Maintaining Intestinal Mucosal Integrity by Plugging Leaks with Homoectoine

Excerpt

The maintenance of a tight intestinal epithelial barrier is fundamental for the continuance of whole-body homeostasis. External (microbiota, alcohol consumption, diet) and internal (inflammation, stress, genetic predisposition) factors are associated with disruption of intestinal epithelial integrity and disease, though, despite intensive research, the specific mechanisms that alter intestinal barrier function remain unknown. Epithelial cells are linked by cell-to-cell adhesion structures: The most apical structure is the tight junction (TJ), followed by the adherens junction and the desmosomes. In addition to its structural function, TJs also significantly contribute to the regulation of paracellular permeability. Most studies assessing paracellular permeability have described at least two populations of pores regulated by TJs: (a) a high-capacity charge-selective pore, permeable to small ions and small uncharged molecules (also referred as the “pore” pathway); and (b) a much larger low-capacity pore (also referred as the “leak” pathway) that is permeable to large ions and solutes regardless of charge. The pore pathway is regulated mainly by the claudin (CLDN) family of TJ proteins and the leak pathway by occludin (OCLN) and TJ proteins of the zonula occludens (ZO) family. The permeability of the leak pathway can be assessed by measuring the transepithelial flux of small–medium size soluble molecules, including ethylene diamine tetraacetic acid (EDTA), mannitol, sucrose, inulin, and polyethylene glycols (PEG), or 4–20 kDa dextrans. In contrast, larger and most lipophilic molecules and intact bacteria do not cross the epithelium via the paracellular pathway; instead, they are either internalized via endocytosis and reach the basolateral pole via transcytosis and posterior exocytosis or enter into the lymphatics via the chylomicron pathway [1]. Altered epithelial barrier integrity, also known as increased intestinal permeability or ‘leaky gut,’ is associated with intestinal disorders such as celiac disease, inflammatory bowel disease (IBD), or functional gastrointestinal (GI) diseases (FGID) such as irritable bowel syndrome (IBS) and functional dyspepsia and in non-intestinal disorders such as diabetes, obesity, sepsis, Alzheimer disease, and multiple sclerosis. At least in intestinal disorders, the current hypothesis regarding the pathophysiological relevance of an altered epithelial barrier function is that luminal compounds (e.g., bacterial metabolites such as short-chain fatty acids) or bacterial structural components such as endotoxin, or food antigens can cross the ‘leaky’ epithelium, activating lamina propria immune cells, enteric and sensory nerves, or other structures expressing cognate receptors such as free fatty acid receptor (FFA) 2–3 or Toll-like receptor 4. In turn, pro-inflammatory cytokines released by immune cells or neural activation can exacerbate or further disrupt epithelial integrity. Inflammation as occurs in IBD and celiac disease can be severe or of a lesser magnitude as happens in FGID. Stress is also associated with gastrointestinal disease and, specifically, with altered intestinal permeability. FGIDs are characterized by higher levels of anxiety and depression; IBD relapse is also associated with stressful events. Basic and clinical studies have indicated that acute and chronic stress, whether physical or psychological, influences intestinal barrier function, including ion and water secretion, permeability, and mucus secretion. Other than direct effects on enterocytes or colonocytes, stress-induced intestinal permeability is also mediated via recruitment and activation of mononuclear immune cells such as mast cells, eosinophils, and macrophages that contribute to the local inflammatory response [2]. …