Antibiotic effects on gut microbiota and metabolism are host dependent
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
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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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 7

Modification of the gut microbiota by antibiotics restores bile acid receptor, TGR5 level in the liver.

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Modification of the gut microbiota by antibiotics restores bile acid rec...
(A) qPCR for Tnfa, Il6, and Il1b mRNA in peritoneal macrophages collected from mice with or without TDCA treatment (0.4%) for 3 weeks. Cells were stimulated with PBS or LPS (10 ng/ml) for 6 hours. Graph shows the fold change of relative expression levels after the stimulation (n = 5). (B) Western blots for TGR5 in the liver of B6J mice on chow or an HFD for 22 weeks and quantitation of TGR5 protein normalized to actin (n = 4 per group). (C) qPCR for Tgr5 expression in Kupffer cells from mice fed chow or an HFD for 4 to 7 months (n = 8–9). (D) Western blots for TGR5 in the liver of 11-week-old B6J mice on chow or an HFD, with or without antibiotic treatment. Quantitation of TGR5 normalized to actin (n = 4 per group; 4 weeks on the HFD; 5 weeks on antibiotics). (E) Western blots for TGR5 in the liver of HFD-fed, GF B6J mice that received bacterial transfer from placebo-, vancomycin-, or metronidazole-treated mice and quantitation of TGR5 protein normalized to actin (n = 5–12 per group; 19-week-old mice; 10 weeks on the HFD; 2 weeks after colonization). (F) qPCR for Tnfa, Il6, and Il1b expression levels in the liver of mice treated with or without RG-239 (10 mg/kg/d) for 2 weeks (n = 3–5). (G) qPCR for Tnfa expression of peritoneal macrophages collected from mice treated with or without RG-239 and stimulated in vitro with or without 10 ng/ml LPS for 6 hours (n = 4–6). *P < 0.05 and **P < 0.01, by unpaired, 2-tailed t test for (A–C and E–G) and by ANOVA, followed by Tukey-Kramer post-hoc for (D).