Background: Integrin α4β7 expression on lymphocytes promotes their localization to the gut. A monoclonal antibody against these integrins (i.e. vedolizumab) is safe and effective treatment for inflammatory bowel disease (IBD). Given the importance of integrins on IBD pathogenesis, we evaluated the role of integrin β7 (Itgb7) in a model of Crohn’s-like ileitis, the TNFΔARE mouse. Methods: The severity of ileitis in β7-deficient TNFΔARE mice (TNFΔARE+/--Itgb7-/-) was compared with that of β7-sufficient TNFΔARE mice (TNFΔARE+/--Itgb7+/+) using a semi-quantitative histological scoring system. Tertiary lymphoid tissues (TLTs) and ileal IgA+ B cells were quantified by morphometry and flow cytometry. Cohousing studies and microbiome sequencing were performed to determine the effects of the gut microbiome on inflammation. Results: TNFΔARE+/--Itgb7-/- mice showed significantly worse ileitis than TNFΔARE+/--Itgb7+/+ mice (13.6±1.3 vs 19.2±1.1, n=19, p<0.05). The number of ileal TLTs were significantly decreased in TNFΔARE+/--Itgb77-/- mice (3.3±0.1 vs 0.4±0.2, n=10, p<0.001), corresponding with decreased ileal lamina propria B-cells, particularly IgA+ B-cells (59,325±10864 vs 21,696±2122, n=3, p<0.05). Co-housing β7-sufficient and β7-deficient pups at weaning resulted in equilibration of gut microbiome differences and intestinal inflammation (19.1±1.2 vs 21.3±1.2, n=15, p=0.2). Conclusions: Loss of Itgb7 results in increased intestinal pathology, impaired TLT formation and decreased IgA+ B-cells in TNFΔARE ileum. Loss of IgA+ B-cells appears to result in microbiome dysbiosis. Equilibration of the microbiome between β7-sufficient and β7-deficient TNFΔARE mice eliminates the difference in ileitis severity. These studies suggest that Itgb7 is critical for the recruitment to TLTs of IgA+ B-cells that regulate the gut microbiome. Potential effects of long-term vedolizumab therapy on IgA+ B cell recruitment may have clinical implications for patients with IBD.
