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Gut microbiome and serum metabolome alterations in obesity and after weight-loss intervention

Abstract

Emerging evidence has linked the gut microbiome to human obesity. We performed a metagenome-wide association study and serum metabolomics profiling in a cohort of lean and obese, young, Chinese individuals. We identified obesity-associated gut microbial species linked to changes in circulating metabolites. The abundance of Bacteroides thetaiotaomicron, a glutamate-fermenting commensal, was markedly decreased in obese individuals and was inversely correlated with serum glutamate concentration. Consistently, gavage with B. thetaiotaomicron reduced plasma glutamate concentration and alleviated diet-induced body-weight gain and adiposity in mice. Furthermore, weight-loss intervention by bariatric surgery partially reversed obesity-associated microbial and metabolic alterations in obese individuals, including the decreased abundance of B. thetaiotaomicron and the elevated serum glutamate concentration. Our findings identify previously unknown links between intestinal microbiota alterations, circulating amino acids and obesity, suggesting that it may be possible to intervene in obesity by targeting the gut microbiota.

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Figure 1: Gut microbial alterations in young, obese individuals.
Figure 2: Associations of gut microbial species with clinical indices.
Figure 3: Associations of gut microbial species with circulating amino acids.
Figure 4: Effects of B. thetaiotaomicron supplementation on adiposity and host metabolism.
Figure 5: Microbial and metabolic alterations during weight-loss intervention by sleeve gastrectomy.

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References

  1. Bäckhed, F. et al. The gut microbiota as an environmental factor that regulates fat storage. Proc. Natl. Acad. Sci. USA 101, 15718–15723 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Cox, A.J., West, N.P. & Cripps, A.W. Obesity, inflammation, and the gut microbiota. Lancet Diabetes Endocrinol. 3, 207–215 (2015).

    Article  CAS  PubMed  Google Scholar 

  3. Ridaura, V.K. et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science 341, 1241214 (2013).

    Article  CAS  PubMed  Google Scholar 

  4. Ley, R.E., Turnbaugh, P.J., Klein, S. & Gordon, J.I. Microbial ecology: human gut microbes associated with obesity. Nature 444, 1022–1023 (2006).

    Article  CAS  PubMed  Google Scholar 

  5. Turnbaugh, P.J. et al. A core gut microbiome in obese and lean twins. Nature 457, 480–484 (2009).

    Article  CAS  PubMed  Google Scholar 

  6. Karlsson, F.H. et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature 498, 99–103 (2013).

    Article  CAS  PubMed  Google Scholar 

  7. Qin, J. et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 490, 55–60 (2012).

    Article  CAS  PubMed  Google Scholar 

  8. Le Chatelier, E. et al. Richness of human gut microbiome correlates with metabolic markers. Nature 500, 541–546 (2013).

    Article  CAS  PubMed  Google Scholar 

  9. Cotillard, A. et al. Dietary intervention impact on gut microbial gene richness. Nature 500, 585–588 (2013).

    Article  CAS  PubMed  Google Scholar 

  10. Furet, J.P. et al. Differential adaptation of human gut microbiota to bariatric surgery–induced weight loss: links with metabolic and low-grade inflammation markers. Diabetes 59, 3049–3057 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kong, L.C. et al. Gut microbiota after gastric bypass in human obesity: increased richness and associations of bacterial genera with adipose tissue genes. Am. J. Clin. Nutr. 98, 16–24 (2013).

    Article  CAS  PubMed  Google Scholar 

  12. Duncan, S.H. et al. Human colonic microbiota associated with diet, obesity and weight loss. Int. J. Obes. (Lond.) 32, 1720–1724 (2008).

    Article  CAS  Google Scholar 

  13. Schwiertz, A. et al. Microbiota and SCFA in lean and overweight healthy subjects. Obesity (Silver Spring) 18, 190–195 (2010).

    Article  Google Scholar 

  14. Claesson, M.J. et al. Composition, variability and temporal stability of the intestinal microbiota of the elderly. Proc. Natl. Acad. Sci. USA 108 (Suppl. 1), 4586–4591 (2011).

    Article  PubMed  Google Scholar 

  15. Mueller, S. et al. Differences in fecal microbiota in different European study populations in relation to age, gender and country: a cross-sectional study. Appl. Environ. Microbiol. 72, 1027–1033 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. David, L.A. et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 505, 559–563 (2014).

    Article  CAS  PubMed  Google Scholar 

  17. Li, J. et al. An integrated catalog of reference genes in the human gut microbiome. Nat. Biotechnol. 32, 834–841 (2014).

    Article  CAS  PubMed  Google Scholar 

  18. Everard, A. et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc. Natl. Acad. Sci. USA 110, 9066–9071 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Miquel, S. et al. Faecalibacterium prausnitzii and human intestinal health. Curr. Opin. Microbiol. 16, 255–261 (2013).

    Article  CAS  PubMed  Google Scholar 

  20. Peterson, C.T., Sharma, V., Elmén, L. & Peterson, S.N. Immune homeostasis, dysbiosis and therapeutic modulation of the gut microbiota. Clin. Exp. Immunol. 179, 363–377 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Yamauchi, T. et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat. Med. 7, 941–946 (2001).

    Article  CAS  PubMed  Google Scholar 

  22. Turnbaugh, P.J., Bäckhed, F., Fulton, L. & Gordon, J.I. Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe 3, 213–223 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ulmer, J.E. et al. Characterization of glycosaminoglycan (GAG) sulfatases from the human gut symbiont Bacteroides thetaiotaomicron reveals the first GAG-specific bacterial endosulfatase. J. Biol. Chem. 289, 24289–24303 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Xu, J. et al. A genomic view of the human–Bacteroides thetaiotaomicron symbiosis. Science 299, 2074–2076 (2003).

    Article  CAS  PubMed  Google Scholar 

  25. Hooper, L.V. et al. Molecular analysis of commensal host–microbial relationships in the intestine. Science 291, 881–884 (2001).

    Article  CAS  PubMed  Google Scholar 

  26. Qian, C. & Cao, X. Regulation of Toll-like receptor signaling pathways in innate immune responses. Ann. NY Acad. Sci. 1283, 67–74 (2013).

    Article  CAS  PubMed  Google Scholar 

  27. Pedersen, H.K. et al. Human gut microbes impact host serum metabolome and insulin sensitivity. Nature 535, 376–381 (2016).

    Article  CAS  PubMed  Google Scholar 

  28. Shoaie, S. et al. Quantifying diet-induced metabolic changes of the human gut microbiome. Cell Metab. 22, 320–331 (2015).

    Article  CAS  PubMed  Google Scholar 

  29. Russell, W.R. et al. Major phenylpropanoid-derived metabolites in the human gut can arise from microbial fermentation of protein. Mol. Nutr. Food Res. 57, 523–535 (2013).

    Article  CAS  PubMed  Google Scholar 

  30. Wang, T.J. et al. Metabolite profiles and the risk of developing diabetes. Nat. Med. 17, 448–453 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Magnusson, M. et al. A diabetes-predictive amino acid score and future cardiovascular disease. Eur. Heart J. 34, 1982–1989 (2013).

    Article  CAS  PubMed  Google Scholar 

  32. Eckburg, P.B. et al. Diversity of the human intestinal microbial flora. Science 308, 1635–1638 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Bunyan, J., Murrell, E.A. & Shah, P.P. The induction of obesity in rodents by means of monosodium glutamate. Br. J. Nutr. 35, 25–39 (1976).

    Article  CAS  PubMed  Google Scholar 

  34. Dolnikoff, M., Martin-Hidalgo, A., Machado, U.F., Lima, F.B. & Herrera, E. Decreased lipolysis and enhanced glycerol and glucose utilization by adipose tissue prior to development of obesity in monosodium glutamate (MSG) treated-rats. Int. J. Obes. Relat. Metab. Disord. 25, 426–433 (2001).

    Article  CAS  PubMed  Google Scholar 

  35. Rubino, F. et al. Metabolic surgery in the treatment algorithm for type 2 diabetes: a joint statement by international diabetes organizations. Diabetes Care 39, 861–877 (2016).

    Article  CAS  PubMed  Google Scholar 

  36. Gralka, E. et al. Metabolomic fingerprint of severe obesity is dynamically affected by bariatric surgery in a procedure-dependent manner. Am. J. Clin. Nutr. 102, 1313–1322 (2015).

    Article  CAS  PubMed  Google Scholar 

  37. Lips, M.A. et al. Roux-en-Y gastric bypass surgery, but not calorie restriction, reduces plasma branched-chain amino acids in obese women independent of weight loss or the presence of type 2 diabetes. Diabetes Care 37, 3150–3156 (2014).

    Article  CAS  PubMed  Google Scholar 

  38. Mutch, D.M. et al. Metabolite profiling identifies candidate markers reflecting the clinical adaptations associated with Roux-en-Y gastric bypass surgery. PLoS One 4, e7905 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Gauffin Cano, P., Santacruz, A., Moya, Á. & Sanz, Y. Bacteroides uniformis CECT 7771 ameliorates metabolic and immunological dysfunction in mice with high-fat-diet induced obesity. PLoS One 7, e41079 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Mar Rodríguez, M. et al. Obesity changes the human gut mycobiome. Sci. Rep. 5, 14600 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Hermanussen, M. et al. Obesity, voracity and short stature: the impact of glutamate on the regulation of appetite. Eur. J. Clin. Nutr. 60, 25–31 (2006).

    Article  CAS  PubMed  Google Scholar 

  42. Olney, J.W. Brain lesions, obesity and other disturbances in mice treated with monosodium glutamate. Science 164, 719–721 (1969).

    Article  CAS  PubMed  Google Scholar 

  43. He, K. et al. Consumption of monosodium glutamate in relation to incidence of overweight in Chinese adults: China Health and Nutrition Survey (CHNS). Am. J. Clin. Nutr. 93, 1328–1336 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Comstock, L.E. & Coyne, M.J. Bacteroides thetaiotaomicron: a dynamic, niche-adapted human symbiont. BioEssays 25, 926–929 (2003).

    Article  CAS  PubMed  Google Scholar 

  45. Hooper, L.V., Falk, P.G. & Gordon, J.I. Analyzing the molecular foundations of commensalism in the mouse intestine. Curr. Opin. Microbiol. 3, 79–85 (2000).

    Article  CAS  PubMed  Google Scholar 

  46. Cuskin, F. et al. Human gut Bacteroidetes can utilize yeast mannan through a selfish mechanism. Nature 517, 165–169 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Vétizou, M. et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350, 1079–1084 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Wang, J. et al. Ablation of LGR4 promotes energy expenditure by driving white-to-brown fat switch. Nat. Cell Biol. 15, 1455–1463 (2013).

    Article  CAS  PubMed  Google Scholar 

  49. Liu, R. et al. Rare loss-of-function variants in NPC1 predispose to human obesity. Diabetes 66, 935–947 (2017).

    Article  CAS  PubMed  Google Scholar 

  50. Li, R. et al. SOAP2: an improved ultrafast tool for short read alignment. Bioinformatics 25, 1966–1967 (2009).

    Article  CAS  PubMed  Google Scholar 

  51. Feng, Q. et al. Gut microbiome development along the colorectal adenoma–carcinoma sequence. Nat. Commun. 6, 6528 (2015).

    Article  CAS  PubMed  Google Scholar 

  52. McArdle, B.H. & Anderson, M.J. Fitting multivariate models to community data: a comment on distance-based redundancy analysis. Ecology 82, 290–297 (2001).

    Article  Google Scholar 

  53. Zapala, M.A. & Schork, N.J. Multivariate regression analysis of distance matrices for testing associations between gene expression patterns and related variables. Proc. Natl. Acad. Sci. USA 103, 19430–19435 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Breiman, L. Random forests. Mach. Learn. 45, 5–32 (2001).

    Article  Google Scholar 

  55. Subramanian, S. et al. Persistent gut microbiota immaturity in malnourished Bangladeshi children. Nature 510, 417–421 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Luan, H. et al. Serum metabolomics reveals lipid metabolism variation between coronary artery disease and congestive heart failure: a pilot study. Biomarkers 18, 314–321 (2013).

    Article  CAS  PubMed  Google Scholar 

  57. Dunn, W.B. et al. Procedures for large-scale metabolic profiling of serum and plasma using gas chromatography and liquid chromatography coupled to mass spectrometry. Nat. Protoc. 6, 1060–1083 (2011).

    Article  CAS  PubMed  Google Scholar 

  58. Wishart, D.S. et al. HMDB 3.0—The Human Metabolome Database in 2013. Nucleic Acids Res. 41, D801–D807 (2013).

    Article  CAS  PubMed  Google Scholar 

  59. Kanehisa, M. & Goto, S. KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 28, 27–30 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Zhang, C. et al. Dietary modulation of gut microbiota contributes to alleviation of both genetic and simple obesity in children. EBioMedicine 2, 968–984 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Zhang, X. et al. The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment. Nat. Med. 21, 895–905 (2015).

    Article  CAS  PubMed  Google Scholar 

  62. Diggle, P.J., Heagerty, P., Liang, K.-Y. & Zeger, S.L. Analysis of Longitudinal Data 2nd edn (Oxford University Press, 2002).

  63. Qian, S.W. et al. BMP4-mediated brown fat–like changes in white adipose tissue alter glucose and energy homeostasis. Proc. Natl. Acad. Sci. USA 110, E798–E807 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Wang, R.F., Cao, W.W. & Cerniglia, C.E. PCR detection and quantitation of predominant anaerobic bacteria in human and animal fecal samples. Appl. Environ. Microbiol. 62, 1242–1247 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Gao, X., Pujos-Guillot, E. & Sébédio, J.L. Development of a quantitative metabolomic approach to study clinical human fecal water metabolome based on trimethylsilylation derivatization and GC/MS analysis. Anal. Chem. 82, 6447–6456 (2010).

    Article  CAS  PubMed  Google Scholar 

  66. Tremaroli, V. et al. Roux-en-Y gastric bypass and vertical banded gastroplasty induce long-term changes on the human gut microbiome contributing to fat mass regulation. Cell Metab. 22, 228–238 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank the field workers for their contribution and the participants for their cooperation. We thank H.B. Nielsen, S.B. Pedersen and H. Zhao for their contribution to data discussions. We thank P. Yin, S. Wang and H. Yu for their assistance in cultivating bacteria. This study was supported by grants from National Natural Science Foundation of China (no. 81621061 (G.N.), 81522011 (J.W.), 81370963 (R.L.), 81570758 (R.L.), 81370949 (J.W.), 81570757 (J.W.), 81471060 (J.H.) and 81670761 (Y.G.)), National International Science Cooperation Foundation (no. 2015DFA30560, W.W.), 973 Foundation (no. 2015CB553600, G.N.) and Shenzhen Municipal Government of China (no. JSGG20140702161403250 (Q.F.), DRC-SZ[2015]162 (Q.F.), JSGG20160229172752028 (J.L.) and JCYJ20160229172757249 (H.J.)).

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W.W., K.K. and G.N. conceived and designed the project. W.W., G.N. J.H., R.L., Y.G. and Jiqiu Wang managed the study. J.H., J.S., Y.G., Y.Z., W.G., B.S., X.D., J.J. and Y.B. made clinical diagnosis, recruited subjects and performed intervention. J.S., P.L., L.X., X.Y., Wanyu Li, R.W., Y. Shen, M.Y. and Y. Sun collected samples and clinical phenotypes. Xiaoqiang Xu, Q.F., D.Z., Xiaokai Wang., H. Xia, Z. Lan, Z.J., J.L., H.Z., and H. Xie performed bioinformatics analyses. Z. Liu, F.L. and X.C. performed metabolomics profiling and data analysis. Xiaolin Wang., X.Z. and G.X. performed targeted amino acid profiling. S.Z. and Wen Liu conducted animal experiments. R.L., K.K., W.W., G.N. and Jiqiu Wang wrote the manuscript. L.M., L.Q., S.L., B.C., H.J., Xun Xu, H.Y. and Jian Wang contributed to text revision and discussion.

Corresponding authors

Correspondence to Guang Ning, Karsten Kristiansen or Weiqing Wang.

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Liu, R., Hong, J., Xu, X. et al. Gut microbiome and serum metabolome alterations in obesity and after weight-loss intervention. Nat Med 23, 859–868 (2017). https://doi.org/10.1038/nm.4358

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