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 9

Treatment with pNAPE-EcN reduces food intake and meal duration during the dark phase of the light cycle.

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Treatment with pNAPE-EcN reduces food intake and meal duration during th...
Mice were given standard drinking water only, water with pEcN, or water with pNAPE-EcN for 4 weeks prior to metabolic monitoring and continued to receive treated water throughout the monitoring period (n = 9–10 mice per group). (A) Average cumulative food intake during the 24-hour light cycle. For each mouse, the cumulative food intake through each 5-minute block of a 24-hour light cycle (6 am–6 am) for each of the 3 days of monitoring was averaged. The mean cumulative food intake for each treatment group is shown. The 72-hour cumulative food traces for individual mice are shown in Supplemental Figure 16. (B) Effect of treatment on meal duration in light and dark phases (mean ± SEM). P = 0.8972 by 1-way ANOVA for light phase; P = 0.0554 by 1-way ANOVA for dark phase; *P < 0.05 versus standard water by Dunnett’s multiple comparison test. (C) Effect of treatment on intermeal interval (mean ± SEM). P = 0.0743 by 1-way ANOVA for light phase; P = 0.1085 by 1-way ANOVA for dark phase. (D) Effect of treatment on meal size (mean ± SEM). Each 5-minute block during which food hopper weight decreased by greater than 0.05 mg was scored as a meal and categorized from 1 (smallest) to 5 (largest), as described in Methods. Category 4, P = 0.0256 by 1-way ANOVA; all other meal categories, P = NS by 1-way ANOVA.