Here, we found B4galnt2 intestinal expression was strongly associated with increased susceptibility to Salmonella as evidenced by increased histopathological changes, intestinal inflammatory cytokines and infiltrating immune cells. Fecal transfer experiments demonstrated a crucial role of the B4galnt2 dependent microbiota in conferring susceptibility to Salmonella infection. Interestingly, the loss of B4galnt2 intestinal expression increased the susceptibility to chronic DSS treatment. A significantly enhanced pathological score was found in B4galnt2 deficient mice, although lower infiltration of CD68+ and CD3+ cells were found in those mice. These data support a critical role for B4galnt2 in intestinal inflammation. We speculate that B4galnt2-specific differences in host susceptibility to intestinal inflammation underlie the strong signatures of balancing selection observed at the B4galnt2 locus in wild mouse populations.