An increasing amount of evidence suggests that the delayed effect of antibiotics (abx) on gut microbiota after its cessation is not as favorable as its immediate effect on host metabolism. However, it is not known how the diverse abx-dependent metabolic effects influence diabetic subjects and how gut microbiota is involved. Here, we treated db/db mice with abx cocktail for 12 days and discontinued for 24 days. We found that db/db mice showed decreased body weight and blood glucose after abx treatment, which rapidly caught up after abx cessation. Twenty-four days after abx withdrawal, db/db mice exhibit increased plasma, hepatic total cholesterol (TC) levels and liver weight. The gut microbiota composition at that time showed decreased relative abundances (RAs) of Desulfovibrionaceae and Rikenellaceae, increased RA of Erysipelotrichaceae and Mogibacteriaceae, which were correlating with the reduced short-chain fatty acids (SCFAs) in gut content, such as propionic acid and valeric acid and with the elevated fecal taurine-conjugated bile acids (BAs) levels. The molecular biology studies showed inhibited hepatic BA synthesis from cholesterol, impeded intracellular transportation and biliary excretion of cholesterol that all conferred to liver TC accumulation. The associations among alterations of gut microbiota composition, microbial metabolite profiles and host phenotypes suggested the existence of gut microbiota-linked mechanisms that mediate the unfavorable delayed effects of abx on db/db mice cholesterol metabolism. Thus, we call upon the caution of applying abx in diabetic animal models for studying microbiota-host interaction and in type 2 diabetes subjects for preventing chronic cardiovascular consequences.
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