Antibiotic effects on gut microbiota and metabolism are host dependent
Shiho Fujisaka, … , Lynn Bry, C. Ronald Kahn
Shiho Fujisaka, … , Lynn Bry, C. Ronald Kahn
Published October 24, 2016
Citation Information: J Clin Invest. 2016;126(12):4430-4443. https://doi.org/10.1172/JCI86674.
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Research Article Gastroenterology Metabolism

Antibiotic effects on gut microbiota and metabolism are host dependent

Abstract

Interactions of diet, gut microbiota, and host genetics play important roles in the development of obesity and insulin resistance. Here, we have investigated the molecular links between gut microbiota, insulin resistance, and glucose metabolism in 3 inbred mouse strains with differing susceptibilities to metabolic syndrome using diet and antibiotic treatment. Antibiotic treatment altered intestinal microbiota, decreased tissue inflammation, improved insulin signaling in basal and stimulated states, and improved glucose metabolism in obesity- and diabetes-prone C57BL/6J mice on a high-fat diet (HFD). Many of these changes were reproduced by the transfer of gut microbiota from antibiotic-treated donors to germ-free or germ-depleted mice. These physiological changes closely correlated with changes in serum bile acids and levels of the antiinflammatory bile acid receptor Takeda G protein–coupled receptor 5 (TGR5) and were partially recapitulated by treatment with a TGR5 agonist. In contrast, antibiotic treatment of HFD-fed, obesity-resistant 129S1 and obesity-prone 129S6 mice did not improve metabolism, despite changes in microbiota and bile acids. These mice also failed to show a reduction in inflammatory gene expression in response to the TGR5 agonist. Thus, changes in bile acid and inflammatory signaling, insulin resistance, and glucose metabolism driven by an HFD can be modified by antibiotic-induced changes in gut microbiota; however, these effects depend on important interactions with the host’s genetic background and inflammatory potential.

Authors

Shiho Fujisaka, Siegfried Ussar, Clary Clish, Suzanne Devkota, Jonathan M. Dreyfuss, Masaji Sakaguchi, Marion Soto, Masahiro Konishi, Samir Softic, Emrah Altindis, Ning Li, Georg Gerber, Lynn Bry, C. Ronald Kahn

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Figure 4

Improvement of glucose metabolism by antibiotic-modified bacteria is transferable.

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Improvement of glucose metabolism by antibiotic-modified bacteria is tra...
(A) Differences between 4-hour fasting blood glucose levels measured at 1 pm in an HFD-fed B6J mice before and after bacterial transfer (days 7, 9, and 11) from donor HFD-fed B6J mice treated with placebo, vancomycin, or metronidazole for 1 week (n = 6 per group). (B–D) OGTT of the HF-fed B6J recipient mice performed before (white circles) and after (solid circles) bacterial transfer (day 11) from mice treated with placebo (B), vancomycin (C), or metronidazole (D) (n = 6). *P < 0.05 and **P < 0.01, by unpaired, 2-tailed t test. (E and F) Western blots for insulin signaling in liver (E) and muscle (F) of the recipient mice. (G) Western blots for insulin signaling in the liver of HFD-fed, GF B6J mice colonized with cecal bacteria from HFD-fed B6J mice treated with placebo, vancomycin, or metronidazole, measured 2 weeks after transfer. Graph shows quantitation of p-AKT protein normalized by actin (n = 4–6). (H) OGTT of HFD-fed, GF B6J mice colonized with cecal bacteria from HFD-fed B6J mice treated with placebo (circles), vancomycin (squares), or metronidazole (triangles) (n = 7–9). *P < 0.05, for placebo versus vancomycin; #P < 0.05 and ##P < 0.01, for placebo versus metronidazole, by ANOVA, followed by Tukey-Kramer post-hoc.