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The microbiome can predict mucosal healing in small intestine in patients with Crohn’s disease

Journal of Gastroenterology volume 55, pages 1138–1149 (2020)Cite this article

Abstract

Background

Mucosal healing is the main treatment goal for Crohn’s disease. In this situation, some patients have difficulty with endoscopic evaluation of the entire small intestine. Crohn’s disease is closely associated with the gut microbiota, but the relationship between the microbiome and disease activity in the small intestine remains unclear. We examined the association between the microbiome and endoscopic findings in the small intestine and determined whether the microbiome can predict mucosal healing.

Methods

The patients with Crohn’s disease who were scheduled for capsule or balloon-assisted endoscopy were included in this prospective study. Patients whose entire small intestine was evaluated were divided into two groups based on ulcerative findings. The microbiomes in the fecal samples were analyzed using 16S rRNA sequencing.

Results

The 38 enrolled patients were divided into the ulcer group (24) and mucosal healing group (14). The ulcer group exhibited lower α diversity. Six genera, namely Faecalibacterium (P = 0.008), Lachnospira (P = 0.009), Paraprevotella (P = 0.01), Dialister (P = 0.012), Streptococcus (P = 0.025), and Clostridium (P = 0.028) were enriched in the mucosal healing group. A predictive score for mucosal healing was defined using these six genera. The area under the curve was 0.795 and the sensitivity and specificity for predicting mucosal healing were 0.643 and 0.917, respectively.

Conclusions

Fecal microbiome is corelated with disease activity in the entire small intestine in Crohn’s disease patients. The predictive score proposed by microbiota characteristics was a potential biomarker for mucosal healing in the small intestine.

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Abbreviations

CD:

Crohn's disease

GI:

Gastrointestinal

CE:

Capsule endoscopy

BAE:

Balloon-assisted endoscopy

CRP:

C-reactive protein

FC:

Fecal calprotectin

PPV:

Positive predictive value

NPV:

Negative predictive value

AUC:

Under the curve

ROC:

Receiver-operating characteristics

LEfSe:

Linear discriminant analysis Effect Size

PCA:

Principal Coordinate Analysis

UC:

Ulcerative colitis

References

  1. Torres J, Mehandru S, Colombel J, et al. Crohn’s disease. Lancet. 2016;6736:1–15.

    Google Scholar 

  2. Peyrin-Biroulet L, Colombel J-F, et al. The natural history of adult Crohn’s disease in population-based cohorts. Am J Gastroenterol. 2010;105:289–97.

    PubMed  Google Scholar 

  3. Pariente B, Cosnes J, Danese S, et al. Development of the Crohn’s disease digestive damage score, the Lémann score. Inflamm Bowel Dis. 2011;17:1415–22.

    PubMed  Google Scholar 

  4. Modigliani R, Mary J-Y, Simon J-F, et al. Clinical, biological, and endoscopic picture of attacks of Crohn’s disease. Gastroenterology. 2011;98:811–8.

    Google Scholar 

  5. Baert F, Moortgat L, Van Assche G, et al. Mucosal healing predicts sustained clinical remission in patients with early-stage Crohn’s disease. Gastroenterology. 2010;138:463–8.

    PubMed  Google Scholar 

  6. Schnitzler F, Fidder H, Ferrante M, et al. Mucosal healing predicts long-term outcome of maintenance therapy with infliximab in Crohn’s disease. Inflamm Bowel Dis. 2009;15:1295–301.

    PubMed  Google Scholar 

  7. Annese V, Daperno M, Rutter MD, et al. European evidence based consensus for endoscopy in inflammatory bowel disease. J Crohn’s Colitis. 2013;7:982–1018.

    Google Scholar 

  8. Takenaka K, Fujii T, Suzuki K, et al. Small bowel healing detected by endoscopy in patients with Crohn’s disease after treatment with antibodies against tumor necrosis factor. Clin Gastroenterol Hepatrol. 2019. https://doi.org/10.1016/j.cgh.2019.08.024.

    Article  Google Scholar 

  9. Melmed GY, Dubinsky MC, Rubin DT, et al. Utility of video capsule endoscopy for longitudinal monitoring of Crohn’s disease activity in the small bowel: a prospective study. Gastrointest Endosc. 2018;88:947–55.

    PubMed  Google Scholar 

  10. Yamamoto H, Kita H, Sunada K, et al. Clinical outcomes of double-balloon endoscopy for the diagnosis and treatment of small-intestinal diseases. Clin Gastroenterol Hepatol. 2004;2:1010–6.

    PubMed  Google Scholar 

  11. Zepeda-Gómez S, Barreto-Zuñiga R, Ponce-De-León S, et al. Risk of hyperamylasemia and acute pancreatitis after double-balloon enteroscopy: a prospective study. Endoscopy. 2011;43:766–70.

    PubMed  Google Scholar 

  12. Mensink P, Haringsma J, Kucharzik TF, et al. Complications of double balloon enteroscopy: a multicenter survey. Endoscopy. 2007;39:613–5.

    CAS  PubMed  Google Scholar 

  13. Langhorst J, Elsenbruch S, Koelzer J, et al. Noninvasive markers in the assessment of intestinal inflammation in inflammatory bowel diseases: performance of fecal lactoferrin, calprotectin, and PMN-elastase, CRP, and clinical indices. Am J Gastroenterol. 2008;103:162–9.

    PubMed  Google Scholar 

  14. Hold GL, Smith M, Grange C, et al. Role of the gut microbiota in inflammatory bowel disease pathogenesis: what have we learnt in the past 10 years? World J Gastroenterol. 2014;20:1192–210.

    PubMed  PubMed Central  Google Scholar 

  15. Wills ES, Jonkers DMAE, Savelkoul PH, et al. Fecal microbial composition of ulcerative colitis and Crohn’s disease patients in remission and subsequent exacerbation. PLoS ONE. 2014;9:1–10.

    Google Scholar 

  16. Swidsinski A, Loening-Baucke V, Vaneechoutte M, et al. Active Crohnʼs disease and ulcerative colitis can be specifically diagnosed and monitored based on the biostructure of the fecal flora. Inflamm Bowel Dis. 2008;14:147–61.

    PubMed  Google Scholar 

  17. Xavier RJ. Microbiota as therapeutic targets. Dig Dis. 2016;34:558–65.

    PubMed  Google Scholar 

  18. Joossens M, Huys G, Cnockaert M, et al. Dysbiosis of the faecal microbiota in patients with Crohn’s disease and their unaffected relatives. Gut. 2011;60:631–7.

    PubMed  Google Scholar 

  19. Willing BP, Dicksved J, Halfvarson J, et al. A pyrosequencing study in twins shows that gastrointestinal microbial profiles vary with inflammatory bowel disease phenotypes. Gastroenterology. 2010;139:1844–54.

    PubMed  Google Scholar 

  20. Willing B, Halfvarson J, Dicksved J, et al. Twin studies reveal specific imbalances in the mucosa-associated microbiota of patients with ileal Crohn’s disease. Inflamm Bowel Dis. 2009;15:653–60.

    PubMed  Google Scholar 

  21. Vandeputte D, Falony G, Vieira-Silva S, et al. Stool consistency is strongly associated with gut microbiota richness and composition, enterotypes and bacterial growth rates. Gut. 2016;65:57–62.

    CAS  PubMed  Google Scholar 

  22. Nishimoto Y, Mizutani S, Nakajima T, et al. High stability of faecal microbiome composition in guanidine thiocyanate solution at room temperature and robustness during colonoscopy. Gut. 2016;65:1574–5.

    PubMed  Google Scholar 

  23. DeSantis TZ, Hugenholtz P, Larsen N, et al. Greengenes, a chimera-checked 16S rRNA gene database and workbench compatible with ARB. Appl Environ Microbiol. 2006;72:5069–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Navas-Molina JA, Peralta-Sánchez JM, González A, et al. Advancing our understanding of the human microbiome using QIIME. Methods Enzymol. 2013;531:371–444.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Segata N, Izard J, Waldron L, et al. Metagenomic biomarker discovery and explanation. Genome Biol. 2011;12:R60.

    PubMed  PubMed Central  Google Scholar 

  26. Prosberg M, Bendtsen F, Vind I, et al. The association between the gut microbiota and the inflammatory bowel disease activity: a systematic review and meta-analysis. Scand J Gastroenterol. 2016;51:1407–15.

    CAS  PubMed  Google Scholar 

  27. Pascal V, Pozuelo M, Borruel N, et al. A microbial signature for Crohn’s disease. Gut. 2017;66:813–22.

    CAS  PubMed  Google Scholar 

  28. Sommer F, Rühlemann MC, Bang C, et al. Microbiomarkers in inflammatory bowel diseases: caveats come with caviar. Gut. 2017;66:1734–8.

    CAS  PubMed  Google Scholar 

  29. Furet JP, Kong LC, Tap J, et al. Differential adaptation of human gut microbiota to bariatric surgery-induced weight loss: links with metabolic and low-grade inflammation markers. Diabetes. 2010;59:3049–57.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Graessler J, Qin Y, Zhong H, et al. Metagenomic sequencing of the human gut microbiome before and after bariatric surgery in obese patients with type 2 diabetes: correlation with inflammatory and metabolic parameters. Pharmacogenomics J. 2013;13:514–22.

    CAS  PubMed  Google Scholar 

  31. Balamurugan R, Rajendiran E, George S, et al. Real-time polymerase chain reaction quantification of specific butyrate-producing bacteria, Desulfovibrio and Enterococcus faecalis in the feces of patients with colorectal cancer. J Gastroenterol Hepatol. 2008;23:1298–303.

    CAS  PubMed  Google Scholar 

  32. Lopez-Siles M, Martinez-Medina M, Surís-Valls R, et al. Changes in the abundance of faecalibacterium prausnitzii phylogroups i and ii in the intestinal mucosa of inflammatory bowel disease and patients with colorectal cancer. Inflamm Bowel Dis. 2016;22:28–41.

    PubMed  Google Scholar 

  33. Sokol H, Pigneur B, Watterlot L, et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci U S A. 2008;105:16731–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Sokol H, Seksik P, Furet JP, et al. Low counts of Faecalibacterium prausnitzii in colitis microbiota. Inflamm Bowel Dis. 2009;15:1183–9.

    CAS  PubMed  Google Scholar 

  35. Machiels K, Joossens M, Sabino J, et al. A decrease of the butyrate-producing species Roseburia hominis and Faecalibacterium prausnitzii defines dysbiosis in patients with ulcerative colitis. Gut. 2014;63:1275–83.

    CAS  PubMed  Google Scholar 

  36. Lopez-Siles M, Martinez-Medina M, Busquets D, et al. Mucosa-associated Faecalibacterium prausnitzii and Escherichia coli co-abundance can distinguish Irritable Bowel Syndrome and Inflammatory Bowel Disease phenotypes. Int J Med Microbiol. 2014;304:464–75.

    PubMed  Google Scholar 

  37. Carlsson AH, Yakymenko O, Olivier I, et al. Faecalibacterium prausnitzii supernatant improves intestinal barrier function in mice DSS colitis. Scand J Gastroenterol. 2013;48:1136–44.

    CAS  PubMed  Google Scholar 

  38. Atarashi K, Tanoue T, Shima T, et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science. 2011;331:337–41.

    CAS  PubMed  Google Scholar 

  39. Gevers D. The treat ment-naïve microbiome in new-onset Crohn’ s disease. Cell Host Microbe. 2014;15:382–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Erickson AR, Cantarel BL, Lamendella R, et al. Integrated metagenomics / metaproteomics reveals human host-microbiota signatures of Crohn’s disease. PLoS ONE. 2012;7:e49138.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Imhann F, Bonder MJ, Vich Vila A, et al. Proton pump inhibitors affect the gut microbiome. Gut. 2016;65:740–8.

    CAS  PubMed  Google Scholar 

  42. Estevinho MM, Rocha C, Correia L, et al. Features of fecal and colon microbiomes associate with responses to biologic therapies for inflammatory bowel diseases: a systematic review. Clin Gastroenterol Hepatol. 2020;18:1054–69.

    CAS  PubMed  Google Scholar 

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Acknowledgements

We received no financial support for this research. We thank Ms. Akina Ooishi at the Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine for technical assistance in DNA isolation and 16S rRNA gene sequencing.

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Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Japan

    Shun Hattori, Masanao Nakamura, Takeshi Yamamura, Yasuyuki Mizutani, Kenta Yamamoto, Takuya Ishikawa, Kazuhiro Furukawa, Eizaburo Ohno, Takashi Honda, Masatoshi Ishigami & Mitsuhiro Fujishiro

  2. Department of Endoscopy, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya, Japan

    Keiko Maeda, Tsunaki Sawada & Hiroki Kawashima

  3. Department of Liver, Biliary Tract, and Pancreas Diseases, Fujita Health University School of Medicine, Aichi, Japan

    Yoshiki Hirooka

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  1. Shun Hattori
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Correspondence to Masanao Nakamura.

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Hattori, S., Nakamura, M., Yamamura, T. et al. The microbiome can predict mucosal healing in small intestine in patients with Crohn’s disease. J Gastroenterol 55, 1138–1149 (2020). https://doi.org/10.1007/s00535-020-01728-1

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  • DOI: https://doi.org/10.1007/s00535-020-01728-1

Keywords

  • Crohn’s disease
  • Gut microbiota
  • Mucosal healing
  • Small intestine