The Gut Microbiome and DiseaseThe Microbiome in Inflammatory Bowel Disease: Current Status and the Future Ahead
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
References (126)
Microbial influences in inflammatory bowel diseases
Gastroenterology
(2008)- et al.
Mucosal flora in inflammatory bowel disease
Gastroenterology
(2002) Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences
Gastroenterology
(2004)- et al.
Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease
Nature
(2012) - et al.
Genetics and pathogenesis of inflammatory bowel disease
Nature
(2011) - et al.
Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review
Gastroenterology
(2012) - et al.
Family and twin studies in inflammatory bowel disease
World J Gastroenterol
(2006) Rethinking mechanisms of autoimmune pathogenesis
J Autoimmun
(2013)- et al.
The role of the gut microbiota in nutrition and health
Nat Rev Gastroenterol Hepatol
(2012) - et al.
The human gut microbiome: current knowledge, challenges, and future directions
Transl Res
(2012)
The gut flora as a forgotten organ
EMBO Rep
A human gut microbial gene catalogue established by metagenomic sequencing
Nature
Structure, function and diversity of the healthy human microbiome
Nature
What are the consequences of the disappearing human microbiota?
Nat Rev Microbiol
Evolution of mammals and their gut microbes
Science
Linking long-term dietary patterns with gut microbial enterotypes
Science
A vegan or vegetarian diet substantially alters the human colonic faecal microbiota
Eur J Clin Nutr
Dietary factors: major regulators of the gut's microbiota
Gut Liver
Increasing incidence of pediatric inflammatory bowel disease in Spain (1996-2009): the SPIRIT Registry
Inflamm Bowel Dis
Unravelling the effects of the environment and host genotype on the gut microbiome
Nat Rev Microbiol
Development of the human gastrointestinal microbiota and insights from high-throughput sequencing
Gastroenterology
Diversity, stability and resilience of the human gut microbiota
Nature
Composition, variability, and temporal stability of the intestinal microbiota of the elderly
Proc Natl Acad Sci U S A
A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease
Nature
Developmental regulation of intestinal angiogenesis by indigenous microbes via Paneth cells
Proc Natl Acad Sci U S A
Crohn's disease-associated Nod2 mutants reduce IL10 transcription
Nat Immunol
Disease phenotype and genotype are associated with shifts in intestinal-associated microbiota in inflammatory bowel diseases
Inflamm Bowel Dis
Fucosyltransferase 2 (FUT2) non-secretor status is associated with Crohn's disease
Hum Mol Genet
Colonic mucosa-associated microbiota is influenced by an interaction of Crohn disease and FUT2 (Secretor) genotype
Proc Natl Acad Sci U S A
A core gut microbiome in obese and lean twins
Nature
Skin microbiome imbalance in patients with STAT1/STAT3 defects impairs innate host defense responses
J Innate Immun
The fundamental basis of inflammatory bowel disease
J Clin Invest
Antiinflammatory effects of enterically coated amoxicillin-clavulanic acid in active ulcerative colitis
Inflamm Bowel Dis
Therapeutic manipulation of the enteric microflora in inflammatory bowel diseases: antibiotics, probiotics, and prebiotics
Gastroenterology
Recent developments in the treatment of inflammatory bowel disease
J Dig Dis
Mucosal antibodies in inflammatory bowel disease are directed against intestinal bacteria
Gut
Reactivity of infiltrating T lymphocytes with microbial antigens in Crohn's disease
Lancet
Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases
Proc Natl Acad Sci U S A
Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment
Genome Biol
Reduced diversity of faecal microbiota in Crohn's disease revealed by a metagenomic approach
Gut
Molecular analysis of the gut microbiota of identical twins with Crohn's disease
ISME J
Dysbiosis of fecal microbiota in Crohn's disease patients as revealed by a custom phylogenetic microarray
Inflamm Bowel Dis
Unstable composition of the fecal microbiota in ulcerative colitis during clinical remission
Am J Gastroenterol
Microbial diversity of inflamed and noninflamed gut biopsy tissues in inflammatory bowel disease
Inflamm Bowel Dis
The treatment-naïve microbiome in new-onset Crohn's disease
Cell Host Microbe
The secret garden's gardeners. Research increasingly appreciates the crucial role of gut viruses for human health and disease
EMBO Rep
Virus-plus-susceptibility gene interaction determines Crohn's disease gene Atg16L1 phenotypes in intestine
Cell
The role of Candida in inflammatory bowel disease. Estimation of transmission of C. albicans fungi in gastrointestinal tract based on genetic affinity between strains
Med Sci Monit
Fungi and inflammatory bowel diseases: alterations of composition and diversity
Scand J Gastroenterol
Host-mediated inflammation disrupts the intestinal microbiota and promotes the overgrowth of Enterobacteriaceae
Cell Host Microbe
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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.).