Phenotypically distinct subsets of CD4+ T cells induce or protect from chronic intestinal inflammation in C. B-17 scid mice

CD4⁺ T cells in the mouse can be subdivided into two fractionsbased on the level of expression of the CD45RB determinant.Previous studies have shown that these subsets are functionallydistinct. We have further characterized the properties of thesesubpopulations in vivo by injecting them into C. B-17 scid mice.The animals restored with the CD45RB^highCD4⁺ T cell populationdeveloped a lethal wasting disease with severe mononuclear cellinfiltrates into the colon and elevated levels of IFN- mRNA.In contrast, animals restored with the reciprocal CD45RB^lowsubset or with unfractionated CD4⁺ T cells did not develop thewasting or colitis. Importantly, the co-transfer of the CD45RB^lowpopulation with the CD45RB^high population prevented the wastingdisease and colitis. These data indicate that important regulatoryinteractions occur between the CD45RB^high and CD45RB^lowCD4⁺T cell subsets and that disruption of this mechanism has fatalconsequences.     

Imbalanced secondary mucosal antioxidant response in inflammatory bowel disease

Intestinal mucosal damage in the inflammatory bowel diseases (IBD) Crohn's disease (CD) and ulcerative colitis (UC) involves reactive oxygen metabolites (ROMs). ROMs are neutralized by endogenous antioxidant enzymes in a carefully balanced two-step pathway. Superoxide dismutases (SODs) convert superoxide anion to hydrogen peroxide (H(2)O(2)), which is subsequently neutralized to water by catalase (CAT) or glutathione peroxidase (GPO). Remarkably changed expression levels of the three isoforms of SOD in paired non-inflamed and inflamed mucosae from CD and UC patients have been previously reported in comparison to normal control mucosa. Most notable was the strong up-regulation of Mn-SOD in inflamed epithelium. It was hypothesized that in order to provide optimal protection against ROM-mediated damage, these changes should be coordinately counterbalanced by an increased H(2)O(2)-neutralizing capacity. Therefore, the same tissue samples were used to assess the levels, activities, and/or localization of the most prominent mucosal H(2)O(2)-related antioxidants CAT, GPO, glutathione (GSH), myeloperoxidase (MPO), and metallothionein (MT). Quantitative measurements showed that in both CD and UC patients, intestinal inflammation was associated with increased activities of CAT, GPO, and MPO, whereas the mucosal GSH content was unaffected and the concentration of MT was decreased. Despite this overall increase in mucosal H(2)O(2)-metabolizing enzyme capacity, immunohistochemical analysis revealed a differentially disturbed antioxidant balance in IBD epithelium and lamina propria. In the lamina propria, the risk of direct H(2)O(2)-mediated damage seemed to be restrained by the increasing numbers of CAT- and MPO-positive monocytes/macrophages and neutrophils that infiltrated the inflamed areas. On the other hand, MPO overexpression might increase the lamina propria levels of hypochlorous acid, a stable ROM with multiple pro-inflammatory effects. In the epithelium, the number of cells that expressed CAT remained unchanged during inflammation and GPO was found in only a very low and constant number of epithelial cells. In addition, the inflamed epithelium displayed decreased expression of the hydroxyl radical (OH(*)) scavenger MT. In view of the high epithelial SOD levels in inflamed IBD epithelium, it is speculated that the efficient removal of excess H(2)O(2) is hampered in these cells, thereby increasing not only the risk of detrimental effects of H(2)O(2) directly, but also those of its extremely reactive derivatives such as OH(*). Taken together, the results suggest an imbalanced and inefficient endogenous antioxidant response in the intestinal mucosa of IBD patients, which may contribute to both the pathogenesis and the perpetuation of the inflammatory processes.     

基于Nrf2/HO-1通路的中医药干预溃疡性结肠炎研究进展

溃疡性结肠炎（UC）是临床常见的一种慢性消化系统疾病,其病情反复且治疗难度大,发病机制复杂,与氧化应激反应相关。核转录因子E₂相关因子2（Nrf2）是抗氧化反应中的重要因子,可调控其下游血红素加氧-1（HO-1）的表达,发挥维持机体氧化还原稳态的作用。UC的病程中Nrf2与HO-1的生物活性及含量水平均下降,组织抗氧化和抗炎能力减弱,肠上皮细胞损伤,肠黏膜屏障破坏。目前西医临床上主要以控制炎症和缓解症状治疗为主,虽有一定疗效,但存在停药后易复发、长期用药不良反应多等问题。研究表明,中医药治疗手段丰富,治疗方法灵活,在UC的防治上有广阔的应用前景。近年来,以Nrf2/HO-1通路为切入点,中医药领域开展了大量关于UC中该信号的基础和临床实验,结果表明Nrf2/HO-1通路是中医药治疗UC的重要潜在靶点。基于虚实夹杂的病因病机,中医药以清热解毒燥湿、活血化瘀止痛、益气补中温里和标本兼治等法调控Nrf2/HO-1通路,提高组织抗氧化应激能力,维持促炎因子与抗炎因子平衡,缓解炎症反应,发挥对UC的治疗作用。该文总结和分析了中医药靶向Nrf2/HO-1信号通路干预UC的机制和作用,以期为科研人员更为全面认识中医药对UC中Nrf2/HO-1通路的作用机制提供帮助,旨在推动今后中医药合理运用于临床UC的防治。     

黄芩汤对溃疡性结肠炎小鼠肠道菌群的影响及肠黏膜屏障的保护作用机制

目的：研究黄芩汤对溃疡性结肠炎(UC)模型小鼠的药效,并探究黄芩汤在UC中是否能调节肠道菌群,发挥屏障保护作用。方法：雄性Balb/c小鼠按体质量随机分为正常组、模型组、黄芩汤高(20 g·kg^-1)、中(10 g·kg^-1)、低(5 g·kg^-1)剂量组、菌群干扰组、菌群干扰模型组、菌群干扰黄芩汤组(黄芩汤,20 g·kg^-1)。灌胃抗生素(杆菌肽200 mg·kg^-1、万古霉素200 mg·kg^-1)8 d构建菌群干扰模型,自由饮用3%葡聚糖硫酸钠(DSS)溶液7 d构建UC模型,黄芩汤给药治疗7 d。实验结束后处死小鼠,取血、结肠及粪便,苏木素-伊红(HE)染色观察结肠病变,酶联免疫吸附测定法(ELISA)检测血清白细胞介素-4(IL-4)、白细胞介素-6(IL-6)、白细胞介素-10(IL-10)、肿瘤坏死因子-α(TNF-α)含量,实时荧光定量聚合酶链式反应(Real-time PCR)及蛋白免疫印迹法(Western blot)检测结肠组织中紧...     

芍药汤及其加减方治疗溃疡性结肠炎的研究进展

芍药汤由黄连、黄芩、大黄、白芍、当归、木香、槟榔、肉桂,甘草构成。因其具有清热利湿、调气活血功效,后世医家皆推此方为治疗湿热泄痢之主方。现代临床应用中,除芍药汤原方,其加减方亦用于溃疡性结肠炎治疗,并可与其他方剂（痛泄要方、白头翁汤、参苓白术散等）、西药（美沙拉嗪、柳氮磺吡啶、英夫利昔单抗等）、中医针刺或艾灸等特色疗法联用。临床疗效结果显示芍药汤及其加减方能明显降低梅奥内镜（Mayo）评分、结肠黏膜病变（Baron）评分、中医证候积分等疾病评分,改善患者肠道症状效果显著且不良反应少。实验药理学研究显示芍药汤可通过抑制肿瘤坏死因子-α(TNF-α)、核转录因子-κB(NF-κB)、白细胞介素-1β(IL-1β)等促炎因子表达,上调白细胞介素-10(IL-10)等抑炎因子来减轻炎症反应;可通过调节炎症信号通路,阻断连环反应,减少细胞凋亡;可通过调节免疫轴平衡、调节免疫蛋白修复异常免疫屏障;可调节肠道菌群平衡、促进肠上皮细胞再生、改善黏膜通透性,从而恢复肠道内环境平衡以达到治疗溃疡性结肠炎的效果;其药物单体黄芩苷、芍药苷、黄连素等可起到抗炎、抗菌、调节代谢等作用。该文就芍药汤治疗溃疡性结肠炎...     

慢溃宁方对DSS诱导溃疡性结肠炎小鼠NLRP3/Caspase-1/GSDMD细胞焦亡通路和肠道菌群的影响

目的 探讨慢溃宁方对葡聚糖硫酸钠（DSS）诱导的溃疡性结肠炎（UC）小鼠肠道菌群的调控作用,和对NOD样受体（NLR）P3/胱天蛋白酶（Caspase）-1/Gasdermin D（GSDMD）细胞焦亡通路所介导炎症的影响。方法 SPF级C57BL/6小鼠60只,随机分为空白组、模型组、慢溃宁方组（20 g·kg^-1）、美沙拉秦组（0.266 g·kg^-1）,各组15只。小鼠通过自由饮用3%DSS溶液,7 d构建UC模型。造模开始12 h后,治疗组每天灌胃给药,其余组灌胃等体积生理盐水。记录小鼠每日体质量等情况,并评估计算疾病活动指数（DAI）。第8天麻醉后,脱臼颈椎处死小鼠,收集结肠和粪便,记量结肠长度;观察结肠组织苏木素-伊红（HE）染色后的病理学改变;结肠中肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）、白细胞介素-18（IL-18）水平用酶联免疫吸附测定法（ELISA）检测;基于16S rRNA测序技术检测各组小鼠粪便中肠道菌群的差异;NLRP3/Caspase-1/GSDMD蛋白结肠组织中含量用蛋白免疫印迹法（Western blot）检测。结果 相较于空白组,模型组小鼠的DAI升高（P<0.01）,结肠长度显著缩短（P<0.01）,结肠黏膜损伤严重,TNFα、IL-1β、IL-18水平均明显升高（P<0.01）,且结肠组织中NLRP3/Caspase-1/GSDMD蛋白含量显著升高（P<0.01）,肠道菌群结构改变,门水平上的放线菌门、拟杆菌门与变形菌门丰度减少,厚壁菌门丰度增加;属水平上的乳酸杆菌、普雷沃氏菌和鼠杆菌属丰度减少,拟杆菌属、芽孢杆菌、毛螺旋菌属NK4A136丰度增加。慢溃宁方组、美沙拉秦组相较于模型组,第3天后DAI显著降低（P<0.01）,结肠长度均显著增加（P<0.01）,结肠的炎症浸润及黏膜结构损伤减轻,且结肠TNF-α、IL-1β、IL-18水平均显著下降（P<0.01）,NLRP3/Caspase-1/GSDMD蛋白在结肠组织中的含量明显降低（P<0.05,P<0.01）,门水平上的变形菌门和拟杆菌门丰度增加,厚壁菌门丰度减少。结论 慢溃宁方可通过抑制细胞经典焦亡通路,缓解UC小鼠结肠炎症反应,减轻结肠损伤,并对肠道菌群紊乱有改善作用。     

The Role of Diet in the Pathogenesis and Management of Inflammatory Bowel Disease: A Review

Inflammatory bowel diseases, which include ulcerative colitis and Crohn’s disease, are chronic relapsing and remitting inflammatory diseases of the gastrointestinal tract that are increasing in prevalence and incidence globally. They are associated with significant morbidity, reduced quality of life to individual sufferers and are an increasing burden on society through direct and indirect costs. Current treatment strategies rely on immunosuppression, which, while effective, is associated with adverse events. Epidemiological evidence suggests that diet impacts the risk of developing IBD and modulates disease activity. Using diet as a therapeutic option is attractive to patients and clinicians alike due to its availability, low cost and few side effects. Diet may influence IBD risk and disease behaviour through several mechanisms. Firstly, some components of the diet influence microbiota structure and function with downstream effects on immune activity. Secondly, dietary components act to alter the structure and permeability of the mucosal barrier, and lastly dietary elements may have direct interactions with components of the immune response. This review will summarise the mechanisms of diet–microbial–immune system interaction, outline key studies examining associations between diet and IBD and evidence demonstrating the impact of diet on disease control. Finally, this review will outline current prescribed dietary therapies for active CD.     

Does Drinking Coffee and Tea Affect Bone Metabolism in Patients with Inflammatory Bowel Diseases?

Patients suffering from Crohn’s disease and ulcerative colitis are at higher risk of osteoporosis due to lower bone mineral density. Risk factors of osteoporosis are divided into unmodifiable, namely, age, gender, genetic factors, as well as modifiable, including diet, level of physical activity, and the use of stimulants. Coffee and tea contain numerous compounds affecting bone metabolism. Certain substances such as antioxidants may protect bones; other substances may increase bone resorption. Nevertheless, the influence of coffee and tea on the development and course of inflammatory bowel diseases is contradictory.     

Effects of Dietary Oat Beta-Glucans on Colon Apoptosis and Autophagy through TLRs and Dectin-1 Signaling Pathways—Crohn’s Disease Model Study

Background: Crohn’s disease (CD) is characterized by chronic inflammation of the gastrointestinal tract with alternating periods of exacerbation and remission. The aim of this study was to determine the time-dependent effects of dietary oat beta-glucans on colon apoptosis and autophagy in the CD rat model. Methods: A total of 150 Sprague–Dawley rats were divided into two main groups: healthy control (H) and a TNBS (2,4,6-trinitrobenzosulfonic acid)-induced colitis (C) group, both including subgroups fed with feed without beta-glucans (βG−) or feed supplemented with low- (βGl) or high-molar-mass oat beta-glucans (βGh) for 3, 7, or 21 days. The expression of autophagy (LC3B) and apoptosis (Caspase-3) markers, as well as Toll-like (TLRs) and Dectin-1 receptors, in the colon epithelial cells, was determined using immunohistochemistry and Western blot. Results: The results showed that in rats with colitis, after 3 days of induction of inflammation, the expression of Caspase-3 and LC3B in intestinal epithelial cells did not change, while that of TLR 4 and Dectin-1 decreased. Beta-glucan supplementation caused an increase in the expression of TLR 5 and Dectin-1 with no changes in the expression of Caspase-3 and LC3B. After 7 days, a high expression of Caspase-3 was observed in the colitis-induced animals without any changes in the expression of LC3B and TLRs, and simultaneously, a decrease in Dectin-1 expression was observed. The consumption of feed with βGl or βGh resulted in a decrease in Caspase-3 expression and an increase in TLR 5 expression in the CβGl group, with no change in the expression of LC3B and TLR 4. After 21 days, the expression of Caspase-3 and TLRs was not changed by colitis, while that of LC3B and Dectin-1 was decreased. Feed supplementation with βGh resulted in an increase in the expression of both Caspase-3 and LC3B, while the consumption of feed with βGh and βGl increased Dectin-1 expression. However, regardless of the type of nutritional intervention, the expression of TLRs did not change after 21 days. Conclusions: Dietary intake of βGl and βGh significantly reduced colitis by time-dependent modification of autophagy and apoptosis, with βGI exhibiting a stronger effect on apoptosis and βGh on autophagy. The mechanism of this action may be based on the activation of TLRs and Dectin-1 receptor and depends on the period of exacerbation or remission of CD.