Isoxanthohumol Improves Obesity and Glucose Metabolism via Regulation of Gut Barrier and Intestinal Lipid Absorption with a Bloom of Akkermansia muciniphila

Dysbiosis is an important factor that leads to metabolic disorders via disruption of the gut barrier function. A decrease in Akkermansia muciniphila (AM) is a phenotype of obesity-induced disruption of the gut barrier. Although interventions to increase AM have been reported to improve glucose metabolism, the underlying mechanism has not been fully understood. The administration of IX suppressed weight gain and steatohepatitis and improved glucose metabolism in diet-induced obese mice. Mechanistically, IX inhibited pancreatic lipase activity and lipid absorption via decreased expression of the lipid absorption transporter, CD36, in the jejunum. Moreover, IX administration improved the gut barrier function and reduced metabolic endotoxemia. In contrast, the observed effects of IX were cancelled by antibiotics and reproduced by fecal microbiota transplantation to GF mice. 16S rRNA sequencing revealed that the microbial community structure changed with a significant increase in AM in the IX-administration group. An anaerobic chamber study showed that IX promoted the growth of AM, while exhibiting antimicrobial activity against some Bacteroides and Clostridium species. To further explore the direct impact of AM on lipid and glucose metabolism in monocolonized mice, we transplanted either AM or Bacteroides thetaiotaomicron to GF mice. AM monocolonization decreased CD36 expression in the jejunum and improved glucose metabolism with decreased multiple classes of fatty acids in plasma metabolomics analysis. In summary, IX contributes to metabolic improvement by decreasing CD36 and lipid absorption in the small intestine which is associated with a bloom of AM, suggesting an important interaction between food ingredients and AM abundance in controlling metabolism. Disclosure Y.Watanabe: None. S.Fujisaka: None. S.Watanabe: None. A.Nishimura: None. T.Kado: None. M.Aslam: None. M.Bilal: None. Y.Morinaga: None. K.Tobe: Other Relationship; MSD K.K., Novo Nordisk Pharma Ltd., Takeda Pharmaceutical Company Limited, Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Suntory Global Corporation, Ltd.,, Taiho Pharmaceutical Co. Ltd., Japan Diabetes Foundation, Japan Association for Diabetes Education and Care. Funding Japan Society for the Promotion of Science (21K20896, 22K16424); Lotte Foundation; Yakult Bio-Science Foundation