Incorporation of therapeutically modified bacteria into gut microbiota inhibits obesity
Zhongyi Chen, … , Kevin D. Niswender, Sean S. Davies
Zhongyi Chen, … , Kevin D. Niswender, Sean S. Davies
Published August 1, 2014; First published June 24, 2014
Citation Information: J Clin Invest. 2014;124(8):3391-3406. https://doi.org/10.1172/JCI72517.
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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 11

Treatment with pNAPE-EcN reduces the insulin resistance index and increases insulin response in mice fed a high-fat diet.

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Treatment with pNAPE-EcN reduces the insulin resistance index and increa...
All values are the mean ± SEM; n = 10 mice per group. (A) Treatment with pNAPE-EcN (HF + N) improved basal glucose levels and glucose tolerance compared with mice treated with standard drinking water (HF + W), but not a low-fat chow diet (LF + W). Fasting glucose levels differed significantly between groups (P < 0.001 by 1-way ANOVA; P < 0.05 by Bonferroni’s post-hoc multiple comparison for HF + W versus HF + N or LF + W, and HF + N versus LF + W. Glucose AUC differed significantly between each treatment group (P < 0.0009 by 1-way ANOVA); P <0.05 by Bonferroni’s post-hoc multiple comparison for HF + W (50,841 ± 2,191 mg/dl/min) versus either HF + N (39,463 ± 1,800) or LF + W (24,573 ± 517), and for HF + N versus LF + W. (B) Treatment with pNAPE-EcN increased insulin responsiveness. Fasting levels of insulin were significantly higher in HF + W versus HF + N or LF + W mice (P < 0.0001 by 1-way ANOVA); P < 0.05 by Bonferroni’s post-hoc multiple comparison for HF + W versus HF + N or LF + W, but not for HF + N versus LF + W. The insulin AUC for each treatment differed significantly: P < 0.0001 by 1-way ANOVA; P < 0.05 by Bonferroni’s post-hoc multiple comparison for LF + W (69.5 ± 5.7 ng/ml/min, mean ± SEM) versus HF + W (193.9 ± 17.0) or HF + N (158.7 ± 8.4, P < 0.05). (C) Treatment with pNAPE-EcN improved the HOMA-IR score compared with a high-fat diet–only treatment. P < 0.0001 by 1-way ANOVA; P < 0.05 by Bonferroni’s post-hoc multiple comparison for HF + W versus HF + N or LF + W, but not for HF + N versus LF + W.