Isoxanthohumol improves obesity and glucose metabolism via inhibiting intestinal lipid absorption with a bloom ofAkkermansia muciniphilain mice

Abstract

AbstractAimsDysbiosis is an important factor that leads to metabolic disorders by disrupting energy balance and insulin sensitivity. A decrease inAkkermansia muciniphilais a phenotype of obesity-induced dysbiosis. Although interventions to increaseA. muciniphilaare expected to improve glucose metabolism, the underlying mechanism has not been fully understood.MethodsIsoxanthohumol (IX), a prenylated flavonoid found in beer hops was administered to high fat diet-fed mice. We analyzed glucose metabolism, gene expression profiles and histology of liver, epididymal adipose tissue and colon. Lipase activity, fecal lipid profiles and plasma metabolomic analysis were assessed. Fecal 16s rRNA sequencing was obtained and selected bacterial species were used for in vitro studies. Fecal microbiota transplantation and monocolonization were conducted to antibiotic-treated or germ-free (GF) mice.ResultsThe administration of IX lowered weight gain, decreased steatohepatitis and improved glucose metabolism. Mechanistically, IX inhibited pancreatic lipase activity and lipid absorption by decreasing the expression of the fatty acid transporter CD36 in the small intestine, which was confirmed by increased lipid excretion in feces. IX administration improved the gut barrier function and reduced metabolic endotoxemia. In contrast, the effects of IX were nullified by antibiotics. As revealed using 16S rRNA sequencing, the microbial community structure changed with a significant increase in the abundance ofA. muciniphilain the IX-treated group. An anaerobic chamber study showed that IX selectively promoted the growth ofA. muciniphilawhile exhibiting antimicrobial activity against someBacteroidesandClostridiumspecies. To further explore the direct effect ofA. muciniphilaon lipid and glucose metabolism, we monocolonized eitherA. muciniphilaorBacteroides thetaiotaomicronto GF mice.A. muciniphilamonocolonization decreased CD36 expression in the jejunum and improved glucose metabolism, with decreased levels of multiple classes of fatty acids determined using plasma metabolomic analysis.ConclusionOur study confirmed a direct role ofA. muciniphilain energy metabolism, which was induced by microbial actions of IX. These highlight new treatment strategies for preventing metabolic syndrome by boosting the gut microbiota with food components.