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Gut microorganisms and their metabolites modulate the severity of acute colitis in a tryptophan metabolism-dependent manner

Abstract

Purpose

Growing evidence shows that nutrient metabolism affects inflammatory bowel diseases (IBD) development. Previously, we showed that deficiency of indoleamine 2,3-dioxygenase 1 (Ido1), a tryptophan-catabolizing enzyme, reduced the severity of dextran sulfate sodium (DSS)-induced colitis in mice. However, the roles played by intestinal microbiota in generating the differences in disease progression between Ido1+/+ and Ido1−/− mice are unknown. Therefore, we aimed to investigate the interactions between the intestinal microbiome and host IDO1 in governing intestinal inflammatory responses.

Methods

Microbial 16s rRNA sequencing was conducted in Ido1+/+ and Ido1−/− mice after DSS treatment. Bacteria-derived tryptophan metabolites were measured in urine. Transcriptome analysis revealed the effects of the metabolite and IDO1 expression in HCT116 cells. Colitis severity of Ido1+/+ was compared to Ido1−/− mice following fecal microbiota transplantation (FMT).

Results

Microbiome analysis through 16S-rRNA gene sequencing showed that IDO1 deficiency increased intestinal bacteria that use tryptophan preferentially to produce indolic compounds. Urinary excretion of 3-indoxyl sulfate, a metabolized form of gut bacteria-derived indole, was significantly higher in Ido1−/− than in Ido1+/+ mice. Transcriptome analysis showed that tight junction transcripts were significantly increased by indole treatment in HCT116 cells; however, the effects were diminished by IDO1 overexpression. Using FMT experiments, we demonstrated that bacteria from Ido1−/− mice could directly attenuate the severity of DSS-induced colitis.

Conclusions

Our results provide evidence that a genetic defect in utilizing tryptophan affects intestinal microbiota profiles, altering microbial metabolites, and colitis development. This suggests that the host and intestinal microbiota communicate through shared nutrient metabolic networks.

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References

  1. 1.

    O'Hara AM, Shanahan F (2006) The gut flora as a forgotten organ. EMBO Rep 7(7):688–693

  2. 2.

    Sartor RB (2008) Microbial influences in inflammatory bowel diseases. Gastroenterology 134(2):577–594

  3. 3.

    Scott KP, Gratz SW, Sheridan PO, Flint HJ, Duncan SH (2013) The influence of diet on the gut microbiota. Pharmacol Res 69(1):52–60

  4. 4.

    Hesla HM, Stenius F, Jäderlund L, Nelson R, Engstrand L, Alm J, Dicksved J (2014) Impact of lifestyle on the gut microbiota of healthy infants and their mothers—the ALADDIN birth cohort. FEMS Microbiol Ecol 90(3):791–801

  5. 5.

    Shin J-H, Sim M, Lee J-Y, Shin D-M (2016) Lifestyle and geographic insights into the distinct gut microbiota in elderly women from two different geographic locations. J Physiol Anthropol 35(1):31–39

  6. 6.

    Yatsunenko T, Rey FE, Manary MJ, Trehan I, Dominguez-Bello MG, Contreras M, Magris M, Hidalgo G, Baldassano RN, Anokhin AP, Heath AC, Warner B, Reeder J, Kuczynski J, Caporaso JG, Lozupone CA, Lauber C, Clemente JC, Knights D, Knight R, Gordon JI (2012) Human gut microbiome viewed across age and geography. Nature 486(7402):222–227

  7. 7.

    Grzeskowiak L, Collado MC, Mangani C, Maleta K, Laitinen K, Ashorn P, Isolauri E, Salminen S (2012) Distinct gut microbiota in southeastern African and northern European infants. J Pediatr Gastroenterol Nutr 54(6):812–816

  8. 8.

    Dehingia M, Talukdar NC, Talukdar R, Reddy N, Mande SS, Deka M, Khan MR (2015) Gut bacterial diversity of the tribes of India and comparison with the worldwide data. Sci Rep 5:18563

  9. 9.

    Senghor B, Sokhna C, Ruimy R, Lagier J-C (2018) Gut microbiota diversity according to dietary habits and geographical provenance. Hum Microbiome J 7:1–9

  10. 10.

    Bassett SA, Young W, Barnett MP, Cookson AL, McNabb WC, Roy NC (2015) Changes in composition of caecal microbiota associated with increased colon inflammation in interleukin-10 gene-deficient mice inoculated with enterococcus species. Nutrients 7(3):1798–1816

  11. 11.

    Gálvez EJ, Iljazovic A, Gronow A, Flavell R, Strowig T (2017) Shaping of intestinal microbiota in Nlrp6-and Rag2-deficient mice depends on community structure. Cell Rep 21(13):3914–3926

  12. 12.

    Kim CJ, Kovacs-Nolan JA, Yang CB, Archbold T, Fan MZ, Mine Y (2010) L-Tryptophan exhibits therapeutic function in a porcine model of dextran sodium sulfate (DSS)-induced colitis. J Nutr Biochem 21(6):468–475

  13. 13.

    Shizuma T, Mori H, Fukuyama N (2013) Protective effect of tryptophan against dextran sulfate sodium- induced experimental colitis. Turk J Gastroenterol 24(1):30–35

  14. 14.

    Ciorba MA (2013) Indoleamine 2, 3 dioxygenase (IDO) in intestinal disease. Curr Opin Gastroenterol 29(2):146

  15. 15.

    Shon W-J, Lee Y-K, Shin JH, Choi EY, Shin D-M (2015) Severity of DSS-induced colitis is reduced in Ido1-deficient mice with down-regulation of TLR-MyD88-NF-kB transcriptional networks. Sci Rep 5:17305

  16. 16.

    Cole JR, Wang Q, Fish JA, Chai B, McGarrell DM, Sun Y, Brown CT, Porras-Alfaro A, Kuske CR, Tiedje JM (2014) Ribosomal Database Project: data and tools for high throughput rRNA analysis. Nucleic Acids Res 42(Database issue):D633–642

  17. 17.

    Edgar RC, Haas BJ, Clemente JC, Quince C, Knight R (2011) UCHIME improves sensitivity and speed of chimera detection. Bioinformatics 27(16):2194–2200

  18. 18.

    Wang GGM, Tiedje JM, Cole JR (2007) Naive Bayesian classifier for rapid assignment of rRNA sequences into the new bacterial taxonomy. Appl Environ Microbiol 73(16):5261–5267

  19. 19.

    Lee Y-K, Lee HB, Shin D-M, Kang MJ, Yi EC, Noh S, Lee J, Lee C, Min C-K, Choi EY (2014) Heme-binding-mediated negative regulation of the tryptophan metabolic enzyme indoleamine 2, 3-dioxygenase 1 (IDO1) by IDO2. Exp Mol Med 46(11):e121

  20. 20.

    Zhang JD, Schindler T, Kung E, Ebeling M, Certa U (2014) Highly sensitive amplicon-based transcript quantification by semiconductor sequencing. BMC Genom 15:565

  21. 21.

    Li Z, Huang J, Zhao J, Chen C, Wang H, Ding H, Wang DW, Wang DW (2014) Rapid molecular genetic diagnosis of hypertrophic cardiomyopathy by semiconductor sequencing. J Transl Med 12:173

  22. 22.

    Hartley JW, Chattopadhyay SK, Lander MR, Taddesse-Heath L, Naghashfar Z, Morse HC 3rd, Fredrickson TN (2000) Accelerated appearance of multiple B cell lymphoma types in NFS/N mice congenic for ecotropic murine leukemia viruses. Lab Invest 80(2):159–169

  23. 23.

    Wu H-J, Ivanov II, Darce J, Hattori K, Shima T, Umesaki Y, Littman DR, Benoist C, Mathis D (2010) Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity 32(6):815–827

  24. 24.

    Karmarkar D, Rock KL (2013) Microbiota signalling through MyD88 is necessary for a systemic neutrophilic inflammatory response. Immunology 140(4):483–492

  25. 25.

    Reikvam DH, Erofeev A, Sandvik A, Grcic V, Jahnsen FL, Gaustad P, McCoy KD, Macpherson AJ, Meza-Zepeda LA, Johansen F-E (2011) Depletion of murine intestinal microbiota: effects on gut mucosa and epithelial gene expression. PLoS ONE 6(3):e17996

  26. 26.

    Segata N, Izard J, Waldron L, Gevers D, Miropolsky L, Garrett WS, Huttenhower C (2011) Metagenomic biomarker discovery and explanation. Genome Biol 12(6):R60

  27. 27.

    Reunanen J, Kainulainen V, Huuskonen L, Ottman N, Belzer C, Huhtinen H, de Vos WM, Satokari R (2015) Akkermansia muciniphila adheres to enterocytes and strengthens the integrity of epithelial cell layer. Appl Environ Microbiol 81(11):3655–3662

  28. 28.

    Sridharan GV, Choi K, Klemashevich C, Wu C, Prabakaran D, Pan LB, Steinmeyer S, Mueller C, Yousofshahi M, Alaniz RC (2014) Prediction and quantification of bioactive microbiota metabolites in the mouse gut. Nat Commun 5:5492

  29. 29.

    Lee J-H, Lee J (2010) Indole as an intercellular signal in microbial communities. FEMS Microbiol Rev 34(4):426–444

  30. 30.

    Yokoyama M, Carlson J (1979) Microbial metabolites of tryptophan in the intestinal tract with special reference to skatole. Am J Clin Nutr 32(1):173–178

  31. 31.

    Russell WR, Duncan SH, Scobbie L, Duncan G, Cantlay L, Calder AG, Anderson SE, Flint HJ (2013) Major phenylpropanoid-derived metabolites in the human gut can arise from microbial fermentation of protein. Mol Nutr Food Res 57(3):523–535

  32. 32.

    Wikoff WR, Anfora AT, Liu J, Schultz PG, Lesley SA, Peters EC, Siuzdak G (2009) Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc Natl Acad Sci USA 106(10):3698–3703

  33. 33.

    Sokol H, Lay C, Seksik P, Tannock GW (2008) Analysis of bacterial bowel communities of IBD patients: what has it revealed? Inflamm Bowel Dis 14(6):858–867

  34. 34.

    Gupta NK, Thaker AI, Kanuri N, Riehl TE, Rowley CW, Stenson WF, Ciorba MA (2012) Serum analysis of tryptophan catabolism pathway: correlation with Crohn's disease activity. Inflamm Bowel Dis 18(7):1214–1220

  35. 35.

    Sun J (2018) Dietary vitamin D, vitamin D receptor, and microbiome. Curr Opin Clin Nutr Metab Care 21(6):471

  36. 36.

    Ghazalpour A, Cespedes I, Bennett BJ, Allayee H (2016) Expanding role of gut microbiota in lipid metabolism. Curr Opin Lipidol 27(2):141–147

  37. 37.

    Gurtner GJ, Newberry RD, Schloemann SR, McDonald KG, Stenson WF (2003) Inhibition of indoleamine 2,3-dioxygenase augments trinitrobenzene sulfonic acid colitis in mice. Gastroenterology 125(6):1762–1773

  38. 38.

    Takamatsu M, Hirata A, Ohtaki H, Hoshi M, Hatano Y, Tomita H, Kuno T, Saito K, Hara A (2013) IDO1 plays an immunosuppressive role in 2, 4, 6-trinitrobenzene sulfate-induced colitis in mice. J Immunol 191(6):3057–3064

  39. 39.

    Shimada Y, Kinoshita M, Harada K, Mizutani M, Masahata K, Kayama H, Takeda K (2013) Commensal bacteria-dependent indole production enhances epithelial barrier function in the colon. PLoS ONE 8(11):e80604

  40. 40.

    Bansal T, Alaniz RC, Wood TK, Jayaraman A (2010) The bacterial signal indole increases epithelial-cell tight-junction resistance and attenuates indicators of inflammation. Proc Natl Acad Sci USA 107(1):228–233

  41. 41.

    Poritz LS, Garver KI, Green C, Fitzpatrick L, Ruggiero F, Koltun WA (2007) Loss of the tight junction protein ZO-1 in dextran sulfate sodium induced colitis. J Surg Res 140(1):12–19

  42. 42.

    Mankertz J, Schulzke JD (2007) Altered permeability in inflammatory bowel disease: pathophysiology and clinical implications. Curr Opin Gastroenterol 23(4):379–383

  43. 43.

    Zelante T, Iannitti RG, Cunha C, De Luca A, Giovannini G, Pieraccini G, Zecchi R, D'Angelo C, Massi-Benedetti C, Fallarino F, Carvalho A, Puccetti P, Romani L (2013) Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity 39(2):372–385

  44. 44.

    Oh S, Go GW, Mylonakis E, Kim Y (2012) The bacterial signalling molecule indole attenuates the virulence of the fungal pathogen Candida albicans. J Appl Microbiol 113(3):622–628

  45. 45.

    Lee JH, Cho HS, Kim Y, Kim JA, Banskota S, Cho MH, Lee J (2013) Indole and 7-benzyloxyindole attenuate the virulence of Staphylococcus aureus. Appl Microbiol Biotechnol 97(10):4543–4552

  46. 46.

    Hashimoto T, Perlot T, Rehman A, Trichereau J, Ishiguro H, Paolino M, Sigl V, Hanada T, Hanada R, Lipinski S, Wild B, Camargo SM, Singer D, Richter A, Kuba K, Fukamizu A, Schreiber S, Clevers H, Verrey F, Rosenstiel P, Penninger JM (2012) ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. Nature 487(7408):477–481

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Acknowledgements

This research was supported by the Seoul National University Research Grant.

Author information

This study was designed, directed, and coordinated by D-MS, EYC, and J-HS. HCM, D-MS, and EYC supervised the project. J-HS, W-JS, and Y-KL acquired data and performed the animal experiments. Detection of metabolites in urine was analyzed by BK and J-YC. J-HS analyzed and interpreted data. JHS and DMS wrote the main paper, and Y-KL and BK wrote the Materials and Methods section. COJ gave technical and material support. All authors discussed the results and implications and commented on the manuscript at all stages.

Correspondence to Eun Young Choi or Dong-Mi Shin.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The protocol of this study was approved by the Institutional Animal Care and Use Committee of the Institute of Laboratory Animal Resources, Seoul National University (Institutional Animal Care and Use Committee permit number: SNU-150119-5).

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Cite this article

Shin, J., Lee, Y., Shon, W. et al. Gut microorganisms and their metabolites modulate the severity of acute colitis in a tryptophan metabolism-dependent manner. Eur J Nutr (2020). https://doi.org/10.1007/s00394-020-02194-4

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Keywords

  • Gut microbiota
  • Indoleamine 2,3-dioxygenase 1
  • Colitis
  • Indole
  • Tryptophan