Clinical relevance of intestinal barrier dysfunction in common gastrointestinal diseases

The intestinal barrier is a complex and well-controlled physiological construct designed to separate luminal contents from the bowel wall. In this review, we focus on the intestinal barrier’s relationship with the host’s immune system interaction and the external environment, specifically the microbiome. The bowel allows the host to obtain nutrients vital to survival while protecting itself from harmful pathogens, luminal antigens, or other pro-inflammatory factors. Control over barrier function and the luminal milieu is maintained at the biochemical, cellular, and immunological level. However, disruption to this highly regulated environment can cause disease. Recent advances to the field have progressed the mechanistic understanding of compromised intestinal barrier function in the context of gastrointestinal pathology. There are numerous examples where bowel barrier dysfunction and the resulting interaction between the microbiome and the immune system has disease-triggering consequences. The purpose of this review is to summarize the clinical relevance of intestinal barrier dysfunction in common gastrointestinal and related diseases. This may help highlight the importance of restoring barrier function as a therapeutic mechanism of action in gastrointestinal pathology.     

活动期溃疡性结肠炎患者血清vaspin水平及其临床意义

脂肪细胞因子与机体内能量稳定相关,并介导多种免疫应答和炎症反应。内脏脂肪特异性丝氨酸蛋白酶抑制剂vaspin是近年发现的一种与炎症反应有关的脂肪细胞因子。目的:检测活动期溃疡性结肠炎(UC)患者的血清vaspin水平并探讨其临床意义。方法:选取2008年1月~2013年4月苏州市立医院收治的150例活动期UC患者,以150名健康体检者作为正常对照组。采用ELISA法检测血清vaspin水平,并分析其与UC临床特征的相关性。结果:UC患者血清vaspin水平显著高于正常对照者[(1.86±0.38)μg/L对(0.96±0.43)μg/L,P0.01],并与血清CRP水平和疾病活动指数呈显著正相关(r=0.628,P0.01;r=0.514,P0.05),与血清ESR水平和病变部位无关(r=0.098,P0.05;r=0.124,P0.0)5)。结论:Vaspin可能在UC发生、发展的病理生理机制中发挥重要作用。     

Type I interferons have opposing effects during the emergence and recovery phases of colitis

The contribution of the innate immune system to inflammatory bowel disease (IBD) is under intensive investigation. Research in animal models has demonstrated that type I interferons (IFN‐Is) protect from IBD. In contrast, studies of patients with IBD have produced conflicting results concerning the therapeutic potential of IFN‐Is. Here, we present data suggesting that IFN‐Is play dual roles as regulators of intestinal inflammation in dextran sodium sulfate (DSS)‐treated C57BL/6 mice. Though IFN‐Is reduced acute intestinal damage and the abundance of colitis‐associated intestinal bacteria caused by treatment with a high dose of DSS, they also inhibited the resolution of inflammation after DSS treatment. IFN‐Is played an anti‐inflammatory role by suppressing the release of IL‐1β from the colon MHC class II⁺ cells. Consistently, IL‐1 receptor blockade reduced the severity of inflammation in IFN‐I receptor‐deficient mice and myeloid cell‐restricted ablation of the IFN‐I receptor was detrimental. The proinflammatory role of IFN‐Is during recovery from DSS treatment was caused by IFN‐I‐dependent cell apoptosis as well as an increase in chemokine production and infiltrating inflammatory monocytes and neutrophils. Thus, IFN‐Is play opposing roles in specific phases of intestinal injury and inflammation, which may be important for guiding treatment strategies in patients.     

Arginase activity in alternatively activated macrophages protects PI3Kp110δ deficient mice from dextran sodium sulfate induced intestinal inflammation

Alternatively activated or M2 macrophages have been reported to protect mice from intestinal inflammation, but the mechanism of protection has not been elucidated. In this study, we demonstrate that mice deficient in the p110δ catalytic subunit activity of class I phosphatidylinositol 3‐kinase (PI3Kp110δ) have increased clinical disease activity and histological damage during dextran sodium sulfate (DSS) induced colitis. Increased disease severity in PI3Kp110δ‐deficient mice is dependent on professional phagocytes and correlates with reduced numbers of arginase I⁺ M2 macrophages in the colon and increased production of inflammatory nitric oxide. We further demonstrate that PI3Kp110δ‐deficient macrophages are defective in their ability to induce arginase I when skewed to an M2 phenotype with IL‐4. Importantly, adoptive transfer of IL‐4‐treated macrophages derived from WT mice, but not those from PI3Kp110δ‐deficient mice, protects mice during DSS‐induced colitis. Moreover, M2 macrophages mediated protection is lost when mice are cotreated with inhibitors that block arginase activity or during adoptive transfer of arginase I deficient M2 macrophages. Taken together, our data demonstrate that arginase I activity is required for M2 macrophages mediated protection during DSS‐induced colitis in PI3Kp110δ‐deficient mice.     

Gastrointestinal complications after kidney transplantation

Gastrointestinal complications are common after renal transplantation, and they have a wide clinical spectrum, varying from diarrhoea to post-transplant inflammatory bowel disease(IBD). Chronic immunosuppression may increase the risk of post-transplant infection and medication-related injury and may also be responsible for IBD in kidney transplant re-cipients despite immunosuppression. Differentiating the various forms of post-transplant colitis is challenging, since most have similar clinical and histological features. Drug-related colitis are the most frequently encountered colitis after kidney transplantation, particularly those related to the chronic use of mycophenolate mofetil, while de novo IBDs are quite rare. This review will explore colitis after kidney transplantation, with a particular focus on different clinical and histological features, attempting to clearly identify the right treatment, thereby improving the final outcome of patients.     

Ulcerative Colitis and Immunoglobulin G4

Background/Aims

Ulcerative colitis (UC) is sometimes associated with autoimmune pancreatitis (AIP). Infiltration of immunoglobulin G4 (IgG4)-positive plasma cells is sometimes detected in the colonic mucosa of AIP or UC patients. This study aimed to clarify the relation between UC and IgG4.

Methods

Associations with UC were reviewed in 85 AIP patients. IgG4 immunostaining was performed on biopsy specimens from the colonic mucosa of 14 AIP and 32 UC patients.

Results

UC was confirmed in two cases (type 1 AIP, n=1; suspected type 2 AIP, n=1). Abundant infiltration of IgG4-positive plasma cells in the colonic mucosa was detected in the case of suspected type 2 AIP with UC and two cases of type 1 AIP without colitis. Abundant infiltration of IgG4-positive plasma cells was detected in 10 UC cases (IgG4-present, 31%). Although 72% of IgG4-absent UC patients showed mild disease activity, 70% of IgG4-present patients showed moderate to severe disease activity (p<0.05).

Conclusions

UC is sometimes associated with AIP, but it seems that UC is not a manifestation of IgG4-related disease. Infiltration of IgG4-positive plasma cells is sometimes detectable in the colonic mucosa of UC patients and is associated with disease activity.