Intestinal barrier dysfunction in irritable bowel syndrome: a systematic review

Abstract

Background and aim: Irritable bowel syndrome (IBS) is a complex and heterogeneous disorder. Sensory, motor and barrier dysfunctions are the key physiological endophenotypes of IBS. Our aim is to review studies evaluating barrier dysfunction in adults and children with IBS, as well as to link those changes with IBS symptomatology and quality of life.

Methods: A comprehensive and systematic review of multiple databases was performed up to March 2020 to identify studies comparing intestinal permeability in IBS patients with healthy controls. Both in vivo and in vitro studies were considered.

Results: We identified 66 studies, of which 27 used intestinal probes to quantify barrier function. The prevalence of barrier dysfunction differed between PI-IBS (17-50%), IBS-D (37-62%) and IBS-C (4-25%). At a group level, permeability was increased compared with healthy controls in IBS-D (9/13 studies) and PI-IBS (4/4 studies), but only a minority of IBS-C (2/7 studies) and not in the only IBS-M study. All four studies in children with IBS demonstrated loss of barrier function. A heterogeneous set of tight junction genes were found to be altered in small and large intestines of adults with IBS, but these have not been evaluated in children. Positive associations were identified between barrier dysfunction and bowel disturbances (6/9 studies), abdominal pain (9/13 studies), overall symptom severity (1/6 studies), depression and anxiety (1/1 study) and quality of life (1/4 studies). Fecal slurry or supernatants of IBS patients were found to induce barrier disruption in animal models (5/6 studies).

Conclusions: Barrier dysfunction is present in a significant proportion of adult and all pediatric IBS studies, especially in the IBS-D and PI-IBS subtype. The majority of studies indicated a positive association between loss of barrier function and symptoms such as abdominal pain and changes in the bowel function.

Keywords: functional gastrointestinal disorders; immune cells; microbiome; occludin; zonula occludens.

Figure 1.

Study schematic. Flowchart describing process for screening and selection of studies included in the systematic review.

Figure 2.

Proportion of patients with increased in vivo permeability in the different IBS subtypes. IBS-D represented by the highest number of studies, which show a much higher proportion of patients (39–62%) with increased permeability. Larger studies tend to have a lower proportion of patients with increased permeability compared with smaller studies.^{* *}Only studies that reported a proportion of IBS patients with increased permeability were included in this figure. Combination, ⩾1 subtype. IBS-C, constipation-predominant irritable bowel syndrome; IBS-D, diarrhea-predominant irritable bowel syndrome; PI-IBS, post-infection irritable bowel syndrome.

Figure 3.

Overview of in vitro and ex vivo barrier function changes in the different parts of the gastrointestinal tract of IBS patients. Most studies are available from the rectosigmoid colon, jejunum and the cecum and studied an IBS-D population. There is a significant heterogeneity in the target proteins assessed and the methodology used for determination of changes in vitro and ex vivo.^{* *}Results of studies that did not specify the exact colonic region where biopsies were taken were not included in this figure, but are discussed in the main text.

Figure 4.

Overview of studies reporting associations between barrier function and stool characteristics, abdominal pain, overall symptom severity, psychological functioning and quality of life in IBS patients. A positive association (red color) indicates study concluded barrier dysfunction to be positively correlated with a more severe symptomatology in IBS patients versus no correlation (blue color) versus a negative correlation (green color).^{§ §}Gecse and colleagues found an association between an increased intestinal permeability and stool frequency, but no association between stool consistency and increased intestinal permeability. Cr-EDTA, 51Cr-EDTA, chromium-51-ethylenediamine tetraacetic acid; CFL, cofilin; CLDN, claudin; JAM-1, junctional adhesion molecule 1; LMR, lactulose-to-mannitol ratio; PEGR, polyethylene glycol 400 to polyethylene glycol 3350 ratio; pMLC, phosphorylated myosin light chain; SER, sucralose-to-erythritol ratio; TEM, transmission electron microscopy; TESK1, testis-associated actin remodeling kinase 1; ZO, zona occludens.