Salubrinal protects against Clostridium difficile toxin B-induced CT26 cell death Shuyi Chen, Chunli Sun, Huawei Gu, Haiying Wang, Shan Li, Yi Ma, and Jufang Wang School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China Acta Biochim Biophys Sin 2017, 49: 228–237; doi: 10.1093/abbs/gmw139 Clostridium difficile (C. difficile) is considered to be the major cause of the antibiotic-associated diarrhea and pseudomembranous colitis in animals and humans. The prevalence of C. difficile infections (CDI) has been increasing since 2000. Two exotoxins of C. difficile, Toxin A (TcdA) and Toxin B (TcdB), are the main virulence factors of CDI, which can induce glucosylation of Rho GTPases in host cytosol, leading to cell morphological changes, cell apoptosis, and cell death. The mechanism of TcdB-induced cell death has been investigated for decades, but it is still not completely understood. It has been reported that TcdB induces endoplasmic reticulum stress via PERK-eIF2α signaling pathway in CT26 cell line (BALB/C mouse colon tumor cells). In this study, we found that salubrinal, a selective inhibitor of eIF2α dephosphorylation, efficiently protects CT26 cell line against TcdB-induced cell death and tried to explore the mechanism underlying in this protective effect. Our results demonstrated that salubrinal protects CT26 cells from TcdB-mediated cytotoxic and cytopathic effect, inhibits apoptosis and death of the toxin-exposed cells via caspase-9-dependent pathway, eIF2α signaling pathway, and autophagy. These findings will be helpful for the development of CDI therapies. Salubrinal against Clostridium difficile TcdB-induced cell death Summary of protective mechanism 阅读全文: http://www.abbs.org.cn/arts.asp?id=4126 获取全文: abbs@sibs.ac.cn 相关论文: 1 Probiotics for prevention of Clostridium difficile infection 2 Dietary trehalose enhances virulence of epidemic Clostridium difficile 3 Ulcerative colitis 4 Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection 5 A Novel Microbiome Therapeutic Increases Gut Microbial Diversity and Prevents Recurrent Clostridium difficile Infection 6 Clostridium difficile infection 7 Clostridium difficile infection: epidemiology, diagnosis and understanding transmission 8 Breakthroughs in the treatment and prevention of Clostridium difficile infection
炎症与癌症的关系已逐渐成为关注热点，也是当前癌症研究领域的共识。可是，对于炎症是如何诱发癌症的问题，科学家们仍然莫衷一是、不置可否。事实上，细菌感染引起的炎症已经成为致癌因素的最大嫌疑！ 昨天，Science以快报（Express）形式发表了英、美、加等国科学家的最新研究成果，探讨大肠杆菌性肠炎与结肠癌及直肠癌的关系，论文题目是“肠炎指向微生物群落的癌症诱导活性”（I ntestinal Inflammation Targets Cancer-Inducing Activity of the Microbiot a）。 为此，ScienceDaily还专门配发了一篇最新评论和背景性介绍，文章的题目是“炎症、细菌群落与癌症的确凿关系被发现”（C lear Links Found Between Inflammation, Bacterial Communities and Canc er）。 这篇文章的新意在于不仅证实了大肠杆菌感染与结直肠癌的关系，而且首次发现只有含“基因毒性岛”（genotoxic island）的大肠杆菌才能诱发结直肠癌。也就是说，过去认为只要是慢性炎症就能致癌的观点不全面，因此为特殊病原体所致炎症才能致癌的观点提供了新证据。 所谓“基因毒性岛”是指大肠杆菌基因组中的聚酮合酶基因（pks）编码序列。最新研究发现，如果把这个pks基因删除掉，尽管肠炎依旧，但致癌性和侵润性减弱。 因此，结直肠癌归根结底还是由肠道细菌感染产生的聚酮类化合物诱发的。不过，聚酮合酶及聚酮类化合物如何参与炎症向癌症的转化还不清楚。 这个实验是在一种特殊的小鼠中完成的，它们的抗炎症细胞因子——白细胞介素10基因被敲除，从而导致肠道菌群改变，大肠杆菌菌株占绝对优势，使偶氮甲烷处理小鼠的侵润性结直肠癌发生率大增。 在另一项研究中还发现，这种pkc+大肠杆菌属于肠粘膜结合细菌，它们在炎性肠病（IBD）及肠炎相关结直肠癌（CRC）患者肠道中所占比例极高。这个结果印证了在小鼠中得出的上述结论。 在正常人中，pkc+毒性大肠杆菌仅有20%，IBD患者体内的毒性大肠杆菌则占40%，而结直肠癌患者体内的毒性大肠杆菌高达66.7%。同时，毒性大肠杆菌占优势的肠道中，非毒性菌群（如粪肠球菌）的比例同步减少。 关于这篇文章的意义，如果要给科学网的读者说得更浅显一点，那就是请大家记住以下三个要点： 一是免疫力低下的人群（如老人）经常腹泻或排便不正常一定要引起足够的重视，以防慢性肠炎最终发展成为结直肠癌； 二是不要滥用抗生素，虽然抗生素能杀死细菌，但也很容易造成肠道菌群紊乱，运气不好就会让大肠杆菌占优势，很可能不幸成为癌症牺牲者； 三是肠道菌群破坏后，还是有补救措施的，那就是经常服用益生菌（如双歧杆菌），在有冷藏设备的大型药店都可以买到含益生菌的药片。 原文现在还无法弄到，下面是其摘要： Inflammation alters host physiology to promote cancer, as seen in colitis-associated colorectal cancer (CRC). Here, we identify the intestinal microbiota as a target of inflammation that impacts the progression of CRC. High-throughput sequencing revealed that inflammation modifies gut microbial composition in colitis-susceptible interleukin-10–deficient ( Il10 −/− ) mice. Monocolonization with the commensal Escherichia coli NC101 promoted invasive carcinoma in azoxymethane (AOM)–treated Il10 −/− mice. Deletion of the polyketide synthase (pks) genotoxic island from E. coli NC101 decreased tumor multiplicity and invasion in AOM/ Il10 −/− mice, without altering intestinal inflammation. Mucosa-associated pks+ E. coli were found in a significantly high percentage of inflammatory bowel disease and CRC patients. This suggests that in mice, colitis can promote tumorigenesis by altering microbial composition and inducing the expansion of microorganisms with genotoxic capabilities.
【文献导读】 今天出版的Nature发表了一篇文章，题目是A CE2 links amino acid malnutrition to microbial ecology and intestina l inflammation（血管紧张素转换酶2将氨基酸营养不良与微生物生态及肠炎相联系），介绍了肠炎、腹泻和营养不良的因果关系及其对策。 内容梗概是：In malnutrition, it is often the associated diarrhoea and intestinal inflammation that cause morbidity and death （营养不良常与致病性及致死性腹泻和肠炎有关）。 A new study implicates angiotensin converting enzyme 2 (ACE2) deficiency as a cause of increased susceptibility to intestinal inflammation（一项新的研究暗示血管紧张素转换酶2缺陷是肠炎易感性增加的原因之一）。 Dietary tryptophan and its metabolite nicotinamide can alleviate the symptoms（在食物中补充色氨酸及其代谢产物烟酰胺可以缓解这一症状）。 This surprising finding explains nutritional effects that have been known for centuries and provides a molecular link between malnutrition and the intestinal microbiome（这个新奇的发现解释了几个世纪以前就了解的营养效应，并在分子水平上将营养不良与肠炎联系起来）。 文章摘要如下：Malnutrition affects up to one billion people in the world and is a major cause of mortality（营养不良影响着世界上近十亿人口，是引起死亡的主要原因）。 In many cases, malnutrition is associated with diarrhoea and intestinal inflammation, further contributing to morbidity and death（在很多情况下，营养不良与腹泻和肠炎有关，进一步增加了致病和致死人数）。 The mechanisms by which unbalanced dietary nutrients affect intestinal homeostasis are largely unknown（非均衡膳食营养如何影响肠道稳态的机理还很不清楚）。 Here we report that deficiency in murine angiotensin I converting enzyme (peptidyl-dipeptidase A) 2 ( Ace2 ), which encodes a key regulatory enzyme of the renin-angiotensin system (RAS), results in highly increased susceptibility to intestinal inflammation induced by epithelial damage（我们在此报道，鼠血管紧张素I转换酶2（ACE2）或肽酰二肽酶A——编码肾素-血管紧张素系统（RAS）的一个关键性调节酶——缺陷，可导致对表皮损伤诱导肠炎的易感性大大增强）。 The RAS is known to be involved in acute lung failure, cardiovascular functions and SARS infections（已知RAS与急性肺病、心血管功能、SARS感染有关）。 Mechanistically, ACE2 has a RAS-independent function, regulating intestinal amino acid homeostasis, expression of antimicrobial peptides, and the ecology of the gut microbiome（从机理而言，ACE2具有不依赖RAS的功能，可调节肠道氨基酸稳态、抗微生物肽表达、肠道微生物群落生态）。 Transplantation of the altered microbiota from Ace2 mutant mice into germ-free wild-type hosts was able to transmit the increased propensity to develop severe colitis（将Ace2突变小鼠改变后的微生物群落移植给无菌的野生型小鼠，就能引起后者出现严重的肠炎）。 ACE2-dependent changes in epithelial immunity and the gut microbiota can be directly regulated by the dietary amino acid tryptophan（ACE2依赖的表皮免疫性及肠道微生物群落的改变直接受膳食中色氨酸调控）。 Our results identify ACE2 as a key regulator of dietary amino acid homeostasis, innate immunity, gut microbial ecology, and transmissible susceptibility to colitis（我们的研究鉴定出ACE2是调节膳食氨基酸稳态、天然免疫性、肠道微生物生态、可转移肠炎易感性的关键因素）。 These results provide a molecular explanation for how amino acid malnutrition can cause intestinal inflammation and diarrhoea（本研究将在分子水平上解释氨基酸营养不良是如何引起肠炎及腹泻的）。 暂时还拿不到该文的全文，特此简要介绍如上。留下一个令人费解的问题：色氨酸为什么能以及如何弥补ACE2基因缺陷？
标签: 肠炎
