Toll-like receptor 5 protects against nonsteroidal anti-inflammatory drug-induced enteropathy in mice.
Haghighi Arezoo A, Demeter Zsuzsanna O ZO, Zsidai Anna A, Lengyel Lili L et al.
Nonsteroidal anti-inflammatory drugs (NSAIDs) can cause small intestinal injury, which largely depends on the presence of gut bacteria and the immune responses triggered by them. While previous studies have emphasised the role of Toll-like receptor 4 (TLR4) and TLR2 in enteropathy, the functional significance of TLR5, a receptor for bacterial flagellin, remains elusive. Thus, we aimed to assess the impact of TLR5 activation and inhibition on NSAID enteropathy in mice. Enteropathy was induced using indomethacin (IND). Mucosal injury, inflammation and the mRNA levels of TLR5, TLR4 and TLR2 were assessed after 24 h. The intestinal flagellin load was measured using Western blot, while bacterial counts were assessed using qPCR. Flagellin (10 and 30 μg) and TH1020 (10 μg) were administered intraperitoneally. TLR5 levels were also determined in the ileum of naproxen-treated rats. NSAID enteropathy was associated with downregulation of TLR5, intestinal inflammation and apoptosis, mucosal histological damage, higher bacterial counts and flagellin load in the intestine, and upregulation of TLR2 and TLR4. IND-induced changes, except the fall in TLR5 expression, were reduced or completely prevented in animals that had been pretreated with flagellin. Importantly, flagellin induced similar robust protection when administered four hours after IND. In contrast to flagellin, treatment with the potent and selective TLR5 antagonist TH1020 exacerbated the intestinal inflammation caused by IND. Our findings reveal that TLR5 activation protects against NSAID-induced enteropathy and may therefore be a new therapeutic avenue.