated with Akkermansia mucuniphila (Akk). The bloom of Akk was observed at one week of BFT treatment. Consistent with the previous reports that Akk improves gut barrier function and prevents from metabolic endotoxemia in obese subjects, BFT decreased the gut permeability as assessed by FITC-dextran gavage assay, which was associated with increased claudin-1 protein in the colon. Furthermore, plasma endotoxin level and hepatic lipopolysaccharide binding protein expression were significantly decreased in BFT group. Antibiotic treatment canceled the metabolic effect of BFT. Moreover, when the gut microbiota of BFT-treated mice were transferred to HFD-fed mice, glucose metabolism was significantly improved with decreased diet -induced inflammation with AKK bloom. These data demonstrate that BFT increases Akk in the gut, which may contribute to improving gut barrier function and preventing metabolic endotoxemia, leading to improved diet-induced inflammation, thereby controlling glucose metabolism. Disclosure S. Fujisaka: Research Support; Self; Mochida Pharmaceutical Co., Ltd., Eli Lilly and Company, MSD K.K., Toyama First Bank. I. Usui: None. A. Nawaz: Research Support; Spouse/Partner; Kobayashi Foundation, Kobayashi Foundation, Kobayashi Foundation. Y. Igarashi: None. T. Kado: None. K. Okabe: None. K. Yagi: None. T. Nakagawa: None. K. Tobe: Research Support; Self; Bristol-Myers Squibb Company, Takeda Pharmaceutical Company, Teijin Pharma Limited, Japan Diabetes Society, Eli Lilly and Company, MSD K.K., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Pfizer Inc., Astellas Parma Inc, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Company, Limited, Novo Nordisk Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Tsumura & Co., Ono Pharmaceutical Co., Ltd., Novartis Pharma K.K., Sumitomo Dainippon Pharma Co.