Interactions between the microbiota and distal gut are important for the maintenance of a healthy immune system. Dysbiosis of colon bacteria has emerged as a likely contributor to diseases that arise at the level of the mucosa. Intraepithelial lymphocytes (IELs) are positioned within the epithelial barrier, and in the small intestine, function to maintain epithelial homeostasis. We hypothesized that IELs of the colon modulate epithelial barrier function through the liberation of cytokines stimulated by interactions with resident bacteria. Our data demonstrate that IL-6 is a major cytokine secreted by colonic IELs in a microbe-dependent fashion. We identify Alistipes species of the phylum Bacteroidetes as candidates to recruit IELs and stimulate their IL-6 secretion. IEL-derived IL-6 is functionally important in the maintenance of the epithelial barrier as IL-6−/− and antibiotic-treated mice were noted to have increased paracellular permeability and closer interaction with luminal bacteria. IL-6 was found to signal in colonic epithelial cells and resulted in increased epithelial barrier integrity and claudin1 expression in model epithelia. Therefore, we conclude that the host microbiota provides a homeostatic role for epithelial barrier function through regulation of IEL derived IL-6.
Citrobacter rodentium infection of mice is frequently used as a model to study host responses during pathogenic gastrointestinal infection. IL-6 signaling in the colon is required for protection against C. rodentium infection; however the cellular source of IL-6 for this protection is unclear. Our previous work has identified IELs as one source of IL-6 in the colon. Therefore, we hypothesized that IL-6 produced by colonic IELs was sufficient to provide protection during C. rodentium infection. To test our hypothesis, we orally infected mice with C. rodentium following transfer of donor IL-6+/+ or IL-6−/− IELs into IL-6+/+ or IL-6−/− recipients. IL-6−/− mice that received IL-6−/− IELs had significantly more weight loss, increased intestinal histopathology, and increased bacterial translocation after 12 days of infection compared to transfer of IL-6+/+ IELs into recipient IL-6−/− mice and IL-6+/+ IELs into IL-6+/+ mice. IEL-derived IL-6 is functionally important in the maintenance of the epithelial barrier as IL-6−/− mice were noted to have increased paracellular permeability, decreased claudin-1 expression, and a thinner mucus-gel layer, all of which were reversed by transfer of IL-6+/+ IELs. In vitro studies utilizing model epithelia confirmed IL-6 was able to signal and increase claudin-1 and mucin-2 expression. Therefore, we conclude that IL-6 expression by IELs is sufficient to restore protection against C. rodentium infection through modulation of the epithelial barrier integrity.
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