Hamza Masood

Background: Ulcerative Colitis (UC) is a form of inflammatory bowel diseases (IBD) that causes mucosal inflammation of the entire colon.¹ This leads to decrease in quality of life due to the remitting and relapsing nature of the disease with increased risk of infection, anxiety, depression, and colon cancer. Ulcerative Colitis etiology is not exactly clear, but it seems to be caused by impaired expression of a nuclear receptor called PPAR γ, which is responsible for downregulating inflammation.¹ Dendritic cells with Toll-like Receptors (TLR) result in inflammatory cascades and productions of cytokines which eventually lead to ulcerative colitis.¹ Current treatment of severe UC are oral or IV corticosteroids for induction and maintenance with other medications used for maintenance as well.² Corticosteroid resistant UC can be treated with surgery, but this leads to significant lifestyle changes as well as risk of sepsis.³ The LPS/TLR4/NF-kB pathway is a key inflammatory pathway that is critical for the development of ulcerative colitis that is being focused on in newer studies.⁴

Objective: The purpose of this narrative review is to explore the TLR4 pathway and possible modifications for treatment of severe corticosteroid resistant UC without surgery.

Search Methods: An online search in the PubMed database was conducted from 2017-2023 using the following keywords: “ulcerative colitis”, “TLR4 pathway”, “inhibitors”, “treatment”.

Results: Triclosan (TCS) is a common antimicrobial used in toothpaste that leads to increased TLR4 activation by enhancing LPS translocation into the gut.⁵ A TCS-diet led to increased basal inflammation, decreased body weight, reduced colon length, and increased crypt damage in mice.⁵ Ganluyin is a traditional Chinese medication which reduces colon inflammation by downregulating expression of TLR4, MyD88, and NF-kB and is especially effective at medium to high doses.⁴ Keratin 8 (CK8) is an intermediate filament of the epithelium of the gut and is downregulated in ulcerative colitis and its associated cancers.⁶ CK8 prevents TLR4 activation by preventing polyubiquitination of TRA6, a factor that binds to TLR4 like LPS does.⁶ Administering TAK242, a TLR4 inhibitor, in mice with CK8 genes knocked out increased colon length and decreased inflammation cytokines.⁶  S100a9 is a damage associated molecular protein that forms a heterodimer with S100a8 and activates TLR4.⁷ This leads to colitis associated carcinogenesis and can be prevented by using a neutralizing antibody called anti-S100a9, which increases colon length, increases body weight, and decreases UC disease activity.⁷ TNF-α is an inflammatory cytokine that is found downstream of the TLR4 pathway.⁸ OPRX-106 is an anti-TNF- α medication that has a long serum half life and contains cellulose to prevent gastric absorption.⁸ OPRX-106 has 67% clinical response and 61% mucosal healing in 24 patients by decreasing proinflammatory cytokines in the gut.⁸

Conclusion: Activation of the TLR4 pathway in the gut leads to increased inflammation, reduced colon length, and increased crypt damage. Focusing on inhibiting TLR4 directly or indirectly can also help reduce ulcerative colitis inflammation and related symptoms; targets include ganluyin, CK8, anti-s100a9 and TCS. Using anti-TNF-a agents like OPRX-106 in conjunction with TLR4 inhibition can be studied to see if there are increased therapeutic effects.

Works Cited:

1. Du L, Ha C. Epidemiology and Pathogenesis of Ulcerative Colitis. Gastroenterol Clin North Am. 2020;49(4):643-654. doi:10.1016/j.gtc.2020.07.005
2. Feuerstein JD, Moss AC, Farraye FA. Ulcerative Colitis [published correction appears in Mayo Clin Proc. 2019 Oct;94(10):2149]. Mayo Clin Proc. 2019;94(7):1357-1373. doi:10.1016/j.mayocp.2019.01.018
3. Murphy B, Kavanagh DO, Winter DC. Modern surgery for ulcerative colitis. Updates Surg. 2020;72(2):325-333. doi:10.1007/s13304-020-00719-4
4. Xiong T, Zheng X, Zhang K, et al. Ganluyin ameliorates DSS-induced ulcerative colitis by inhibiting the enteric-origin LPS/TLR4/NF-κB pathway. J Ethnopharmacol. 2022;289:115001. doi:10.1016/j.jep.2022.115001
5. Yang H, Wang W, Romano KA, et al. A common antimicrobial additive increases colonic inflammation and colitis-associated colon tumorigenesis in mice. Sci Transl Med. 2018;10(443):eaan4116. doi:10.1126/scitranslmed.aan4116
6. Liu C, Liu ED, Meng YX, et al. Keratin 8 reduces colonic permeability and maintains gut microbiota homeostasis, protecting against colitis and colitis-associated tumorigenesis. Oncotarget. 2017;8(57):96774-96790. Published 2017 May 27. doi:10.18632/oncotarget.18241
7. Zhang X, Wei L, Wang J, et al. Suppression Colitis and Colitis-Associated Colon Cancer by Anti-S100a9 Antibody in Mice. Front Immunol. 2017;8:1774. Published 2017 Dec 13. doi:10.3389/fimmu.2017.01774
8. Almon E, Shaaltiel Y, Sbeit W, et al. Novel Orally Administered Recombinant Anti-TNF Alpha Fusion Protein for the Treatment of Ulcerative Colitis: Results From a Phase 2a Clinical Trial. J Clin Gastroenterol. 2021;55(2):134-140. doi:10.1097/MCG.0000000000001314