Transcytotic passage of intestinal bacteria across epithelial cells under proinflammatory stress

Linda Yu, Yu-Chen Pai

Abstract


Gastrointestinal epithelial layer strategically acts as a physical barrier to prevent the entry of bacteria to the body proper. Nevertheless, a leaky gut manifested by increases in transcellular and paracellular permeability of epithelial cells is observed in many clinical diseases, including inflammatory bowel disease, celiac disease, intestinal obstruction, and pathogen infection. Disorganization of intercellular tight junction (TJ) proteins and disarray of brush border (BB) contribute to the epithelial barrier dysfunctions in inflammatory disorders. Proinflammatory cytokines such as interferon gamma (IFNγ), tumor necrosis factor alpha, and interleukin-1 induced TJ disruption and increased paracellular permeability. On the other hand, accumulating evidence showed that lower doses of IFNγ (below the threshold to induce TJ impairment) caused BB fanning and bacterial transcytosis, suggesting an alternative portal for bacterial influx across epithelial cells. Both paracellular and transcellular permeability defects induced by IFNγ are dependent on the phosphorylation of epithelial myosin light chain (MLC) by myosin light chain kinase (MLCK), of which the differential regulatory mechanisms remain unclear. This article highlights the evidence of bacterial transcytosis preceding TJ damage in disease models, and discusses possible mechanisms such as splicing variants of MLCK or isoforms of MLC for regulation of transepithelial bacterial influx. The epithelial recognition of intracellular bacteria following the internalization of commensals under proinflammatory stress, and the invasion of pathobionts (opportunistic pathogens converted by commensals) are also discussed. In sum, epithelial barrier defect in transcellular or paracellular pathways potentially leads to bacterial translocation to mucosa and extraintestinal organs, and may predispose the host to inflammatory disorders. The understanding of the molecular mechanisms of epithelial barrier regulation may shed light to therapeutic development for management of chronic inflammation.

Keywords


barrier, bacterial internalization, tight junctions, brush borders, proinflammatory cytokines, myosin light chain kinase

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References


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DOI: http://dx.doi.org/10.18103/imr.v3i8.539

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