Integrin β7 is required for B cell migration and regulation of the intestinal microbiota during colitis

Abstract

Abstract The incidence of ulcerative colitis (UC) is increasing worldwide. A proven therapeutic strategy for UC is the inhibition of leukocyte trafficking via blockade of integrin β7. Despite this, the mechanism of action of vedolizumab (anti-α4β7) is poorly defined. Clear definitions of the immune subsets targeted by vedolizumab are essential for understanding the pathogenesis of UC, and development of biological endpoints for assessing treatment efficacy. Methods The IL-10−/− colitis model was crossed with integrin β7 deficient mice, and clinical features and histological scores were recorded. Flow cytometry of B-cell populations was conducted in colonic cell isolations. 16S bacterial sequencing was conducted on intestinal content. Results IL-10−/−β7−/− mice displayed increased mortality compared to IL-10−/− mice at 12 weeks and uniformly developed rectal prolapses. IL-10−/−β7−/− mice displayed increased colonic inflammatory indices (n>10, p<0.001), associated with a reduced B-cell, but normal T-cell, intestinal infiltrate (n>6, p<0.001). IL-10−/−β7−/− mice displayed a resulting IgA deficiency and significant alterations to the resident microbiota. The presence of systemic bacterial infection was observed. Blockade of the α4β7 ligand MAdCAM-1 in IL-10−/− mice resulted in a parallel phenotype. Discussion Integrin β7 deficiency results in a worsening of colitis in mice, resulting from a B-cell deficit in the inflamed colon and control the microbiota, via IgA. B-cells are largely ignored in the field of IBD and the potential complications associated with chronic integrin blockade. Our data suggests that the role of integrin β7 on B-cell migration may have important implications on the pathogenesis of colitis in mice and humans.