The gastrointestinal mucosa constitutes a critical barrier where millions of microbes and environmental antigens come in close contact with the host immune system. Intestinal barrier defects have been associated with a broad range of diseases and therefore denote a new therapeutic target. Areas covered: This review is based on an extensive literature search in PubMed of how the intestinal barrier contributes to health and as a trigger for disease. It discusses the anatomy of the intestinal barrier and explains the available methods to evaluate its function. Also reviewed is the importance of diet and lifestyle factors on intestinal barrier function, and three prototypes of chronic diseases (inflammatory bowel disease, celiac disease and nonalcoholic fatty liver disease) that have been linked to barrier defects are discussed. Expert commentary: The intestinal barrier has been investigated by various methods, but correlation of results across studies is difficult, representing a major shortcoming in the field. New upcoming techniques and research on the effect of barrier-restoring therapeutics may improve our current understanding of the gut barrier, and provide a step forward towards personalised medicine.

We found genetic and transcriptomic dysregulations of key epithelial barrier genes and components in IBD. Of these, we believe that mucus genes, in particular MUC1 and MUC4, play an essential role in the pathogenesis of IBD and could represent interesting targets for treatment.

Background and Aims In vitro studies using immortalised cancer cell lines showed that butyrate has an overall positive effect on epithelial barrier integrity, but the physiological relevance of cancer cell lines is limited. We developed epithelial monolayers from human tissue samples of patients with ulcerative colitis [UC] to assess the effect of butyrate on epithelial barrier function. Methods A protocol to establish monolayers from primary epithelial cells of UC patients [n = 10] and non-UC controls [n = 10] was optimised. The monolayers were treated with 8 mM sodium butyrate ± tumour necrosis factor alpha [TNFα] and type II interferon [IFNγ] for 48 h. Changes in transepithelial electrical resistance were monitored. Barrier gene expression levels were measured. Inflammatory proteins in the supernatant of the cells were quantified with OLINK. Results We demonstrated that primary monolayer cultures can be grown within 1 week of culture with robust resistance values and polarised tight junction expression. Butyrate treatment of the cultures increased resistance but was detrimental in combination with TNFα and IFNγ. The combined treatment further induced even higher IL8 mRNA and inflammatory protein secretion than for the inflammatory mediators alone. The observed effects were similar in cultures from patients and non-UC controls, suggesting that there were no patient-specific responses responsible for these findings. Conclusions We found that butyrate does not protect against inflammation-induced barrier dysfunction and even worsens its effects in primary epithelial monolayers of UC patients and controls. The basic mechanisms of butyrate should therefore be reconsidered in future studies, in particular in patients with active inflammation and pre-existing barrier defects as is known for UC.

Background Oncostatin M (OSM) has been implicated in the pathogenesis of inflammatory bowel disease (IBD) and as a marker for nonresponsiveness to anti-tumor necrosis factor (TNF) therapy. We further unraveled the potential of OSM and related receptors as markers of diagnosis, prognosis, and therapy response in IBD. Methods We collected inflamed mucosal biopsies and serum from patients with Crohn disease (CD) and with ulcerative colitis: (1) newly diagnosed patients who were treatment-naïve, (2) patients initiating anti-TNF or (3) vedolizumab therapy, (4) postoperative patients with CD, and (5) multiple-affected families with IBD including unaffected first-degree relatives (FDRs). We measured the gene expression of mucosal OSM and its receptors OSMR/LIFR and co-receptor IL6ST, and the protein expression of serum OSM. Statistical significance was defined as P < 0.05. Results Newly diagnosed patients showed significantly increased mucosal OSM/OSMR compared with control patients, with the highest enrichment for OSM (fold change [FC] >17.9). Likewise, ileal OSM/OSMR were significantly upregulated in postoperative recurrent CD. Serum OSM was increased in newly diagnosed patients and postoperative patients with recurrent CD (FC ≥ 2.6). In families with IBD, higher serum levels were observed in FDRs than in control families (FC = 2.2). Furthermore, elevated colonic OSM/OSMR (but not serum OSM) were associated with the early need for biologic therapy (FC ≥ 1.9), and higher OSM was also predictive of primary nonresponse to both anti-TNF and vedolizumab therapy (FC ≥ 2.4). Immunohistochemistry highlighted mucosal OSM expression in macrophages. Conclusions We found that OSM is a diagnostic biomarker in the tissue and serum not only of newly diagnosed patients with IBD and postoperative patients with recurrent CD but also of their FDRs. Higher colonic OSM levels are furthermore associated with poor prognosis and with primary nonresponse to biologic therapies. Therefore, OSM could guide clinical decision-making.

Background and Aims Early treatment of Crohn’s disease [CD] is required in order to optimize patient outcomes. To this end, we need to gain a better understanding of the molecular changes at the onset of CD. Methods As a model for the earliest mucosal CD lesions, we study post-operative recurrent CD [Rutgeerts score ≥ i2b]. We are the first to analyse gene and microRNA [miRNA] expression profiles in ileal biopsies from these patients, and compare them with those of newly diagnosed [≤18 months] and late-stage [>10 years after diagnosis] CD patients. Results Except for one gene [WNT5A], there are no differential genes in CD patients without post-operative recurrence [i0], showing that previous disease did not influence gene expression in the neoterminal ileum, and that this model can be used to study early mucosal CD lesions. Gene expression and co-expression network dysregulation is more pronounced in newly diagnosed and late-stage CD than in post-operative recurrent CD, with most important modules associated with [a]granulocyte adhesion/diapedesis, and cholesterol biosynthesis. In contrast, we found a role for snoRNAs/miRNAs in recurrent CD, highlighting the potential importance of regulatory RNAs in early disease stages. Immunohistochemistry confirmed the expression of key dysregulated genes in damaged/regenerating epithelium and immune cells in recurrent CD. Conclusions Aside from regulatory RNAs, there are no clear gene signatures separating post-operative recurrent, newly diagnosed, and late-stage CD. The relative contribution of dysregulated genes and networks differs, and suggests that surgery may reset the disease at the mucosal site, and therefore post-operative recurrent CD might be a good model a good model to study to study early mucosal CD lesions.