The Gut Microbiome as a Target for IBD Treatment: Are We There Yet?
Purpose of review
This review aims to highlight recent research on the gut microbiome in IBD and the application of microbiome-modulating therapies for the treatment of IBD including the use of the microbiome as an indicator for disease severity and treatment response.
Despite the high number of gut microbiome studies and emerging evidence supporting the gut microbiome’s involvement in disease pathogenesis, no single microorganism has been identified as a pathogenic agent in IBD. Retrospective studies and meta-analyses on antibiotic use in ulcerative colitis and Crohn’s disease and long-term outcomes are conflicting. Similarly, the use of probiotics for the treatment of IBD remains inconclusive; however, some encouraging results are emerging as microbial concoctions are optimized to include beneficial bacterial strains. Fecal microbial transplantation (FMT) is currently emerging as one of the more promising microbiome-modulating IBD therapies. FMT studies in ulcerative colitis have shown improved remission rates compared to placebo; however, relatively small study sample sizes and varied treatment methods, limit definitive conclusions.
With clear evidence of an IBD gut dysbiosis, novel therapies to treat and prevent disease relapse will undoubtedly require a microbiome-modulating approach. The complexity and variability of IBD disease pathogenesis (disease phenotype, gut microbiome, host genetic susceptibility, and environmental factors) will likely require a personalized and multidimensional treatment approach where microbiome-modulating therapy is coupled with other therapies to target other IBD disease components.
KeywordsInflammatory bowel disease Gut microbiota Fecal microbiota transplant Antibiotics Probiotics Prebiotics Gut microbiome Microbiota-modifying treatment
Clostridium difficile infection
exclusive enteral nutrition (EEN)
inflammatory bowel disease
fecal microbiota transplantation
microbial dysbiosis index
specific carbohydrate diet
Gary Van Domselaar receives operational funding from the Public Health Agency of Canada and has also received research support from the Multiple Sclerosis Society of Canada, the Canadian Institutes of Health Research, The National Sciences and Engineering Research Council, and Genome Canada.
Compliance with ethical standards
Conflict of interest
Charles Bernstein is supported in part by the Bingham Chair in Gastroenterology. He has served on advisory boards of Abbvie Canada, Ferring Canada, Janssen Canada, Pfizer Canada, Shire Canada, Takeda Canada, Napo Pharmaceuticals, and has consulted to 4D Pharm and Mylan Pharmaceuticals. He has received educational grants from Abbvie Canada, Janssen Canada, Pfizer Canada, Shire Canada, and Takeda Canada.
Human and animal rights and informed consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 1.• Ng SC, Shi HY, Hamidi N, Underwood FE, Tang W, Benchimol EI, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet. 2017;390:2769–78. This review updates current epidemiological data on IBD incidence and prevalence from around the world, highlighting the ongoing emergence of IBD in the developing world.CrossRefGoogle Scholar
- 10.Baumgart M, Dogan B, Rishniw M, Weitzman G, Bosworth B, Yantiss R, et al. Culture independent analysis of ileal mucosa reveals a selective increase in invasive Escherichia coli of novel phylogeny relative to depletion of Clostridiales in Crohn’s disease involving the ileum. ISME J. 2007;1:403–18.CrossRefGoogle Scholar
- 12.Fang X, Monk J, Nurk S, Akseshina M, Zhu Q, Gemmell C, et al. Metagenomics-based, strain-level analysis of Escherichia coli from a time-series of microbiome samples from a Crohn’s disease patient. Front Microbiol [Internet]. 2018 [cited 2018 Oct 18];9. Available from: https://www.frontiersin.org/articles/10.3389/fmicb.2018.02559/abstract. Accessed 1 Nov 2018.
- 16.• Imhann F, Vila AV, Bonder MJ, Fu J, Gevers D, Visschedijk MC, et al. Interplay of host genetics and gut microbiota underlying the onset and clinical presentation of inflammatory bowel disease. Gut. 2018;67:108–19. This study investigated the link between the IBD host genotype and gut microbiome using 16S rRNA sequencing of stool samples and host genotyping data in comparison to healthy controls. A key finding from this study was evidence that a gut dysbiosis commonly associated with IBD may precede disease manifestation. Healthy controls with high IBD genetic susceptibility were significantly associated with a lower abundance of Roseburia.CrossRefGoogle Scholar
- 17.•• Rothschild D, Weissbrod O, Barkan E, Kurilshikov A, Korem T, Zeevi D, et al. Environment dominates over host genetics in shaping human gut microbiota. Nature. 2018;555:210–5. Using independent cohorts, this study provides evidence that the influence of host genetics on the gut microbiome is likely minimal and report that only a small proportion of the gut microbiome is heritable; environmental factors impart a much larger effect on the human gut microbiome composition.CrossRefGoogle Scholar
- 18.•• Schirmer M, Franzosa EA, Lloyd-Price J, LJ MI, Schwager R, Poon TW, et al. Dynamics of metatranscription in the inflammatory bowel disease gut microbiome. Nature Microbiol. 2018;3:337–46. One of the first studies to combine both metagenomics and metatranscriptomics approaches on fecal samples taken from IBD patients and healthy controls. Their results highlight variability in the sequence data generated from both approaches suggesting that the transcriptional activity may unravel additional disease mechanisms not possible through microbial DNA sequence abundance data.CrossRefGoogle Scholar
- 23.El Mouzan M, Wang F, Al Mofarreh M, Menon R, Al Barrag A, Korolev KS, et al. Fungal microbiota profile in newly diagnosed treatment-naïve children with Crohn’s disease. J Crohn Col. 2017;11:586–92.Google Scholar
- 30.•• Levine A, Kori M, Kierkus J, Boneh RS, Sladek M, Escher JC, et al. Azithromycin and metronidazole versus metronidazole-based therapy for the induction of remission in mild to moderate paediatric Crohn’s disease : a randomised controlled trial. Gut. 2018;68:gutjnl-2017–315199. This study was a randomized controlled trial of azithromycin plus metronidazole versus metronidazole alone in children with Crohn’s disease. The group randomized to azithromycin had a higher remission rate. The remission rate in the azithromycin group was sufficiently high to raise concerns about the impact of lack of blinding.Google Scholar
- 36.•• Paramsothy S, Kamm MA, Kaakoush NO, Walsh AJ, van den Bogaerde J, Samuel D, et al. Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial. Lancet. 2017;389:1218–28. This was the most recent published randomized placebo controlled trial of fecal microbial transplantation in the treatment of UC. It suggested a magnitude of benefit similar to that seen in the previously reported Canadian study.CrossRefGoogle Scholar
- 39.•• Kao D, Roach B, Silva M, Beck P, Rioux K, Kaplan GG, et al. Effect of oral capsule– vs colonoscopy-delivered fecal microbiota transplantation on recurrent Clostridium difficile infection: a randomized clinical trial. JAMA. 2017;318:1985–93. This randomized controlled trial showed that encapsulated stool was comparably effective at reducing recurrence of C difficile as colonoscopically administered fecal microbial transplantation.CrossRefGoogle Scholar
- 45.Debelius J, Song SJ, Vazquez-Baeza Y, Xu ZZ, Gonzalez A, Knight R. Tiny microbes, enormous impacts: what matters in gut microbiome studies? Genome Biol [Internet]. 2016 [cited 2018 Oct 28];17. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5072314/. Accessed 1 Nov 2018.
- 49.Suskind DL, Cohen SA, Brittnacher MJ, Wahbeh G, Lee D, Shaffer ML, et al. Clinical and fecal microbial changes with diet therapy in active inflammatory bowel disease. J Clin Gastroenterol. 2018;52:155–63.Google Scholar
- 50.Gerasimidis K, Bertz M, Hanske L, Junick J, Biskou O, Aguilera M, et al. Decline in presumptively protective gut bacterial species and metabolites are paradoxically associated with disease improvement in pediatric Crohn’s disease during enteral nutrition. Inflamm Bowel Dis. 2014;20:861–71.CrossRefGoogle Scholar
- 51.Ashton JJ, Colquhoun CM, Cleary DW, Coelho T, Haggarty R, Mulder I, et al. 16S sequencing and functional analysis of the fecal microbiome during treatment of newly diagnosed pediatric inflammatory bowel disease. Medicine (Baltimore) [Internet]. 2017 [cited 2018 Oct 3];96. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5500076/Accessed 1 Nov 2018.