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Review
. 2018 Nov 9;25(1):79.
doi: 10.1186/s12929-018-0483-8.

Microbiota Dysbiosis and Barrier Dysfunction in Inflammatory Bowel Disease and Colorectal Cancers: Exploring a Common Ground Hypothesis

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Free PMC article
Review

Microbiota Dysbiosis and Barrier Dysfunction in Inflammatory Bowel Disease and Colorectal Cancers: Exploring a Common Ground Hypothesis

Linda Chia-Hui Yu. J Biomed Sci. .
Free PMC article

Abstract

Inflammatory bowel disease (IBD) is a multifactorial disease which arises as a result of the interaction of genetic, environmental, barrier and microbial factors leading to chronic inflammation in the intestine. Patients with IBD had a higher risk of developing colorectal carcinoma (CRC), of which the subset was classified as colitis-associated cancers. Genetic polymorphism of innate immune receptors had long been considered a major risk factor for IBD, and the mutations were also recently observed in CRC. Altered microbial composition (termed microbiota dybiosis) and dysfunctional gut barrier manifested by epithelial hyperpermeability and high amount of mucosa-associated bacteria were observed in IBD and CRC patients. The findings suggested that aberrant immune responses to penetrating commensal microbes may play key roles in fueling disease progression. Accumulative evidence demonstrated that mucosa-associated bacteria harbored colitogenic and protumoral properties in experimental models, supporting an active role of bacteria as pathobionts (commensal-derived opportunistic pathogens). Nevertheless, the host factors involved in bacterial dysbiosis and conversion mechanisms from lumen-dwelling commensals to mucosal pathobionts remain unclear. Based on the observation of gut leakiness in patients and the evidence of epithelial hyperpermeability prior to the onset of mucosal histopathology in colitic animals, it was postulated that the epithelial barrier dysfunction associated with mucosal enrichment of specific bacterial strains may predispose the shift to disease-associated microbiota. The speculation of leaky gut as an initiating factor for microbiota dysbiosis that eventually led to pathological consequences was proposed as the "common ground hypothesis", which will be highlighted in this review. Overall, the understanding of the core interplay between gut microbiota and epithelial barriers at early subclinical phases will shed light to novel therapeutic strategies to manage chronic inflammatory disorders and colitis-associated cancers.

Keywords: Colitis; bacterial internalization; barrier function; colorectal cancers; epithelial permeability; intestinal dysbiosis.

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Figures

Fig. 1
Fig. 1
Transcellular and paracellular pathways of epithelial barrier prevents intestinal bacterial influx. Gut barrier is composed of epithelial cells with brush border (BB) as the transcellular barrier, and joined at their apical side by tight junctions (TJs) as the paracellular barrier. The BBs and TJs are physical ultrastructural barriers to prevent influx of commensal bacteria in healthy conditions. Upon epithelial barrier damages such as BB fanning and TJ opening, commensals and pathobionts may gain access to the lamina propria. Photoimages at the left side are (a) scanning electron micrographs of the en face view and (b) transmission electron micrographs of the longitudinal view of the highly organized brush borders in physiological conditions. Photoimages at the right side are (c) scanning electron micrographs of the en face view and (d) transmission electron micrographs of the longitudinal view of the disarrayed brush borders in pathological conditions. (a, c) Bar = 5 μm; (b, d) Bar = 0.5 μm
Fig. 2
Fig. 2
Proposed schema of early pathophysiological changes in epithelial barrier defects and bacterial invasiveness, which causes microbiota dysbiosis and chronic inflammation. The proposed common ground hypothesis depicting the early abnormality of leaky gut that drives microbiota dysbiosis would lead to chronic inflammation. The hypothesis is that endogenous and exogenous factors that trigger gut barrier impairment and low grade immune activation could impose selective pressure on the intestinal microbiota. The subclinical mucosal abnormalities which developed in individuals with genetic predisposition then favor the growth of opportunistic microbes for conversion to pathobionts. The pathobionts subsequently aggravate morphologic and functional changes in gut tissues and remote organs with pathological consequences, and result in chronic inflammation and clinical symptoms. Further postulation with a detailed focus on the gut barriers are added here. We speculate that the initial epithelial barrier dysfunction manifested by transcellular hyperpermeability and passive bacterial internalization may instigate a selection pressure on microbiota (such as positive inforcement by anchorage and growth advantage, and negative impediment by aerotolerance and immune evasion), leading to the emergence of invasive virulent pathobionts. The selection pressure and mucosal pathobionts may cause a shift in the fecal microbial community. On the host’s side, bacterial internalization may also cause epithelial cytoskeletal disorganization and paracellular TJ destruction. The combination of broken epithelial barrier and invasive pathobionts results in a massive amount of bacterial translocation, which leads to clinical features of morphological damage and chronic inflammation. Additional evidence also showed that chronic inflammation may impact on the gut microbiota and cause epithelial death-dependent barrier loss, which eventually leads to vicious cycles of uncontrollable colitis

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