Bacterial Colonization and Development of Innate Intestinal Host Defense

Emory University, Atlanta GA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): [unreadable] The goal of this proposal is to elucidate the role of bacterial colonization in the development of innate intestinal host defense. Disregulation of intestinal host defense mechanisms likely plays an important role in the pathophysiology of inflammatory bowel disease (IBD) and necrotizing eneterocolitis (NEC). Commensal bacteria interact with the mammalian intestine in a symbiotic fashion to regulate the expression of genes important for barrier function, digestion, and angiogenesis [1]. Since intestinal colonization develops postnatally as dietary changes occur, it may play an important role in the postnatal maturation of intestinal host defenses [13]. This may be especially important in the premature infant whose immature intestine may be particularly susceptible to injury due to poor barrier function, underdeveloped innate immunity, and/or immature circulatory regulation. Furthermore, development in an artificial hospital environment coupled with almost universal antibiotic administration likely negatively affects the normal intestinal colonization. Thus, premature infants may be particularly susceptible to necrotizing enterocolitis, (NEC) due to pathologic bacterial colonization and/or immature bacterial-host interactions. We hypothesize that normal bacterial colonization of the intestine plays a key role in the development and maintenance of postnatal host defenses. Our long-term objective is to define the mechanisms by which commensal bacteria regulate the development of intestinal host defense. Specifically in this proposal, we plan to utilize our ex vivo model of intestinal infection to study the postnatal development of proinflammatory and anti-apoptotic responses in the developing mouse. The specific aims of this project are to: (i) examine the developmental regulation of the proinflammatory response (ii) examine the developmental regulation of the apoptotic response (iii) examine the role of bacterial colonization on development of the innate immune response. These studies will elucidate the role of commensal bacteria in the development of intestinal host defense and innate immunity, and contribute to our understanding of the pathophysiology of many intestinal inflammatory disorders. [unreadable] [unreadable]