Effect of chemical modulation of toll-like receptor 4 in an animal model of ulcerative colitis



The partial ineffectiveness and side effects of inflammatory bowel disease (IBD) current therapies drive basic research to look for new therapeutic target in order to develop new drug lead. Considering the pivotal role played by toll-like receptors (TLRs) in gut inflammation, we evaluate here the therapeutic effect of the synthetic glycolipid TLR4 antagonist FP7.


The anti-inflammatory effect of FP7, active as TLR4 antagonist, was evaluated on peripheral blood mononuclear cells (PBMCs) and lamina propria mononuclear cells (LPMCs) isolated from IBD patients, and in a mouse model of ulcerative colitis.


FP7 strongly reduced the inflammatory responses induced by lipopolysaccharide (LPS) in vitro, due to its capacity to compete with LPS for the binding of TLR4/MD-2 receptor complex thus inhibiting both the MyD88- and TRIF-dependent inflammatory pathways. Colitic mice treated with FP7 exhibit reduced colonic inflammation and decreased levels of pro-inflammatory cytokines.


This study suggests that TLR4 chemical modulation can be an effective therapeutic approach to IBD. The selectivity of FP7 on TLR4 makes this molecule a promising drug lead for new small molecules-based treatments.

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Crohn’s disease


Danger-associated molecular patterns


Dextran sulfate sodium


Inflammatory bowel disease




Lipopolysaccharide binding protein


Lamina propria mononuclear cells


Myeloid differentiation primary response gene(88)




Pathogen-associated molecular patterns


Peripheral blood mononuclear cells


Pattern recognition receptors


Toll-like receptor


Ulcerative colitis


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The Italian Ministry for Foreign Affairs and International Cooperation (MAECI).

Author contribution statement

Ivan Monteleone, Francesco Peri, Giovanni Monteleone, and Fabio A. Facchini designed the study. Fabio A. Facchini performed all the experimental work presented with the help of Davide Di Fusco and Simona Barresi. In particular, in vivo experimentation and processing of patients’ biopsy and specimens were performed with Davide Di Fusco, while western blot analysis was performed with the help of Simona Barresi and Francesca Granucci. Andrea Luraghi and Alberto Minotti synthesized the molecule FP7.


Project H2020-MSC-ETN-642157 TOLLerant.

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Correspondence to Francesco Peri or Ivan Monteleone.

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Facchini, F.A., Di Fusco, D., Barresi, S. et al. Effect of chemical modulation of toll-like receptor 4 in an animal model of ulcerative colitis. Eur J Clin Pharmacol 76, 409–418 (2020). https://doi.org/10.1007/s00228-019-02799-7

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  • Inflammatory bowel disease (IBD)
  • Toll-like receptor 4 (TLR4)
  • Synthetic small molecules
  • Crohn disease
  • Ulcerative colitis
  • Lipopolysaccharide (LPS)