Dysbiosis in Hirschsprung Associated Enterocolitis Pathogenesis

先天性巨结肠相关性小肠结肠炎(HAEC)是先天性巨结肠的一种危及生命的并发症 (HSCR)，新生儿肠梗阻的常见原因，由发育不全引起 肠道神经系统(ENS)。HAEC影响30%-60%的HSCR婴儿，发病率保持不变 手术前后的死亡率为5%-10%，大多数死亡发生在新生儿 在最终的操作之前。该领域的一个关键障碍是HAEC的病因学定义不明确，而且目前还不清楚 治疗仍然是经验性的(肠道休息、直肠冲洗、广谱抗生素)，并针对 缓解急性症状，而不是针对潜在的病理生理。我们研究的长期目标是 是确定HAEC的病理生理学，以便开发减少发病率的新的治疗方法 和HSCR患者的死亡率。我们的初步和已发表的发现，得到了其他实验室的支持， 支持中心假设，即宿主-微生物群互惠关系的扰动，包括免疫逃避 非生物微生物群对肠道淤滞的排斥和强化，推动了HAEC的发展。我们的 目的是1)确定HAEC中IgA产生和分泌受损的机制，2)确定 HAEC微生物组的致病成员，以及3)决定HAEC微生物组如何 加强肠道停滞。这项拟议的研究具有创新性，因为它将利用新的临床前模型 建立微生态失调与HAEC发病机制的因果关系及潜在的治疗方法 目标。我们集团是唯一有资格完成目标的人，因为我们在HSCR和HAEC方面的专业知识，东道主- 微生物组相互作用、微生物内分泌学和肠道上皮细胞生物学。预期的结果 这些研究将对HAEC的病理生理机制有更深入的了解，并为新的HAEC的鉴定 预防或治疗HAEC的治疗方法。

Hirschsprung-associated enterocolitis (HAEC) is a life-threatening complication of Hirschsprung Disease (HSCR), a common cause of intestinal obstruction in the newborn that results from incomplete development of the enteric nervous system (ENS). HAEC affects 30-60% of infants with HSCR, occurs with unchanged incidence pre- and post-operatively, and carries a mortality of 5-10%, with the majority of deaths occurring in newborns prior to definitive operation. A critical barrier in the field is that the etiology of HAEC is poorly defined and current treatment remains empiric (bowel rest, rectal washouts, broad-spectrum antibiotics) and directed toward alleviating acute symptoms rather than targeting underlying pathophysiology. The long-term goal of our research is to define the pathophysiology of HAEC in order to develop novel therapeutic approaches that reduce morbidity and mortality in HSCR patients. Our preliminary and published findings, reinforced by those of other laboratories, support the central hypothesis that perturbation of host-microbiome mutualism, including evasion of immune exclusion and reinforcement of intestinal stasis by dysbiotic microbiota, drives the development of HAEC. Our objectives are to 1) define the mechanisms for impaired IgA production and secretion in HAEC, 2) identify the disease-promoting members of the dysbiotic HAEC microbiome, and 3) determine how the HAEC microbiome reinforces intestinal stasis. The proposed research is innovative because it will utilize novel, preclinical models to establish a causative relationship between dysbiosis and HAEC pathogenesis and test potential therapeutic targets. Our group is uniquely qualified to complete the aims because of our expertise in HSCR & HAEC, host- microbiome interactions, microbial endocrinology, and intestinal epithelial cell biology. The expected outcome of these studies will be a deeper understanding of the pathophysiology of HAEC and identification of novel therapeutic approaches for prevention or treatment of HAEC.