p-Hydroxybenzoic acid alleviates inflammatory responses and intestinal mucosal damage in DSS-induced colitis by activating ERβ signaling

Abstract p-Hydroxybenzaldehyde (HD), the main active component of Nostoc commune, has been shown to attenuate dextran sulfate sodium (DSS)-induced experimental colitis. However, it is still unclear whether HD or its metabolites exert a protective role in ulcerative colitis (UC). In this study, we showed that p-hydroxybenzoic acid (HA) is the active metabolite of HD and demonstrated the effects of HA in alleviating colitis and its potential mechanism. Mice with colitis induced by DSS were orally administered or intraperitoneally injected with therapeutic drugs (including HD, HA, mesalazine and PHTPP) for 10 days. Caco-2 cells were treated with TNF-α (10 ng/ml) and therapeutic drugs (including HA, mesalazine and PHTPP) for 24 h. The results showed that oral supplementation, but not intraperitoneal injection, of HD (40 mg/kg) significantly ameliorated DSS-induced colitis. Oral administration of HA (10-40 mg/kg) dose-dependently attenuated various colitis phenotypes in DSS-treated mice. Treatment with HA also decreased the expression of proinflammatory cytokines and increased the expression of tight junction proteins in mice and Caco-2 cells. However, combined treatment of HA with PHTPP, a highly selective antagonist of the estrogen receptor β (ERβ), did not show anti-colitis effects. Collectively, our results demonstrate that both HD and HA are active substances capable of inhibiting inflammatory responses and improving intestinal mucosal damage via the activation of ERβ signaling in DSS-induced colitis.