Gastroenterology

Gastroenterology

Volume 146, Issue 6, May 2014, Pages 1489-1499
Gastroenterology

The Gut Microbiome and Disease
The Microbiome in Inflammatory Bowel Disease: Current Status and the Future Ahead

https://doi.org/10.1053/j.gastro.2014.02.009Get rights and content

Studies of the roles of microbial communities in the development of inflammatory bowel disease (IBD) have reached an important milestone. A decade of genome-wide association studies and other genetic analyses have linked IBD with loci that implicate an aberrant immune response to the intestinal microbiota. More recently, profiling studies of the intestinal microbiome have associated the pathogenesis of IBD with characteristic shifts in the composition of the intestinal microbiota, reinforcing the view that IBD results from altered interactions between intestinal microbes and the mucosal immune system. Enhanced technologies can increase our understanding of the interactions between the host and its resident microbiota and their respective roles in IBD from both a large-scale pathway view and at the metabolic level. We review important microbiome studies of patients with IBD and describe what we have learned about the mechanisms of intestinal microbiota dysfunction. We describe the recent progress in microbiome research from exploratory 16S-based studies, reporting associations of specific organisms with a disease, to more recent studies that have taken a more nuanced view, addressing the function of the microbiota by metagenomic and metabolomic methods. Finally, we propose study designs and methodologies for future investigations of the microbiome in patients with inflammatory gut and autoimmune diseases in general.

Section snippets

Diet

One of the most important environmental factors affecting microbial composition is dietary preference, which has been shown to determine microbiome composition throughout mammalian evolution.15 Although no specific diet has been shown to directly cause, prevent, or treat IBD, it is important to take interactions between nutrients and microbiota into account when studying the role of the microbiome in disease. Thus far, only limited information on this topic has been gathered in humans,

IBD Genetics Point to an Interplay Between the Immune System and Microbiota in IBD

A potential link between genetics and the microbiome has long been suspected. The first identified CD susceptibility gene was NOD2,24 which stimulates an immune reaction on recognizing muramyl dipeptide, a cell wall peptidoglycan constituent of gram-positive and gram-negative bacteria. NOD2 is expressed in Paneth cells, which are located predominantly in the terminal ileum at the base of intestinal crypts, and produce antimicrobial defensins.25 Therefore, it may not be surprising that mutations

An Overview of Gut Microbiome Studies in IBD

Many IBD susceptibility loci suggest an impaired response to microbes in disease, but the causality of this relationship is unclear. The pathogenesis of IBD may result from a dysregulation of the mucosal immune system driving a pathogenic immune response against the commensal gut flora.32 Some studies have shown that the gut microbiota is an essential factor in driving inflammation in IBD1; indeed, short-term treatment with enterically coated antibiotics dramatically reduces intestinal

Microbes Enriched in IBD May Potentiate Disease

Specific taxonomic shifts have been reported in IBD (Table 1). The Enterobacteriaceae are increased in relative abundance both in patients with IBD and in mouse models.50 Escherichia coli, particularly adherent-invasive E coli strains, have been isolated from ileal CD (iCD) biopsy specimens in culture-based studies51 and are enriched in patients with UC.52 This enrichment is more pronounced in mucosal samples than in fecal samples.53 The increase in Enterobacteriaceae may indicate the

Protective Effects of Microbes in IBD

Several lines of evidence suggest that specific groups of gut bacteria may have protective effects against IBD. For example, the colitis phenotype after treatment with dextran sulfate sodium is more severe in mice that are reared germ-free compared with conventionally reared mice.72 One mechanism by which the commensal microbiota may protect the host is colonization resistance, in which commensals occupy niches within the host and prevent colonization by pathogens73 and help outcompete

Functional Composition of the Gut Microbiota in IBD

At the phylogenetic level, there is generally high variability in the human microbiota between and within individual subjects over time.13 However, the functional composition (ie, the functional potential of the gene content of the metagenome) of the gut microbiota is strikingly stable.13 Metagenomic approaches may therefore provide greater insight into the function of the gut microbiota in disease than taxonomic profiling87, 88; indeed, one such metagenomics study of the IBD microbiome found

The Gut Microbiota in Related Diseases

A number of parallels can be drawn between IBD and related metabolic diseases such as type 2 diabetes mellitus (T2DM) and obesity. For example, there is an overall decrease in diversity in obesity at both the phylogenetic level (ie, a reduced number of distinct species)30 and the metagenomic gene count level (ie, a reduced number of distinct genes).93 Major shifts in clade abundances include a reduction of the Firmicutes and Clostridia in T2DM94 and a significant increase in the Firmicutes to

IBD Treatments Affecting the Microbiome

An array of antibiotics have been shown to lead to a bloom of E coli.101 Because increased Enterobacteriaceae is a distinctive feature of intestinal inflammation and oxidative stress, the relationship between microbial composition, inflammation, and antibiotic use forms an important topic for future research. In contrast, some promising data show that antibiotic therapy specifically in IBD does induce remission or prevent relapse, but this topic will require further controlled trials.102 To

Future Directions

Studies thus far have been able to address many aspects of IBD, including genetics, immune responses, microbial dysbiosis, and microbial functional activity. However, because of the complexity of the human microbiome as a dynamically interacting system, only limited data have been produced to bridge the gap between pathogenesis in a human host, individual microbes, and alterations in microbial metabolism and function. This suggests the need for a more multifaceted approach to the microbiome in

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    Conflicts of interest The authors disclose no conflicts.

    Funding Supported by grants from the Crohn's and Colitis Foundation of America (to R.J.X.) and National Institutes of Health grants U54 DE023798 and R01 DK092405 (to R.J.X.).

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