Incidence susceptibility and environmental factors, the fact that

Incidence and
prevalence of inflammatory bowel diseases (IBD) are increasing extensively all
over the world. Industrialized Western countries such as North America show the
incidence of IBD in 400-600 cases per 100,000 persons. 1 The incidence and prevalence of IBD are dramatically
increasing in developing countries such as Asia and Latin America. 2, 3 IBD, which include Crohn’s
disease (CD) and ulcerative colitis (UC), are complex chronic diseases in the
gastrointestinal tract caused by dysregulated intestinal immune response
towards the intestinal microbiota. Pathological symptoms of IBD include
diarrhea, lower gastrointestinal bleeding, abdominal pain, weight loss and
fever as a chronic bowel-relapsing inflammatory disease. 4 Whereas UC exhibits
inflammation and ulcers only in the colon, CD affects any part of the
gastrointestinal tract. 5 Treatment for
IBD depends on the suppression of disease severity via the application of anti-inflammatory
steroids, non-steroidal anti-inflammatory drugs (NSAID) or biologics.

The etiology of IBD involves a complex interplay of genetic susceptibility
(>200 IBD-associated gene loci),6–9 environmental
factors (e.g. diet, geography, smoking, stress and medications),10–14 intestinal
microbiota 15, 16 and immune
response. 17, 18 Current
genome-wide association studies (GWAS) identified more than 200 susceptibility
loci for IBD in over 75,000 patients and controls, indicating that genetic
variants affect intestinal immune homeostasis through different mechanisms like
e.g. the defect in IL10 signaling and nucleotide-binding oligomerization domain
containing protein 2 (NOD2) gene variants associated with autophagy deficiency.
19–22 Unlike the
protective effect of smoking in UC, several studies consistently demonstrated
that smoking is associated with a more severe course and a relapse of CD
through a nicotine-mediated increase in the plasmacytoid DC and Th1 cells. 23, 24 Similar to
the relationship with smoking, dietary fat consumption is a high risk factor
for the development of IBD. 25, 26 Physiological
stress also affects alteration of immune function, resulting in an increased
risk of developing IBD. 27, 28 Apart from genetic and environmental factors, the intestinal microbial
ecosystem affects intestinal inflammation and IBD pathogenesis. However, despite recent progress in unravelling the
pathogenesis of IBD comprising various genetical susceptibility and
environmental factors, the fact that initial triggers of chronic inflammation
are still unclear in susceptible individuals indicates the highly complex
etiology of IBD. 29, 30The gastrointestinal tract contains 1014 diverse microorganisms including bacteria, fungi and
protozoa. 31, 32 The human intestinal microbiota is estimated to
comprise approximately 500 different bacterial species, and is composed of the
phyla Firmicutes, Bacteroidetes, Actinobacteria and Proteobacteria which account
for about 99% of all bacteria in the intestine. 33, 34 The intestinal microbiota plays an essential role in
different aspects of host physiology. 35, 36 Gut microbiota affects host metabolism, intestinal
homeostasis, development and regulation of the immune system. 37–39 The intestinal bacteria contribute to the host
digestion through the indirect regulation of various enzymes and metabolic
pathways and through the secreted bacterial enzymes which digest nutrients in
the intestine. 31, 40, 41 Bacteria in the intestine are essential for the
oligosaccharide fermentation and the conversion of dietary fiber into short
chain fatty acids (SCFA). 42–44 In addition, certain bacteria in the intestine contribute
to the initial degradation of complex substrates such as plant-derived polysaccharides,
45 the vitamin synthesis and the absorption of calcium
and magnesium. 46–48 Gut microbiota are associated with metabolic diseases
such as diabetes, atherosclerosis and obesity through the change in microbiota
composition, the dysregulation in host energy homeostasis and the systemic
inflammation. 49–52 The intestinal microbiota is a highly diverse
ecosystem performing abundant functions such as bile acid metabolism,
peristaltic movement of the gastrointestinal tract and degradation of
pancreatic proteases in the large intestine. 53–56 Furthermore, intestinal bacteria have benefits
relating to the prevention of pathogenic colonization and the reduction of
infections. 53, 57 Importantly, gut microbiota develops the intestinal
mucosal and systemic immune system. GF mice have deficits in the number of
different immune cells in immune associated tissues and organs. 58, 59 Specific bacteria promote the maturation and
expansion of T lymphocytes and the regulation of dendritic cells (DCs) and Th17
cells. 60–62 Also, gut microbiota modulate host immune response
towards tolerance through the prevention of NF-kB activation, the
detoxification of LPS and the downregulation of endotoxin signaling. 63–65 Gut microbiota control their numbers to maintain the homeostatic immune responses through the production of secretory IgA and
antimicrobial peptides. 66–68

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The intestinal
microbiota plays a pivotal role for the onset and progression of IBD. Several
study showed that alteration of microbiota composition, especially the reduced
number of Bacteroidetes and Lachnospiraceae in CD and UC patients, 69 and the increase in Gammaproteobacteria and Enterobacteriaceae
in UC and CD patients, 70, 71 implicate the triggering inflammation in disease
susceptible hosts. 15, 72 In other studies, depletion of Faecalibacterium prausnitzii was observed in CD patients compared
to healthy people, suggesting that anti-inflammatory properties of F. prausnitzii prevents ileitis
development. 73 The increase in infiltrated mucosa-associated E.coli in the colonic layer was
associated with the recruitment of macrophage and granulomatous colitis. 74, 75 The intestinal microbiota dysbiosis triggers
inflammation in onset or relapse of IBD through immunogenic properties (e,g. H. hepaticus-mediated colitis). 76 Analysis of fecal samples and serum revealed that
detection level of C. concisus was significantly
increased in UC and CD patients compared to healthy controls. 77, 78 Thus, compositional changes in the intestinal
microbiota induce chronic inflammation and IBD development. IBD are characterized by a vicious circle
of inflammation, impaired barrier function and microbial dysbiosis in the
intestine (Figure 1). However, the
initial triggers leading to chronic inflammation is unknown and may differ between
patients.