New insights into epithelial barrier dysfunction in the intestine: relevance for IBD.

Alterations in the complex inter-relationship between intestinal epithelial cells, the mucosal immune system responses and the gut microbiota are responsible for the development of inflammatory bowel disease in humans. Two recent papers have presented data which give us some new insight into the different ways that this relationship may be affected.

A paper from Okumura et al. published in the journal Nature (doi:10.1038/nature17406), focuses on the protein Lypd8.

Key features of Lypd8:

Expressed by epithelial cells at the very top of the large intestinal crypts;

Secreted into the mucous layer;

Localises to the region between the dense inner mucous layer and more fluid outer layer (where commensal microorganisms may be found); Also found in the lumen.

Okumura and colleagues presented findings from investigations on patient samples and in vivo and in vitro models, which demonstrated:

Colonic tissue from patients with ulcerative colitis shows reduced Lypd8- specific immunoreactivity;

In Lypd8-/- mice, flagellated bacteria can penetrate the inner mucous layer and reach the epithelial surface and colonise down into the colonic crypts from the lumen of the bowel;

Lypd8-/- mice do not show spontaneous intestinal inflammation, but they do demonstrate increased severity of colitis in response to administration of DSS;

Lypd8 function can be attributed to its ability to bind to and inhibit the motility of flagellated bacteria.

These findings raise the possibility of using Lypd8 (and perhaps other related molecules) in managing inflammation associated with flagellated bacteria.

In a second paper Tetz and Tetz describe an alternative mechanism whereby the epithelial barrier can be compromised. In a letter to Gut Pathogens (doi: 10.1186/s13099-016-0109-1), they discuss their observations following administration of commercially-available bacteriophage cocktails, which were able to infect species such as Staphylococcus, Proteus, Salmonella and Streptococcus, to rats.

Key findings:

Bacteriophage administration was associated with increases in gut permeability and levels of circulating immune complexes,

Infected animals show weight loss, loss of condition and reduced levels of activity.

Tetz and Tetz hypothesise that bacteriophage infection in humans could result in changes in the gut microbiota that lead to increased intestinal permeability and as a consequence, bacterial translocation; in turn, this could promote chronic inflammatory conditions such as Crohn's disease and rheumatoid arthritis.

Epistem has a range of experimental tools which may be used to assess intestinal epithelial barrier function, including cell culture and in vivo models. If you would like to discuss these options for your research project, then do get in touch with our team.

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