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The beneficial effects of genetically engineered Escherichia coli Nissle 1917 in obese C57BL/6J mice

International Journal of Obesity volume 46, pages 1002–1008 (2022)Cite this article

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Abstract

Background

Genetically modified probiotics have potential for use as a novel approach to express bioactive molecules for the treatment of obesity. The objective of the present study was to investigate the beneficial effect of genetically modified Escherichia coli Nissle 1917 (EcN-GM) in obese C57BL/6J mice.

Methods

First, an obesity model in C57BL/6J mice was successfully established. Then, the obese mice were randomly assigned into three groups: obese mice (OB), obese mice + EcN-GM (OB + EcN-GM), and obese mice + orlistat (OB + orlistat) (n = 10 in each group). The three groups were gavaged with 0.3 ml of 1010 CFU/ml control EcN, EcN-GM (genetically engineered EcN) and 10 ml/kg orlistat. Body weight, food consumption, fat pad and organ weight, hepatic biochemistry and hepatic histopathological alterations were measured. The effects of EcN-GM on the levels of endocrine peptides and the intestinal microbiota were also analyzed.

Results

After supplementation for 8 weeks, EcN-GM was associated with decreases in body weight gain, food intake, fat pad and liver weight, and alleviation hepatocyte steatosis in obese mice. EcN-GM also increased the level of GLP-1 in serum and alleviated leptin and insulin resistance. Moreover, supplementation with EcN-GM increased the α-diversity of the intestinal microbiota but did not significantly influence the relative abundance of Firmicutes and Bacteroidetes.

Conclusions

These results indicated that EcN-GM, a genetically modified E. coli strain, may be a potential therapeutic approach to treat obesity. The beneficial effect of EcN-GM may be independent of the alteration of the diversity and composition of the intestinal microbiota in obese mice.

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Fig. 1: Effect of EcN-GM on body weight and food intake in obese C57BL/6J mice.
Fig. 2: Effect of EcN-GM on fat pad weight of obese C57BL/6J mice.
Fig. 3: Effect of EcN-GM on organ weight of obese C57BL/6J mice.
Fig. 4: Effect of EcN-GM on the levels of hepatic triglycerides and total cholester in obese C57BL/6J mice.
Fig. 5: Effect of EcN-GM on the levels of GLP-1, leptin and insulin in the serum of obese C57BL/6J mice.
Fig. 6
Fig. 7: Effect of EcN-GM on intestinal microbiota composition.

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References

  1. Kyle TK, Dhurandhar EJ, Allison DB. Regarding obesity as a disease: evolving policies and their implications. Endocrinol Metab Clin North Am. 2016;45:511–20.

    Article  PubMed Central  Google Scholar 

  2. Obesity: preventing and managing the global epidemic. Report of a WHO consultation. World Health Organ Tech Rep Ser. 2000;894:1–253.

  3. Bray GA, Kim KK, Wilding JPH, World Obesity F. Obesity: a chronic relapsing progressive disease process. A position statement of the World Obesity Federation. Obes Rev. 2017;18:715–23.

    Article  CAS  Google Scholar 

  4. O’Neil PM, Birkenfeld AL, McGowan B, Mosenzon O, Pedersen SD, Wharton S, et al. Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial. Lancet. 2018;392:637–49.

    Article  Google Scholar 

  5. Apovian CM, Aronne LJ, Bessesen DH, McDonnell ME, Murad MH, Pagotto U, et al. Pharmacological management of obesity: an endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2015;100:342–62.

    Article  CAS  Google Scholar 

  6. Srivastava G, Apovian CM. Current pharmacotherapy for obesity. Nat Rev Endocrinol. 2018;14:12–24.

    Article  CAS  Google Scholar 

  7. Bessesen DH, Van Gaal LF. Progress and challenges in anti-obesity pharmacotherapy. Lancet Diabetes Endocrinol. 2018;6:237–48.

    Article  Google Scholar 

  8. Komaroff AL. The microbiome and risk for obesity and diabetes. JAMA. 2017;317:355–6.

    Article  Google Scholar 

  9. Heymsfield SB, Wadden TA. Mechanisms, pathophysiology, and management of obesity. N Engl J Med. 2017;376:254–66.

    Article  CAS  Google Scholar 

  10. Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006;444:1027–31.

    Article  Google Scholar 

  11. Pedrolli DB, Ribeiro NV, Squizato PN, de Jesus VN, Cozetto DA, Team AQAUai. Engineering microbial living therapeutics: the synthetic biology toolbox. Trends Biotechnol. 2019;37:100–15.

    Article  CAS  Google Scholar 

  12. Reardon S. Genetically modified bacteria enlisted in fight against disease. Nature. 2018;558:497–8.

    Article  CAS  Google Scholar 

  13. Hendrikx T, Duan Y, Wang Y, Oh JH, Alexander LM, Huang W, et al. Bacteria engineered to produce IL-22 in intestine induce expression of REG3G to reduce ethanol-induced liver disease in mice. Gut. 2019;68:1504–15.

    Article  CAS  Google Scholar 

  14. Chen Z, Guo L, Zhang Y, Walzem RL, Pendergast JS, Printz RL, et al. Incorporation of therapeutically modified bacteria into gut microbiota inhibits obesity. J Clin Invest. 2014;124:3391–406.

    Article  CAS  PubMed Central  Google Scholar 

  15. Wassenaar TM. Insights from 100 years of research with probiotic E. Coli. Eur J Microbiol Immunol. 2016;6:147–61.

    Article  Google Scholar 

  16. Grozdanov L, Raasch C, Schulze J, Sonnenborn U, Gottschalk G, Hacker J, et al. Analysis of the genome structure of the nonpathogenic probiotic Escherichia coli strain Nissle 1917. J Bacteriol. 2004;186:5432–41.

    Article  CAS  PubMed Central  Google Scholar 

  17. Hancock V, Dahl M, Klemm P. Probiotic Escherichia coli strain Nissle 1917 outcompetes intestinal pathogens during biofilm formation. J Med Microbiol. 2010;59:392–9.

    Article  Google Scholar 

  18. Kurtz CB, Millet YA, Puurunen MK, Perreault M, Charbonneau MR, Isabella VM. et al. An engineered E. coli Nissle improves hyperammonemia and survival in mice and shows dose-dependent exposure in healthy humans. Sci Transl Med. 2019;11:eaau7975.

    Article  Google Scholar 

  19. Isabella VM, Ha BN, Castillo MJ, Lubkowicz DJ, Rowe SE, Millet YA, et al. Development of a synthetic live bacterial therapeutic for the human metabolic disease phenylketonuria. Nat Biotechnol. 2018;36:857–64.

    Article  CAS  Google Scholar 

  20. Hwang IY, Koh E, Wong A, March JC, Bentley WE, Lee YS, et al. Engineered probiotic Escherichia coli can eliminate and prevent Pseudomonas aeruginosa gut infection in animal models. Nat Commun. 2017;8:15028.

    Article  CAS  PubMed Central  Google Scholar 

  21. Ma J, Li C, Wang J, Gu J. Genetically engineered Escherichia coli Nissle 1917 secreting GLP-1 analog exhibits potential antiobesity effect in high-fat diet-induced obesity mice. Obesity. 2020;28:315–22.

    Article  CAS  Google Scholar 

  22. Yumuk V, Tsigos C, Fried M, Schindler K, Busetto L, Micic D, et al. European guidelines for obesity management in adults. Obes Facts. 2015;8:402–24.

    Article  PubMed Central  Google Scholar 

  23. Collaborators GBDO, Afshin A, Forouzanfar MH, Reitsma MB, Sur P, Estep K, et al. Health effects of overweight and obesity in 195 countries over 25 years. N Engl J Med. 2017;377:13–27.

    Article  Google Scholar 

  24. Reid G, Sanders ME, Gaskins HR, Gibson GR, Mercenier A, Rastall R, et al. New scientific paradigms for probiotics and prebiotics. J Clin Gastroenterol. 2003;37:105–18.

    Article  Google Scholar 

  25. Yadav H, Lee JH, Lloyd J, Walter P, Rane SG. Beneficial metabolic effects of a probiotic via butyrate-induced GLP-1 hormone secretion. J Biol Chem. 2013;288:25088–97.

    Article  CAS  PubMed Central  Google Scholar 

  26. Kang JH, Yun SI, Park MH, Park JH, Jeong SY, Park HO. Anti-obesity effect of Lactobacillus gasseri BNR17 in high-sucrose diet-induced obese mice. PLoS ONE. 2013;8:e54617.

    Article  CAS  PubMed Central  Google Scholar 

  27. Valsecchi C, Carlotta Tagliacarne S, Castellazzi A. Gut microbiota and obesity. J Clin Gastroenterol. 2016;50:S157–8. Suppl 2Proceedings from the 8th Probiotics, Prebiotics & New Foods for Microbiota and Human Health meeting held in Rome, Italy on September 13–15, 2015.

    Article  CAS  Google Scholar 

  28. Wei P, Yang Y, Li T, Ding Q, Sun H. A engineered Bifidobacterium longum secreting a bioative penetratin-Glucagon-like peptide 1 fusion protein enhances Glucagon-like peptide 1 absorption in the intestine. J Microbiol Biotechnol. 2015. Epub ahead of print.

  29. Duan FF, Liu JH, March JC. Engineered commensal bacteria reprogram intestinal cells into glucose-responsive insulin-secreting cells for the treatment of diabetes. Diabetes. 2015;64:1794–803.

    Article  CAS  PubMed Central  Google Scholar 

  30. Rao S, Hu S, McHugh L, Lueders K, Henry K, Zhao Q, et al. Toward a live microbial microbicide for HIV: commensal bacteria secreting an HIV fusion inhibitor peptide. Proc Natl Acad Sci USA. 2005;102:11993–8.

    Article  CAS  PubMed Central  Google Scholar 

  31. Federico A, Dallio M, Rosa DIS, Giorgio V, Miele L. Gut microbiota, obesity and metabolic disorders. Minerva Gastroenterol Dietol. 2017;63:337–44.

    PubMed  Google Scholar 

  32. Bäckhed F, Ding H, Wang T, Hooper LV, Koh GY, Nagy A, et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci USA. 2004;101:15718–23.

    Article  PubMed Central  Google Scholar 

  33. Boulange CL, Neves AL, Chilloux J, Nicholson JK, Dumas ME. Impact of the gut microbiota on inflammation, obesity, and metabolic disease. Genome Med. 2016;8:42.

    Article  PubMed Central  Google Scholar 

  34. Patterson E, Ryan PM, Cryan JF, Dinan TG, Ross RP, Fitzgerald GF, et al. Gut microbiota, obesity and diabetes. Postgrad Med J. 2016;92:286–300.

    Article  CAS  Google Scholar 

  35. Madsen MSA, Holm JB, Palleja A, Wismann P, Fabricius K, Rigbolt K, et al. Metabolic and gut microbiome changes following GLP-1 or dual GLP-1/GLP-2 receptor agonist treatment in diet-induced obese mice. Sci Rep. 2019;9:15582.

    Article  PubMed Central  Google Scholar 

  36. Zhang N, Tao J, Gao L, Bi Y, Li P, Wang H, et al. Liraglutide attenuates nonalcoholic fatty liver disease by modulating gut microbiota in rats administered a high-fat diet. Biomed Res Int. 2020;2020:2947549.

    PubMed  PubMed Central  Google Scholar 

  37. Liu Q, Cai BY, Zhu LX, Xin X, Wang X, An ZM, et al. Liraglutide modulates gut microbiome and attenuates nonalcoholic fatty liver in db/db mice. Life Sci. 2020;261:118457.

    Article  CAS  Google Scholar 

  38. Ehrlich SD. Probiotics—little evidence for a link to obesity. Nat Rev Microbiol. 2009;7:901.

    Article  CAS  Google Scholar 

  39. Daniel H, Gholami AM, Berry D, Desmarchelier C, Hahne H, Loh G, et al. High-fat diet alters gut microbiota physiology in mice. ISME J. 2014;8:295–308.

    Article  CAS  Google Scholar 

  40. Kanoski SE, Hayes MR, Skibicka KP. GLP-1 and weight loss: unraveling the diverse neural circuitry. Am J Physiol Regul Integr Comp Physiol. 2016;310:R885–95.

    Article  PubMed Central  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Research and Development, Weichuang Tianyi Biotechnology Co., Ltd, Chengdu, Sichuan, PR China

    Jie Ma

  2. Department of Research and Development, LiTong Bio-Medical Science, Chengdu, Sichuan, PR China

    Jie Ma & Lu Xu

  3. Savaid Medical School, University of Chinese Academy of Sciences, Beijing, PR China

    Junrui Wang

  4. Department of Orthopaedics, Chengdu Second People’s Hospital, Chengdu, Sichuan, PR China

    Junrui Wang

  5. College of Comprehensive Health Management, Xihua University, Chengdu, Sichuan, PR China

    Yuanqi Liu

  6. Department of Neurosurgery, PLA Strategic Support Force Characteristic Medical Center, Beijing, PR China

    Jianwen Gu

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  1. Jie Ma
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  3. Lu Xu
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  4. Yuanqi Liu
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Contributions

All authors contributed to this work. JM, JW, and JG designed the experiment. JM and JW performed the experiment. LX and YL analyzed the data. JM and JW drafted the manuscript. JM, LX, and YL prepared the figures. JM, JW, LX, and JG critically revised the manuscript. All the listed authors reviewed and approved the submitted manuscript.

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Correspondence to Jie Ma or Jianwen Gu.

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Ma, J., Wang, J., Xu, L. et al. The beneficial effects of genetically engineered Escherichia coli Nissle 1917 in obese C57BL/6J mice. Int J Obes 46, 1002–1008 (2022). https://doi.org/10.1038/s41366-022-01073-8

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