BackgroundAround 30% of patients with inflammatory bowel disease (IBD) are refractory to current IBD drugs or relapse over time. Novel treatments are called for, and low dose Naltrexone (LDN) may provide a safe, easily accessible alternative treatment option for these patients. We investigated the potential of LDN to induce clinical response in therapy refractory IBD patients, and investigated its direct effects on epithelial barrier function.MethodsPatients not in remission and not responding to conventional therapy were offered to initiate LDN as a concomitant treatment. In total 47 IBD patients prescribed LDN were followed prospectively for 12 weeks. Where available, endoscopic remission data, serum and biopsies were collected. Further the effect of Naltrexone on wound healing (scratch assay), cytokine production and endoplasmic reticulum (ER) stress (GRP78 and CHOP western blot analysis, immunohistochemistry) were investigated in HCT116 and CACO2 intestinal epithelial cells, human IBD intestinal organoids and patient samples.ResultsLow dose Naltrexone induced clinical improvement in 74.5%, and remission in 25.5% of patients. Naltrexone improved wound healing and reduced ER stress induced by Tunicamycin, lipopolysaccharide or bacteria in epithelial barriers. Inflamed mucosa from IBD patients showed high ER stress levels, which was reduced in patients treated with LDN. Cytokine levels in neither epithelial cells nor serum from IBD patients were affected.ConclusionsNaltrexone directly improves epithelial barrier function by improving wound healing and reducing mucosal ER stress levels. Low dose Naltrexone treatment is effective and safe, and could be considered for the treatment of therapy refractory IBD patients.Electronic supplementary materialThe online version of this article (10.1186/s12967-018-1427-5) contains supplementary material, which is available to authorized users.

ObjectivePregnancy may affect the disease course of IBD. Both pregnancy and IBD are associated with altered immunology and intestinal microbiology. However, to what extent immunological and microbial profiles are affected by pregnancy in patients with IBD remains unclear.DesignFaecal and serum samples were collected from 46 IBD patients (31 Crohn’s disease (CD) and 15 UC) and 179 healthy controls during first, second and third trimester of pregnancy, and prepregnancy and postpartum for patients with IBD. Peripheral blood cytokine profiles were determined by ELISA, and microbiome analysis was performed by sequencing the V4 region of the bacterial 16S rRNA gene.ResultsProinflammatory serum cytokine levels in patients with IBD decrease significantly on conception. Reduced interleukin (IL)-10 and IL-5 levels but increased IL-8 and interferon (IFN)γ levels compared with healthy controls were seen throughout pregnancy, but cytokine patterns remained stable during gestation. Microbial diversity in pregnant patients with IBD was reduced compared with that in healthy women, and significant differences existed between patients with UC and CD in early pregnancy. However, these microbial differences were no longer present during middle and late pregnancy. Dynamic modelling showed considerable interaction between cytokine and microbial composition.ConclusionSerum proinflammatory cytokine levels markedly improve on conception in pregnant patients with IBD, and intestinal microbiome diversity of patients with IBD normalises during middle and late pregnancy. We thus conclude that pregnancy is safe and even potentially beneficial for patients with IBD.

Background: Pregnancy is often described as an immune-tolerant state, and a disease modulatory role for pregnancy on inflammatory bowel disease (IBD) has been suggested. The direct effect of estrogen and progesterone on the intestinal epithelial barrier is underexplored. We investigated the direct consequences of these pregnancy hormones on barrier cells and their function. Methods: We used IBD patient-derived inflammatory organoid models and 2D cell lines models. Epithelial barrier function was analyzed by measuring transepithelial electrical resistance; wound closure was determined by scratch assay; and cell viability was measured by MTT assays. Pro-inflammatory cytokine production was determined by enzyme-linked immunosorbent assays. Molecular modulation of endoplasmic reticulum (ER) stress induced by tunicamycin was studied by western blot analysis of the ER stress markers GRP78, CHOP and p-IRE1. Results: Progesterone and estrogen improved wound healing and epithelial barrier function in intestinal epithelial cells via upregulation of tight junction proteins. Furthermore, these sex hormones significantly reduced ER-stress and reduce pro-inflammatory cytokine production in intestinal epithelial models. Conclusion: Our study shows that estrogen and progesterone alleviate ER stress, decrease pro-inflammatory cytokine production, stimulate wound healing, and increase barrier function of epithelial cells. Combined, these data suggest that pregnancy hormones can have beneficial effects on disease activity by positively modulating the intestinal epithelial lining.

The disease course of autoimmune diseases such as rheumatoid arthritis is altered during pregnancy, and a similar modulatory role of pregnancy on inflammatory bowel disease (IBD) has been proposed. Hormonal, immunological, and microbial changes occurring during normal pregnancy may interact with the pathophysiology of IBD. IBD consists of Crohn's disease and ulcerative colitis, and because of genetic, immunological, and microbial differences between these disease entities, they may react differently during pregnancy and should be described separately. This review will address the pregnancy-induced physiological changes and their potential effect on the disease course of ulcerative colitis and Crohn's disease, with emphasis on the modulation of epithelial barrier function and immune profiles by pregnancy hormones, microbial changes, and microchimerism.