The Role of Intestinal Permeability in Gastrointestinal Disorders and Current Methods of Evaluation

Abstract

An increased intestinal permeability has been described in various gastrointestinal and non-gastrointestinal disorders. Nevertheless, the concept and definition of intestinal permeability is relatively broad and includes not only an altered paracellular route, regulated by tight junction proteins, but also the transcellular route involving membrane transporters and channels, and endocytic mechanisms. Paracellular intestinal permeability can be assessed in vivo by using different molecules (e.g., sugars, polyethylene glycols, 51Cr-EDTA) and ex vivo in Ussing chambers combining electrophysiology and probes of different molecular sizes. The latter is still the gold standard technique for assessing the epithelial barrier function, whereas in vivo techniques, including putative blood biomarkers such as intestinal fatty acid-binding protein and zonulin, are broadly used despite limitations. In the second part of the review, the current evidence of the role of impaired barrier function in the pathophysiology of selected gastrointestinal and liver diseases is discussed. Celiac disease is one of the conditions with the best evidence for impaired barrier function playing a crucial role with zonulin as its proposed regulator. Increased permeability is clearly present in inflammatory bowel disease, but the question of whether this is a primary event or a consequence of inflammation remains unsolved. The gut-liver axis with a crucial role in impaired intestinal barrier function is increasingly recognized in chronic alcoholic and metabolic liver disease. Finally, the current evidence does not support an important role for increased permeability in bile acid diarrhea.

Intestinal Permeability and Depression in Patients with Inflammatory Bowel Disease

“…Several mechanisms have been called into question, but the theories are still developing. Thus, dysfunctions on the hypothalamic–pituitary axis, neurotransmitters, vagus nerve, short-chain fatty acid metabolites, tryptophan, inflammatory factors and the brain–gut–microbiota axis have been investigated [ 9 , 10 , 11 , 12 ]. It has been proved that not only do stress-related disorders bring changes in the composition of the intestinal microbiota through the hypothalamic–pituitary–adrenal axis but also the intestine has an effect on the central nervous system through vagal stimulation, intestinal permeability and the release of inflammatory and anti-inflammatory compounds and changes in circulating agents in the blood [ 13 ].…”

Ischemic Heart Disease in Patients with Inflammatory Bowel Disease: Risk Factors, Mechanisms and Prevention

“…Chronic systemic inflammation has been shown to be implicated in all phases of IHD, from vascular endothelial dysfunction to the onset and rupture of atherosclerotic plaque [ 54 ]. Increased permeability is clearly present in IBD, and could be a hypothesis leading to abnormal absorption of bacteria and toxic substances from the intestinal microbiota, which drives, as a consequence, both enteric and systemic inflammatory reactions and the diffusion in the bloodstream of bacterial endotoxins [ 55 ]. Inflammatory cytokines and modified lipoproteins are also largely responsible for the increased production of reactive oxygen species, which increases the expression of cell adhesion molecules by stimulating leukocyte migration to the subendothelial space, a key component in initiating and maintaining the atherosclerotic process [ 56 , 57 ].…”

Is Intestinal Dysbiosis-Associated With Immunosuppressive Therapy a Key Factor in the Pathophysiology of Post-Transplant Diabetes Mellitus?

“…In transplant patients, immunosuppressive drugs can alter the intestinal barrier integrity and favour intestinal permeability. Intestinal permeability is characterized by a loss of the gut epithelial wall integrity allowing different sizes of compounds to enter the systemic circulation (food antigens, commensal or pathogens bacteria, and their metabolites) ( 50 ). By using an intestinal epithelial cell line, Qasim et al have demonstrated the potential of mycophenolic acid to alter tight junction proteins expression and distribution and induce intestinal permeability that may be responsible for gastrointestinal adverse effects observed in transplant patients ( 51 ).…”