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World J Gastroenterol. Jan 7, 2023; 29(1): 110-125
Published online Jan 7, 2023. doi: 10.3748/wjg.v29.i1.110
Unveiling the biological role of sphingosine-1-phosphate receptor modulators in inflammatory bowel diseases
Evanthia Tourkochristou, Athanasia Mouzaki, Christos Triantos
Evanthia Tourkochristou, Christos Triantos, Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras 26504, Greece
Athanasia Mouzaki, Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Patras 26504, Greece
Author contributions: Triantos C conceived and coordinated the study; Tourkochristou E and Mouzaki A conducted the literature search and analysis and wrote the manuscript; Triantos C and Mouzaki A were responsible for revising the manuscript for important intellectual content; Tourkochristou E, Mouzaki A, and Triantos C approved the submitted version of the manuscript.
Conflict-of-interest statement: There is no conflict of interest associated with the senior author or any of the other coauthors who contributed their efforts in this manuscript.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Christos Triantos, FAASLD, MD, PhD, Assistant Professor, Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Rion, Patras 26504, Greece. chtriantos@hotmail.com
Received: September 20, 2022
Peer-review started: September 20, 2022
First decision: November 5, 2022
Revised: November 16, 2022
Accepted: December 13, 2022
Article in press: December 13, 2022
Published online: January 7, 2023
Abstract

Inflammatory bowel disease (IBD) is chronic inflammation of the gastrointestinal tract that has a high epidemiological prevalence worldwide. The increasing disease burden worldwide, lack of response to current biologic therapeutics, and treatment-related immunogenicity have led to major concerns regarding the clinical management of IBD patients and treatment efficacy. Understanding disease pathogenesis and disease-related molecular mechanisms is the most important goal in developing new and effective therapeutics. Sphingosine-1-phosphate (S1P) receptor (S1PR) modulators form a class of oral small molecule drugs currently in clinical development for IBD have shown promising effects on disease improvement. S1P is a sphingosine-derived phospholipid that acts by binding to its receptor S1PR and is involved in the regulation of several biological processes including cell survival, differentiation, migration, proliferation, immune response, and lymphocyte trafficking. T lymphocytes play an important role in regulating inflammatory responses. In inflamed IBD tissue, an imbalance between T helper (Th) and regulatory T lymphocytes and Th cytokine levels was found. The S1P/S1PR signaling axis and metabolism have been linked to inflammatory responses in IBD. S1P modulators targeting S1PRs and S1P metabolism have been developed and shown to regulate inflammatory responses by affecting lymphocyte trafficking, lymphocyte number, lymphocyte activity, cytokine production, and contributing to gut barrier function.

Keywords: Inflammatory bowel disease, Sphingosine-1-phosphate, Intestinal inflammation, T helper 1/T helper 17, Sphingosine 1 phosphate, Modulators, Immune responses

Core Tip: Recent literature has highlighted the use of novel oral small molecules, so-called sphingosine-1- phosphate (S1P) receptor modulators, in the therapeutic treatment of inflammatory bowel disease (IBD). Reviews and clinical trials have reported the safety profile and role of S1P modulators in alleviating IBD, but little information is available on their biological function. This is a comprehensive mini-review describing key biological mechanisms beyond the activity of S1P modulators reported in preclinical and clinical studies. The data from this study will contribute to the research field of developing therapeutic strategies in IBD based on the pathogenic biological background.