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Genetic deficiency of indoleamine 2,3-dioxygenase promotes gut microbiota-mediated metabolic health

Abstract

The association between altered gut microbiota, intestinal permeability, inflammation and cardiometabolic diseases is becoming increasingly clear but remains poorly understood1,2. Indoleamine 2,3-dioxygenase is an enzyme induced in many types of immune cells, including macrophages in response to inflammatory stimuli, and catalyzes the degradation of tryptophan along the kynurenine pathway. Indoleamine 2,3-dioxygenase activity is better known for its suppression of effector T cell immunity and its activation of regulatory T cells3,4. However, high indoleamine 2,3-dioxygenase activity predicts worse cardiovascular outcome5,6,7,8,9 and may promote atherosclerosis and vascular inflammation6, suggesting a more complex role in chronic inflammatory settings. Indoleamine 2,3-dioxygenase activity is also increased in obesity10,11,12,13, yet its role in metabolic disease is still unexplored. Here, we show that obesity is associated with an increase of intestinal indoleamine 2,3-dioxygenase activity, which shifts tryptophan metabolism from indole derivative and interleukin-22 production toward kynurenine production. Indoleamine 2,3-dioxygenase deletion or inhibition improves insulin sensitivity, preserves the gut mucosal barrier, decreases endotoxemia and chronic inflammation, and regulates lipid metabolism in liver and adipose tissues. These beneficial effects are due to rewiring of tryptophan metabolism toward a microbiota-dependent production of interleukin-22 and are abrogated after treatment with a neutralizing anti-interleukin-22 antibody. In summary, we identify an unexpected function of indoleamine 2,3-dioxygenase in the fine tuning of intestinal tryptophan metabolism with major consequences on microbiota-dependent control of metabolic disease, which suggests indoleamine 2,3-dioxygenase as a potential therapeutic target.

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Fig. 1: Ido1−/− mice are protected from obesity, inflammation, liver steatosis and insulin resistance.
Fig. 2: IDO activity controls gut microbiota-dependent regulation of obesity and its complications.
Fig. 3: IDO deficiency preserves the intestinal barrier through IL-22 in the setting of obesity.
Fig. 4: A shift of Trp metabolism towards more Kyn and less IAA in the context of human obesity and type 2 diabetes.

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References

  1. Tang, W. H., Kitai, T. & Hazen, S. L. Gut microbiota in cardiovascular health and disease. Circ. Res. 120, 1183–1196 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Schroeder, B. O. & Backhed, F. Signals from the gut microbiota to distant organs in physiology and disease. Nat. Med. 22, 1079–1089 (2016).

    CAS  PubMed  Google Scholar 

  3. Puccetti, P. & Grohmann, U. IDO and regulatory T cells: a role for reverse signalling and non-canonical NF-kappaB activation. Nat. Rev. Immunol. 7, 817–823 (2007).

    CAS  PubMed  Google Scholar 

  4. Mellor, A. L. & Munn, D. H. IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat. Rev. Immunol. 4, 762–774 (2004).

    CAS  PubMed  Google Scholar 

  5. Wirleitner, B. et al. Immune activation and degradation of tryptophan in coronary heart disease. Eur. J. Clin. Invest. 33, 550–554 (2003).

    CAS  PubMed  Google Scholar 

  6. Metghalchi, S. et al. Indoleamine 2,3-dioxygenase fine-tunes immune homeostasis in atherosclerosis and colitis through repression of interleukin-10 production. Cell Metab. 22, 460–471 (2015).

    CAS  PubMed  Google Scholar 

  7. Pedersen, E. R. et al. Systemic markers of interferon-γ-mediated immune activation and long-term prognosis in patients with stable coronary artery disease. Arterioscler. Thromb. Vasc. Biol. 31, 698–704 (2011).

    CAS  PubMed  Google Scholar 

  8. Pedersen, E. R. et al. Associations of plasma kynurenines with risk of acute myocardial infarction in patients with stable angina pectoris. Arterioscler. Thromb. Vasc. Biol. 35, 455–462 (2015).

    CAS  PubMed  Google Scholar 

  9. Eussen, S. J. et al. Kynurenines as predictors of acute coronary events in the Hordaland Health Study. Int. J. Cardiol. 189, 18–24 (2015).

    PubMed  Google Scholar 

  10. Brandacher, G. et al. Bariatric surgery cannot prevent tryptophan depletion due to chronic immune activation in morbidly obese patients. Obes. Surg. 16, 541–548 (2006).

    PubMed  Google Scholar 

  11. Wolowczuk, I. et al. Tryptophan metabolism activation by indoleamine 2,3-dioxygenase in adipose tissue of obese women: an attempt to maintain immune homeostasis and vascular tone. Am. J. Physiol. Regul. Integr. Comp. Physiol. 303, R135–143 (2012).

    CAS  PubMed  Google Scholar 

  12. Mangge, H. et al. Disturbed tryptophan metabolism in cardiovascular disease. Curr. Med. Chem. 21, 1931–1937 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Favennec, M. et al. The kynurenine pathway is activated in human obesity and shifted toward kynurenine monooxygenase activation. Obesity 23, 2066–2074 (2015).

    CAS  PubMed  Google Scholar 

  14. Yoshida, R., Imanishi, J., Oku, T., Kishida, T. & Hayaishi, O. Induction of pulmonary indoleamine 2,3-dioxygenase by interferon. Proc. Natl Acad. Sci. USA 78, 129–132 (1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432 (1994).

    CAS  PubMed  Google Scholar 

  16. Hotamisligil, G. S. Inflammation and metabolic disorders. Nature 444, 860–867 (2006).

    CAS  PubMed  Google Scholar 

  17. Odegaard, J. I. & Chawla, A. Pleiotropic actions of insulin resistance and inflammation in metabolic homeostasis. Science 339, 172–177 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  19. Cherayil, B. J. Indoleamine 2,3-dioxygenase in intestinal immunity and inflammation. Inflamm. Bowel Dis. 15, 1391–1396 (2009).

    PubMed  Google Scholar 

  20. Cani, P. D. et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56, 1761–1772 (2007).

    CAS  PubMed  Google Scholar 

  21. Suarez-Zamorano, N. et al. Microbiota depletion promotes browning of white adipose tissue and reduces obesity. Nat. Med. 21, 1497–1501 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Turnbaugh, P. J. et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–1031 (2006).

    PubMed  Google Scholar 

  23. Kim, K. A., Gu, W., Lee, I. A., Joh, E. H. & Kim, D. H. High fat diet-induced gut microbiota exacerbates inflammation and obesity in mice via the TLR4 signaling pathway. PLoS One 7, e47713 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Clarke, S. F. et al. Targeting the microbiota to address diet-induced obesity: a time dependent challenge. PLoS One 8, e65790 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Moyer, B. J. et al. Inhibition of the aryl hydrocarbon receptor prevents Western diet-induced obesity. Model for AHR activation by kynurenine via oxidized-LDL, TLR2/4, TGFbeta, and IDO1. Toxicol. Appl. Pharmacol. 300, 13–24 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Agudelo, L. Z. et al. Kynurenic acid and Gpr35 regulate adipose tissue energy homeostasis and inflammation. Cell. Metab. 27, 378–392.e5 (2018).

    CAS  PubMed  Google Scholar 

  27. Lamas, B. et al. CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nat. Med. 22, 598–605 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Garidou, L. et al. The gut microbiota regulates intestinal CD4 T cells expressing RORγt and controls metabolic disease. Cell. Metab. 22, 100–112 (2015).

    CAS  PubMed  Google Scholar 

  29. Wang, X. et al. Interleukin-22 alleviates metabolic disorders and restores mucosal immunity in diabetes. Nature 514, 237–241 (2014).

    CAS  PubMed  Google Scholar 

  30. Sonnenberg, G. F., Fouser, L. A. & Artis, D. Border patrol: regulation of immunity, inflammation and tissue homeostasis at barrier surfaces by IL-22. Nat. Immunol. 12, 383–390 (2011).

    CAS  PubMed  Google Scholar 

  31. Rutz, S., Eidenschenk, C. & Ouyang, W. IL-22, not simply a Th17 cytokine. Immunol. Rev. 252, 116–132 (2013).

    PubMed  Google Scholar 

  32. Gulhane, M. et al. High fat diets induce colonic epithelial cell stress and inflammation that is reversed by IL-22. Sci. Rep. 6, 28990 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Murakami, Y. & Saito, K. Species and cell types difference in tryptophan metabolism. Int. J. Tryptophan Res. 6, 47–54 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Salazar, M. R. et al. Relation among the plasma triglyceride/high-density lipoprotein cholesterol concentration ratio, insulin resistance, and associated cardio-metabolic risk factors in men and women. Am. J. Cardiol. 109, 1749–1753 (2012).

    CAS  PubMed  Google Scholar 

  35. Sonnenberg, G. F. & Artis, D. Innate lymphoid cell interactions with microbiota: implications for intestinal health and disease. Immunity 37, 601–610 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Berglund, E. D. et al. Glucose metabolism in vivo in four commonly used inbred mouse strains. Diabetes 57, 1790–1799 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Allison, D. B., Paultre, F., Maggio, C., Mezzitis, N. & Pi-Sunyer, F. X. The use of areas under curves in diabetes research. Diabetes Care 18, 245–250 (1995).

    CAS  PubMed  Google Scholar 

  38. Ferchaud-Roucher, V., Pouteau, E., Piloquet, H., Zair, Y. & Krempf, M. Colonic fermentation from lactulose inhibits lipolysis in overweight subjects. Am. J. Physiol. Endocrinol. Metab. 289, E716–720 (2005).

    CAS  PubMed  Google Scholar 

  39. Cansell, C. et al. Dietary triglycerides act on mesolimbic structures to regulate the rewarding and motivational aspects of feeding. Mol. Psychiatry 19, 1095–1105 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Speakman, J. R., Fletcher, Q. & Vaanholt, L. The ‘39 steps’: an algorithm for performing statistical analysis of data on energy intake and expenditure. Dis. Model Mech. 6, 293–301 (2013).

    PubMed  PubMed Central  Google Scholar 

  41. Schmieder, R. & Edwards, R. Quality control and preprocessing of metagenomic datasets. Bioinformatics 27, 863–864 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Edgar, R. C. Search and clustering orders of magnitude faster than BLAST. Bioinformatics 26, 2460–2461 (2010).

    CAS  PubMed  Google Scholar 

  43. McDonald, D. et al. An improved Greengenes taxonomy with explicit ranks for ecological and evolutionary analyses of bacteria and archaea. ISME J. 6, 610–618 (2012).

    CAS  PubMed  Google Scholar 

  44. Segata, N. et al. Metagenomic biomarker discovery and explanation. Genome. Biol. 12, R60 (2011).

    PubMed  PubMed Central  Google Scholar 

  45. Gao, X. et al. Metabolite analysis of human fecal water by gas chromatography/mass spectrometry with ethyl chloroformate derivatization. Anal. Biochem. 393, 163–175 (2009).

    CAS  PubMed  Google Scholar 

  46. Maneglier, B. et al. Simultaneous measurement of kynurenine and tryptophan in human plasma and supernatants of cultured human cells by HPLC with coulometric detection. Clin. Chem. 50, 2166–2168 (2004).

    CAS  PubMed  Google Scholar 

  47. Ferraresi, C. et al. Time response of increases in ATP and muscle resistance to fatigue after low-level laser (light) therapy (LLLT) in mice. Lasers. Med. Sci. 30, 1259–1267 (2015).

    PubMed  Google Scholar 

  48. Wu, H. et al. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat. Med. 23, 850–858 (2017).

    CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by INSERM, Fondation pour la Recherche Médicale (A.T.) and Fondation de France (S.T.). H.S. received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (ERC-2016-StG-71577).We are grateful to S. Billon-Crossouard from the Platform of Mass Spectrometry of Nantes University for SCFA analysis. We acknowledge the technical platform metabolism of the Unit “Biologie Fonctionnelle et Adaptative” (University Paris Diderot, Sorbonne Paris Cité, BFA, UMR 8251 CNRS, 75205 Paris, France) for metabolic analysis and the animal core facility “Buffon” of the University Paris Diderot Paris 7/Institut Jacques Monod, Paris for animal husbandry. We are thankful to the Genomics Platform of Translational Research Department, Institut Curie, PSL Research University for sharing their expertise and helping us with NanoString analysis. We thank members of our animal and histology facilities. We thank B. Gaye for his help with statistical analysis. We thank N. Vodovar for discussions and C. Heymes for his help with human sample preparation.

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L.L. was involved in experimental design, conducted most experiments and analyzed data. N.V. provided technical and conceptual help on obesity experiments and discussed results. Y.H., M.Chajadine., S.M. and B.S. helped in some experiments. R.G.P.D. designed, performed, analyzed and interpreted the indirect calorimetry exploration. F.A. helped with experiments and performed immunohistological staining. M.S., C.M. and S.J. provided technical help for microbiota analysis. T.V. and B.T. performed and discussed PET analysis. B.E. helped with in vivo studies. J.-M.L., J.D. and J.C. measured all biochemical parameters in mouse and human samples. S.H.L. provided funding and contributed to calorimetry data analysis and interpretation. M.Cardellini., J.-M.M.-N., M.F., J.M.F.-R. and R.B. provided human material and clinical data. A.T. and Z.M. discussed results and edited the manuscript. H.S. performed and interpreted gut microbiota analysis, provided some of human samples and discussed results. S.T. designed the study, analyzed and interpreted the data and wrote the manuscript.

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Correspondence to Soraya Taleb.

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Laurans, L., Venteclef, N., Haddad, Y. et al. Genetic deficiency of indoleamine 2,3-dioxygenase promotes gut microbiota-mediated metabolic health. Nat Med 24, 1113–1120 (2018). https://doi.org/10.1038/s41591-018-0060-4

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