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

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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

    CAS  PubMed  Google Scholar 

  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

    CAS  PubMed  Google Scholar 

  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

    PubMed  PubMed Central  Google Scholar 

  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

    CAS  PubMed  PubMed Central  Google Scholar 

  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

    PubMed  Google Scholar 

  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

    CAS  PubMed  PubMed Central  Google Scholar 

  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

    Google Scholar 

  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

    CAS  PubMed  PubMed Central  Google Scholar 

  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

    PubMed  Google Scholar 

  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

    CAS  PubMed  Google Scholar 

  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

    PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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

    CAS  PubMed  PubMed Central  Google Scholar 

  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

    CAS  Google Scholar 

  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

    CAS  PubMed  PubMed Central  Google Scholar 

  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

    CAS  PubMed  PubMed Central  Google Scholar 

  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

    CAS  PubMed  PubMed Central  Google Scholar 

  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

    Google Scholar 

  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

    PubMed  PubMed Central  Google Scholar 

  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

    CAS  PubMed  Google Scholar 

  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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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

    CAS  PubMed  PubMed Central  Google Scholar 

  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

    PubMed  PubMed Central  Google Scholar 

  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

    CAS  PubMed  PubMed Central  Google Scholar 

  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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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

    CAS  PubMed  Google Scholar 

  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

    CAS  PubMed  Google Scholar 

  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

    CAS  PubMed  Google Scholar 

  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

    PubMed  Google Scholar 

  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

    PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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

    CAS  PubMed  PubMed Central  Google Scholar 

  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

    CAS  PubMed  Google Scholar 

  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

    CAS  PubMed  Google Scholar 

  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

    PubMed  PubMed Central  Google Scholar 

  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

    CAS  PubMed  Google Scholar 

  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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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

    CAS  Google Scholar 

  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

    CAS  PubMed  Google Scholar 

  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

    CAS  PubMed  Google Scholar 

  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

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

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

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Authors and Affiliations

  1. Department of Food and Nutrition, Seoul National University College of Human Ecology, Seoul, 08826, Korea

    Ji-Hee Shin, Woo-Jeong Shon & Dong-Mi Shin

  2. Research Group of Healthcare, Research Division of Food Functionality, Korea Food Research Institute, Wanju-gun, 55365, Republic of Korea

    Ji-Hee Shin

  3. Department of Biomedical Sciences, Graduate School of Seoul National University, Seoul, 03080, Republic of Korea

    Young-Kwan Lee & Eun Young Choi

  4. Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, 03080, Republic of Korea

    Bora Kim & Joo-Youn Cho

  5. Department of Life Science, Chung-Ang University, 84 Huekseok-ro, Dongjak-gu, Seoul, 06974, Republic of Korea

    Che Ok Jeon

  6. Virology and Cellular Immunology Section, Laboratory of Immunogenetics, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, 20852, USA

    Herbert C. Morse III

  7. Research Institution of Human Ecology, Seoul National University, Seoul, 08826, Republic of Korea

    Dong-Mi Shin

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  1. Ji-Hee Shin
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Contributions

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.

Corresponding authors

Correspondence to Eun Young Choi or Dong-Mi Shin.

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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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Shin, JH., Lee, YK., Shon, WJ. et al. Gut microorganisms and their metabolites modulate the severity of acute colitis in a tryptophan metabolism-dependent manner. Eur J Nutr 59, 3591–3601 (2020). https://doi.org/10.1007/s00394-020-02194-4

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  • DOI: https://doi.org/10.1007/s00394-020-02194-4

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