S. P. Kessler et al. show that HAS1/HAS3 null mice are less susceptible to chemically induced chronic inflammation than wild-type mice and do not develop colitis, indicating that hyaluronan production in the intestine, primarily by HAS3, is responsible for promoting chronic intestinal inflammation and inducing pathological changes in vasculature and leukocyte infiltration underlying colitis. Here, HAS3 is linked to colitis.