Recent Advances in Characterizing the Gastrointestinal Microbiome in Crohn's Disease: A Systematic Review

ORIGINAL ARTICLE Recent Advances in Characterizing the Gastrointestinal Microbiome in Crohn’s Disease: A Systematic Review Emily K. Wright, MD,* ,† Michael A. Kamm, MD, PhD,* ,†,‡ Shu Mei Teo, PhD,† Michael Inouye, PhD,† Josef Wagner, PhD,§ and Carl D. Kirkwood, PhD§ microbiota as well as specific taxonomic and functional shifts have been reported in Crohn’s disease and may play a central role in the inflammatory process. The aim was to systematically review recent developments in the structural and functional changes observed in the gastrointestinal microbiome in patients with Crohn’s Disease. Results: Seventy-two abstracts were included in this review. The effects of host genetics, disease phenotype, and inflammatory bowel disease treatment on the gastrointestinal microbiome in Crohn’s disease were reviewed, and taxonomic shifts in patients with early and established disease were described. The relative abundance of Bacteroidetes is increased and Firmicutes decreased in Crohn’s disease compared with healthy controls. Enterobacteriaceae, specifically Eschericia coli, is enriched in Crohn’s disease. Faecalibacterium prausnitzii is found at lower abundance in Crohn’s disease and in those with postoperative recurrence. Observed functional changes include major shifts in oxidative stress pathways, a decrease in butanoate and propanoate metabolism gene expression, lower levels of butyrate, and other short-chain fatty acids, decreased carbohydrate metabolism, and decreased amino acid biosynthesis. Conclusions: Changes in microbial composition and function have been described, although a causative role remains to be established. Larger, prospective, and longitudinal studies are required with deep interrogation of the microbiome if causality is to be determined, and refined microbial manipulation is to emerge as a focused therapy. (Inflamm Bowel Dis 2015;21:1219–1228) Key Words: Crohn’s disease, microbiota, microbiome, dysbiosis T he pathogenesis of Crohn’s disease, an inflammatory bowel disease (IBD), involves interactions between the host genome, gastrointestinal (GI) microbiota, and mucosal immune system. The initiating and perpetuating stimuli for immune dysregulation in IBD are not explained fully by genetic predisposition; other modifying factors must therefore be present.1 Genetic loci associated with the development of IBD can perturb the delicate relationship between the microbiota and the host leading to a dysregulated immune response and intestinal inflammation.2 The microbiome therefore plays a critical role in the pathogenesis of Crohn’s disease.3 The GI microbiota of healthy humans is dominated by 4 major bacterial phyla: Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria.4,5 There is some debate about the temporal Received for publication January 3, 2015; Accepted February 3, 2015. From the *Department of Gastroenterology, St Vincent’s Hospital Melbourne, Australia; †Department of Pathology, University of Melbourne, Australia; ‡Imperial College, London, United Kingdom; and §Enteric Virus Group, Murdoch Children’s Research Institute, Melbourne, Australia. The authors have no conflicts of interest to disclose. Reprints: Michael A. Kamm, MD, PhD, St Vincent’s Hospital, Victoria Parade, Fitzroy 3065, Melbourne, Australia (e-mail: ). Copyright © 2015 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1097/MIB.0000000000000382 Published online 3 April 2015. Inflamm Bowel Dis
Volume 21, Number 6, June 2015 stability of the microbiota in healthy subjects.5–8 Stability is challenged by factors such as the environment,9 travel,8 proximity to other humans and animals,10 diet,11,12 antibiotics,8,13 and smoking.14,15 Taxonomic changes or imbalance in a microbial community, termed dysbiosis, can be associated with the development of disease. Dysbiosis of the GI microbiota has been implicated in numerous conditions affecting human health including obesity,16,17 colorectal cancer,18,19 liver disease,20 irritable bowel syndrome,21–23 and IBD.24,25 However, the critical question remains as to whether changes in the composition of the microbiome precede, follow, cause, or only correlate with the onset of disease. Low-resolution methods used to define the GI microbiota in the past such as quantitative PCR, fluorescent in situ hybridization, denaturing gradient gel electrophoresis, terminal restriction fragment length polymorphism, and phylogenic microarray have differing levels of discrimination limiting the ability to make accurate and specific comparisons across studies. The recent development of the next generation sequencing techniques has allowed for unbiased highresolution description of the composition, function, and ecology of the microbial community and has improved the understanding of the role of the GI microbiota in health and disease.5,26 Of the many conditions believed to be associated with dysbiosis of the GI microbiome, Crohn’s disease has received the most interest. Broad patterns have begun to emerge in patients www.ibdjournal.org | 1219 Background: The intestinal microbiota is involved in the pathogenesis of inflammatory bowel disease. A reduction in the diversity of the intestinal Inflamm Bowel Dis
Volume 21, Number 6, June 2015 Wright et al METHODS This systematic review adheres to the relevant criteria from the PRISMA statement (Preferred Reporting Items for Systematic Reviews and Meta-Analyses).35 The methods used, including identification, screening, eligibility, and inclusion, were agreed by authors (E.K.W. and M.A.K.) in advance. An electronic search of the English language medical literature was conducted using Medline (EBSCOhost) and PubMed to identify published articles on the GI microbiome and Crohn’s disease. The final search date was July 2014. This search strategy used a combination of the following prespecified MeSH headings and keywords alone or in combination: Crohn’s disease, inflammatory bowel disease microbiota, microbiome, and dysbiosis. Boolean operators (“not,” “and,” “or”) were also used in succession to narrow or widen the search. The search was restricted to English language and human studies. Handsearching of abstracts from relevant international conferences was undertaken to obtain conference abstracts that would not 1220 | www.ibdjournal.org be identifiable through electronic searching. In addition, handsearching of the reference lists of relevant reviews and included studies was undertaken to identify further relevant references. Inclusion Criteria Studies examining the GI microbiota/microbiome through investigation of intestinal tissue or feces in patients of any age with Crohn’s disease or subjects with a family history of Crohn’s disease were included. In studies examining a mixed IBD cohort, only results from the Crohn’s disease subset were reviewed. Exclusion Criteria Non-English language studies and animal studies were excluded. Studies examining a mixed IBD cohort where there was no separate analysis for th (...truncated)