Anti-TNF-α antibodies improve intestinal barrier function in Crohn's disease

Abstract

Background and aims: Intestinal barrier function in Crohn's disease patients and their first degree healthy relatives is impaired. The increased intestinal permeability may result in an enhanced mucosal immune response and thereby aggravate intestinal inflammation. Humanised anti-TNF-α antibodies have been shown to be effective in the treatment of active Crohn's disease and in the treatment of entero-cutaneous fistula. The aim of the present study was to investigate the influence of anti-TNF-α antibody (infliximab) treatment on the intestinal barrier function of patients with active Crohn's disease. Methods: The differential intestinal uptake of lactulose and mannitol was measured to quantify intestinal permeability in patients with long standing active Crohn's disease (n = 17) directly before and seven days after treatment with infliximab (5 mg/kg bodyweight). In parallel, intestinal permeability was studied in a healthy control group (n = 20). Serum samples were analysed with pulsed amperometric detection after separation on an anion exchange column. Results: Intestinal permeability was significantly increased in all patients with Crohn's disease (L/M ratio 0.24 ± 0.17) prior to infliximab treatment compared to the control group (L/M ratio 0.01 ± 0.02; p-value b 1 × 10 − 7 ). Treatment of patients with infliximab resulted in a marked decrease of intestinal permeability as measured by L/M ratio from 0.24 ± 0.17 before to 0.02 ± 0.02 (p-value b 1 × 10 − 7 ) seven days after infliximab application.Conclusions: Treatment with anti-TNF-α antibodies improved impaired intestinal barrier function in patients with Crohn's disease. This effect may correlate to the well documented antiinflammatory effect of TNF-α blockade in this intestinal disease.

Pro-inflammatory effects of matrix metalloproteinase 7 in acute inflammation

“…Increased gut permeability has been observed in multiorgan failure and in gastrointestinal disease 39,40 For example, in Crohn's disease, inflammation and loss of gut barrier integrity are associated with TNF as they are dramatically decreased by anti-TNF treatment. 41 As TNF injection has been reported to lead to loss of gut permeability, 42 it is interesting that MMP7 À / À mice were also substantially protected against the TNFinduced lethal response (Figure 3i). …”

Differential Roles for Interleukin-23 and Interleukin-17 in Intestinal Immunoregulation

“…IFN-g + IL-17 + coproducing CD4 + T cells are specifically enriched in the inflamed intestinal mucosa in Crohn's disease and ulcerative colitis patients, and coproduction of these cytokines has been identified as a hallmark of pathogenic Th17 cells in murine models and humans Perhaps most strikingly, IL-17RA inhibition promoted breakdown of the intestinal epithelial barrier. Indirect (sCD14 and LBP) and direct (lactulose, mannitol, sucralose) barrier integrity measurements have been used to monitor the leakiness of the gut barrier in humans and animals and are associated with disease progression and relapse (Lakatos et al, 2011;Noth et al, 2012;Olson et al, 2006;Pastor Rojo et al, 2007). With these measurements, we observed an increase in intestinal permeability in the presence of IL-17RA inhibition, well beyond what normally occurs in the diseased state.…”

“…Such methods have been used in mice and humans to gauge the ''leakiness'' of the gut and correlate with disease severity and relapse (Noth et al, 2012;Olson et al, 2006;Wild et al, 2003). Sugar dosing was done at the first clinical signs of colitis (early time point) or at the standard terminal endpoint (late time point).…”

Role of programmed necrosis and cell death in intestinal inflammation

“…Currently, there is no cure for IBD and therapy only allows management of the symptoms. Anti-tumor necrosis factor (TNF) monoclonal antibodies, a main biological treatment of IBD, have been shown to improve clinical symptoms, promoting mucosal healing [19] and restoring barrier integrity [20,21]. However, a fraction of IBD patients are refractory to anti-TNF therapy [22].…”