Incorporation of therapeutically modified bacteria into gut microbiota inhibits obesity
Zhongyi Chen, Lilu Guo, Yongqin Zhang, Rosemary L. Walzem, Julie S. Pendergast, Richard L. Printz, Lindsey C. Morris, Elena Matafonova, Xavier Stien, Li Kang, Denis Coulon, Owen P. McGuinness, Kevin D. Niswender, Sean S. Davies
Zhongyi Chen, Lilu Guo, Yongqin Zhang, Rosemary L. Walzem, Julie S. Pendergast, Richard L. Printz, Lindsey C. Morris, Elena Matafonova, Xavier Stien, Li Kang, Denis Coulon, Owen P. McGuinness, Kevin D. Niswender, Sean S. Davies
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Technical Advance Metabolism

Incorporation of therapeutically modified bacteria into gut microbiota inhibits obesity

Abstract

Metabolic disorders, including obesity, diabetes, and cardiovascular disease, are widespread in Westernized nations. Gut microbiota composition is a contributing factor to the susceptibility of an individual to the development of these disorders; therefore, altering a person’s microbiota may ameliorate disease. One potential microbiome-altering strategy is the incorporation of modified bacteria that express therapeutic factors into the gut microbiota. For example, N-acylphosphatidylethanolamines (NAPEs) are precursors to the N-acylethanolamide (NAE) family of lipids, which are synthesized in the small intestine in response to feeding and reduce food intake and obesity. Here, we demonstrated that administration of engineered NAPE-expressing E. coli Nissle 1917 bacteria in drinking water for 8 weeks reduced the levels of obesity in mice fed a high-fat diet. Mice that received modified bacteria had dramatically lower food intake, adiposity, insulin resistance, and hepatosteatosis compared with mice receiving standard water or control bacteria. The protective effects conferred by NAPE-expressing bacteria persisted for at least 4 weeks after their removal from the drinking water. Moreover, administration of NAPE-expressing bacteria to TallyHo mice, a polygenic mouse model of obesity, inhibited weight gain. Our results demonstrate that incorporation of appropriately modified bacteria into the gut microbiota has potential as an effective strategy to inhibit the development of metabolic disorders.

Authors

Zhongyi Chen, Lilu Guo, Yongqin Zhang, Rosemary L. Walzem, Julie S. Pendergast, Richard L. Printz, Lindsey C. Morris, Elena Matafonova, Xavier Stien, Li Kang, Denis Coulon, Owen P. McGuinness, Kevin D. Niswender, Sean S. Davies

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Figure 12

Treatment with pNAPE-EcN preserves insulin sensitivity in liver by protecting against inhibitory phosphorylation of IRS1 by JNKs.

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Treatment with pNAPE-EcN preserves insulin sensitivity in liver by prote...
Mice treated with standard water only (W), with pEcN (E), or with pNAPE-EcN (N) for 6 weeks were fasted for 4 hours and then injected intraperitoneally with either saline (to determine response to endogenous levels of insulin; n = 5 mice per group) or 0.75 IU/kg insulin (to determine response to exogenous, pharmacological levels of insulin; n = 4–5 mice per group). 15 minutes after injection, mice were euthanized and tissue collected. Data are the mean ± SEM. (A) Extent of activating phosphorylation of Ser473 of AKT (p-AKT) in liver of saline-injected mice. Values were normalized to plasma insulin (INS) and expressed relative to the average for water-only–treated mice. P = 0.0225 by 1-way ANOVA; *P < 0.05 versus standard water by Dunnett’s multiple comparison test. (B) Extent of inhibitory Ser307 phosphorylation of IRS1. Values were normalized to heat shock protein (HSP) and expressed relative to the average for standard water-only–treated mice. P = 0.0173 by 1-way ANOVA; *P < 0.05 versus standard water by Dunnett’s multiple comparison test. (C) Extent of activating phosphorylation of JNK isoforms p46 and p54. Values were normalized to HSP and expressed relative to the average for standard water-only–treated mice. For p46-JNK, P = 0.0084 by 1-way ANOVA; *P < 0.05 versus standard water by Dunnett’s multiple comparison test. For p54-JNK, P = 0.0134 by 1-way ANOVA; *P < 0.05 versus standard water by Dunnett’s multiple comparison test. There were no significant differences between groups stimulated with the exogenous insulin.