Bacteroidales recruit IL-6-producing intraepithelial lymphocytes in the colon to promote barrier integrity

Abstract

Interactions between the microbiota and distal gut are important for the maintenance of a healthy intestinal barrier; dysbiosis of intestinal microbial communities 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 colonic IELs promote epithelial barrier function through the expression of cytokines in response to interactions with commensal bacteria. 16S rRNA profiling revealed that candidate bacteria in the order Bacteroidales are sufficient to promote IEL presence in the colon, which in turn, produce IL-6 in a MyD88-dependent fashion. 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, leading to protection of mice in response to Citrobacter rodentium infection. Therefore, we conclude that microbiota provide a homeostatic role for epithelial barrier function through regulation of IEL-derived IL-6.

Cytokine Tuning of Intestinal Epithelial Function

“…A study by Kuhn et al provided more evidence for the crucial relationship between the microbiota, immune system, and intestinal epithelial barrier ( 71 ). Bacteria in the order Bacteroidales were sufficient to induce localization of intraepithelial lymphocytes in the colons of mice, and these cells were an important source of IL-6.…”

The Complex Interplay between Chronic Inflammation, the Microbiome, and Cancer: Understanding Disease Progression and What We Can Do to Prevent It

“…In fact, many therapies under development aim to mobilize T-cell populations to seek and destroy tumor cells [ 109 ], a common goal of immunotherapies (discussed below in more detail). Another study by Kuhn et al demonstrated Bacteroidales to be important for intestinal membrane integrity by stimulating intraepithelial lymphocyte secretion of IL-6; however, while low levels of IL-6 are tolerable, increased levels of IL-6 promotes tumourigenesis by signaling proliferation, angiogenesis, and invasiveness while inhibiting apoptosis [ 110 , 111 ]. Cytokines such as IL-1β, TNF-α, and IL-6 are also produced by cells infected with viruses including Epstein-Barr Virus (EBV), HBV, HCV, and Kaposi’s sarcoma herpesvirus (KSHV), which induces an inflammatory environment and promotes tumourigenesis [ 112 , 113 , 114 ].…”

Compartmentalized Response of IL-6/STAT3 Signaling in the Colonic Mucosa Mediates Colitis Development

“…If a challenge induces the release of high levels of IFN-g, mimicked in this study by the i.p. injection of the cytokine, apical secretion of IL-6 will stimulate the activation of STAT3 in crypt surface epithelial cells to strength epithelial barrier functions (36,40). Lack of activation of STAT3 in IECs after i.p.…”

“…3D). However, the amount of Claudin-1, an epithelial protein induced by STAT3 (36) to strength barrier function in the gut, was strongly decreased in the colon in the absence of Crtam (Fig. 6E).…”