Cellular and Molecular Therapeutic Targets in Inflammatory Bowel Disease-Focusing on Intestinal Barrier Function

Abstract

The human gut relies on several cellular and molecular mechanisms to allow for an intact and dynamical intestinal barrier. Normally, only small amounts of luminal content pass the mucosa, however, if the control is broken it can lead to enhanced passage, which might damage the mucosa, leading to pathological conditions, such as inflammatory bowel disease (IBD). It is well established that genetic, environmental, and immunological factors all contribute in the pathogenesis of IBD, and a disturbed intestinal barrier function has become a hallmark of the disease. Genetical studies support the involvement of intestinal barrier as several susceptibility genes for IBD encode proteins with key functions in gut barrier and homeostasis. IBD patients are associated with loss in bacterial diversity and shifts in the microbiota, with a possible link to local inflammation. Furthermore, alterations of immune cells and several neuro-immune signaling pathways in the lamina propria have been demonstrated. An inappropriate immune activation might lead to mucosal inflammation, with elevated secretion of pro-inflammatory cytokines that can affect the epithelium and promote a leakier barrier. This review will focus on the main cells and molecular mechanisms in IBD and how these can be targeted in order to improve intestinal barrier function and reduce inflammation.

Keywords: Crohn’s disease; innate and adaptive immunity; intestinal permeability therapeutic targets; ulcerative colitis.

Figure 1

A schematic overview of the main cell types and molecular features as targets related to intestinal barrier function for therapeutic strategies in inflammatory bowel disease. AMPs = antimicrobial peptides, CRH = corticotrophin releasing hormone, ENS = enteric nervous system, EOS = eosinophil, GC = goblet cell, JAK = Janus kinases, Mϕ = macrophage MC = mast cell, NEUT = neutrophil NLR = nod-like receptor, PC = Paneth cell, SP = substance P, TJs = tight junctions, TLR = toll-like receptor, Treg = regulatory T cell, VIP = vasoactive intestinal polypeptide.

Figure 2

Current and potential therapies directed against targets to reduce inflammation and improve intestinal barrier function in patients with inflammatory bowel disease. AMPs = antimicrobial peptides, CRH = corticotrophin releasing hormone, ENS = enteric nervous system, EOS = eosinophil, FMT = fecal microbiota transplantation, GC = goblet cell, JAK = Janus kinases, Mϕ = macrophage MC = mast cell, NEUT = neutrophil NLR = nod-like receptor, OSM = oncostatin M, PC = Paneth cell, SP = substance P, TJs = tight junctions, TLR = toll-like receptor, Treg = regulatory T cell, VIP = vasoactive intestinal polypeptide.