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Published on: April 21, 2015
Toll-like receptor 5 protects against nonsteroidal anti-inflammatory drug-induced enteropathy in mice
Arezoo Haghighi1, Zsuzsanna O Demeter1, Anna Zsidai1
1Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary; Center for Pharmacology and Drug Research & Development, Semmelweis University, Budapest, Hungary.
Background And Aims:
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.
Materials And Methods:
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.
Key Findings:
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.
Significance:
Our findings reveal that TLR5 activation protects against NSAID-induced enteropathy and may therefore be a new therapeutic avenue.
Insights
Toll-like receptor 5 (TLR5) activation protects against nonsteroidal anti-inflammatory drug (NSAID)-induced enteropathy. Inhibiting TLR5 worsened intestinal inflammation, suggesting TLR5 activation is a potential therapeutic target for NSAID-induced gut injury.
Area of Science:
- Gastroenterology
- Immunology
- Microbiology
Background:
- Nonsteroidal anti-inflammatory drugs (NSAIDs) can cause small intestinal injury, influenced by gut bacteria and immune responses.
- Toll-like receptor 4 (TLR4) and TLR2 roles in NSAID enteropathy are known, but TLR5's function is unclear.
Purpose of the Study:
- To investigate the impact of Toll-like receptor 5 (TLR5) activation and inhibition on NSAID-induced enteropathy in mice.
Main Methods:
- Enteropathy was induced using indomethacin (IND).
- Assessed mucosal injury, inflammation, and mRNA levels of TLR5, TLR4, and TLR2.
- Measured intestinal flagellin load and bacterial counts.
- Administered flagellin or TLR5 antagonist TH1020.
Main Results:
- NSAID enteropathy showed decreased TLR5 expression, increased inflammation, and higher bacterial/flagellin load.
- Flagellin pretreatment or post-treatment protected against IND-induced enteropathy.
- TLR5 antagonist TH1020 worsened IND-induced intestinal inflammation.
Conclusions:
- TLR5 activation demonstrates a protective effect against NSAID-induced enteropathy.
- Targeting TLR5 activation represents a potential new therapeutic strategy for NSAID enteropathy.
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