Identifying Novel Therapeutic Strategies Targeting Toll-Like Receptors for NSAID-Induced Enteropathy
Arezoo Haghighi
Gyógyszertudományok és Egészségügyi Technológiák Tagozat
Dr. Zelkó Romána
SE Farmakológiai és Farmakoterápiás Intézet Knoll József terem
2026-07-16 10:00:00
Experimental and Clinical Pharmacology
Dr. Szökő Éva
Dr. Zádori Zoltán
Dr. Maléth József
Dr. Petschner Péter
Dr. Zelkó Romána
Dr. Alberti-Dér Ágnes
Dr. Holló Zsolt
Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely used medications worldwide, but their use is frequently limited by serious gastrointestinal toxicity, particularly NSAID-induced enteropathy affecting the small intestine. Current therapeutic options for this condition are very limited. This thesis aimed to explore the role of Toll-like receptors (TLRs) in the pathogenesis of NSAID enteropathy and to identify novel therapeutic strategies targeting these receptors.
In the first part of the study, we comprehensively analyzed changes in intestinal TLR expression (TLR1, TLR2, TLR4, TLR5, TLR6, TLR9) and their associations with inflammation and gut microbiota dysbiosis in both acute and chronic NSAID-induced enteropathy models in rats. We found that TLR5 expression was consistently downregulated during enteropathy, showing a strong negative correlation with intestinal inflammation. In contrast, TLR1/TLR2 expression correlated positively with inflammation, while TLR4 expression was more closely associated with dysbiosis (particularly Enterobacteriaceae expansion).
In the second part, we focused on the functional role of TLR5 using mouse models. We demonstrated that systemic administration of the TLR5 agonist flagellin (both prophylactically and therapeutically) significantly reduced intestinal inflammation, histological damage, and bacterial dysbiosis induced by indomethacin. Conversely, pharmacological inhibition of TLR5 with TH1020 aggravated the inflammatory response. Interestingly, flagellin treatment reduced overall mucosal injury and preserved epithelial integrity, even though neutrophil infiltration at damaged sites and Nos2 expression remained elevated, suggesting a selective protective effect on the intestinal epithelium.
These findings provide the first direct evidence that TLR5 signaling plays a protective role against NSAID-induced enteropathy. The results highlight TLR5 as a promising therapeutic target for the prevention and treatment of this common and serious condition. Activation of TLR5 could offer a novel strategy to improve the safety of long-term NSAID therapy.
