Acute Infectious Gastroenteritis Potentiates a Crohn's Disease Pathobiont to Fuel Ongoing Inflammation in the Post-Infectious Period.
Acute Infectious Gastroenteritis Potentiates a Crohn's Disease Pathobiont to Fuel Ongoing Inflammation in the Post-Infectious Period.
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DOI：
10.1371/journal.ppat.1005907
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发表时间：
2016-10
期刊：
影响因子：
6.7
通讯作者：
Coombes BK
中科院分区：
文献类型：
--
作者：
Small CL;Xing L;McPhee JB;Law HT;Coombes BK
克罗恩病 (CD) 是一种病因多样的慢性炎症性疾病。接触引起急性胃肠炎的食源性病原体会在感染后期产生长期的克罗恩病风险，但这种与疾病发作持续关系的机制基础尚不清楚。我们开发了两种新模型来研究由鼠伤寒沙门氏菌或啮齿类柠檬酸杆菌引起的急性胃肠炎的合并症，这些小鼠体内有粘附侵袭性大肠杆菌 (AIEC)，这是一种与 CD 相关的细菌病原体。在这里，我们发现胃肠炎后感染后时期的疾病活动是由常驻 AIEC 病原体的组织相关扩张驱动的，伴随着免疫病理学、屏障缺陷和病原体清除后粘膜恢复延迟的增加。这些特征需要 AIEC 对宿主防御肽具有抵抗力，并对肠道病原体产生暴发性炎症反应。我们的结果表明，在急性传染性胃肠炎时被 AIEC 定植的个体可能面临更大的 CD 发病风险。重要的是，我们的数据将 AIEC 确定为一种可治疗的疾病调节剂，这一发现可用于开发高危人群感染性胃肠炎后的治疗干预措施。西方社会炎症性肠病（IBD）的发病率异常高，尤其是在青少年群体中，发病率不断上升。大量证据支持肠道细菌参与人类肠道疾病病理生理学的观点。统一的概念是由粘膜免疫系统的微生物刺激引起的慢性炎症。然而，致病菌或共生微生物相互协同作用以及与宿主反应使这种炎症持续存在的机制尚不清楚。粘附侵袭性大肠杆菌 (AIEC) 是与克罗恩病 (CD) 相关的细菌，与疾病病理有关。 AIEC 具有促炎性，可能在维持慢性炎症以应对其他克罗恩病危险因素（例如急性传染性胃肠炎）方面发挥核心作用。在这里，我们证明，急性传染性胃肠炎确实在肠道中产生了炎症环境，导致 AIEC 扩张并使疾病严重程度恶化。疾病严重程度的增加与 AIEC 大量繁殖严格相关，因为通过使 AIEC 对宿主防御敏感来阻止这种大量繁殖也可以改善宿主的健康状况。从急性胃肠炎恢复到新发 CD 之间的时间较长，可能允许采取有针对性的干预措施来降低 AIEC 阳性个体患 CD 的风险。
Crohn’s disease (CD) is a chronic inflammatory condition of diverse etiology. Exposure to foodborne pathogens causing acute gastroenteritis produces a long-term risk of CD well into the post-infectious period but the mechanistic basis for this ongoing relationship to disease onset is unknown. We developed two novel models to study the comorbidity of acute gastroenteritis caused by Salmonella Typhimurium or Citrobacter rodentium in mice colonized with adherent-invasive Escherichia coli (AIEC), a bacterial pathobiont linked to CD. Here, we show that disease activity in the post-infectious period after gastroenteritis is driven by the tissue-associated expansion of the resident AIEC pathobiont, with an attendant increase in immunopathology, barrier defects, and delays in mucosal restitution following pathogen clearance. These features required AIEC resistance to host defense peptides and a fulminant inflammatory response to the enteric pathogen. Our results suggest that individuals colonized by AIEC at the time of acute infectious gastroenteritis may be at greater risk for CD onset. Importantly, our data identify AIEC as a tractable disease modifier, a finding that could be exploited in the development of therapeutic interventions following infectious gastroenteritis in at-risk individuals. Western societies have a disproportionately high rate of inflammatory bowel disease (IBD), with growing incidence especially in the adolescent population. A large body of evidence supports the view that bacteria in the gut participate in the pathophysiology of human bowel diseases. The unifying concept is chronic inflammation that is driven by microbial stimulation of the mucosal immune system. However, the mechanisms by which pathogenic or commensal microbes work in concert with each other and with host responses to perpetuate this inflammation is not well known. Adherent-invasive E. coli (AIEC) are Crohn’s disease (CD)-associated bacteria that are implicated in disease pathology. AIEC are pro-inflammatory and may play a central role in maintaining chronic inflammation in response to other CD risk factors, such as acute infectious gastroenteritis. Here, we show that indeed, acute infectious gastroenteritis creates an inflammatory environment in the gut that drives AIEC expansion and worsens disease severity. The increase in disease severity strictly correlates with this AIEC bloom because blocking this bloom by sensitizing AIEC to host defenses also improves the health status of the host. The long time period between recovery from acute gastroenteritis and new onset CD may allow for targeted interventions to mitigate the risk of CD in AIEC-positive individuals.
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