A family of Toll-Like Receptors (TLRs) stimulates the innate immune system upon encountering microbial pattern molecules, lipopolysaccharide [LPS] or peptidoglycans [PG]. When the gastrointestinal tract is initially colonized by microbes at birth, the mucosal innate immune system requires attenuation to avoid chronic inflammation by activation of TLR pathways. In term infants, perinatal downregulation of intestinal TLRs may provide this attenuation. In premature infants born before this developmental regulation, intestinal colonization could activate TLR pathways, leading to chronic inflammation. An inappropriate immune response to bacterial exposure could lead to generalized inflammation and bowel necrosis, such as occurs in necrotizing enterocolitis (NEC). In this proposal, we will study the ontogeny of TLR receptor expression, signaling, and inhibition, and determine its role in regulating innate immune responses. Steroids and probiotic therapy have been shown to prevent the onset of some premature infants predisposed to NEC. The mechanism of steroid action and the role of probiotic therapy will be determined. The probiotic factors that prevent excessive activation of the gut epithelium by microflora in term infants will be identified. The hypothesis is that colonization of the premature infant gut prior to maturation of the TLR signaling pathway can lead to excessive inflammation of the infant gut characteristic of NEC. The capacity of health-promoting probiotic bacteria to accelerate ontogeny of negative regulators of TLR pathways, thereby preventing excessive inflammation, will be investigated. We have developed specific human in-vivo and in-vitro intestinal models for gut inflammation to address this hypothesis.
Our specific aims address whether: (1) coordinated downregulation of TLR receptors and its signaling intermediates and negative regulators prevents excessive inflammatory response to bacterial colonization at birth;(2) pretreatment with glucocorticoids prevents hyperresponsiveness to newly colonizing bacteria by inducing maturation of the TLR signaling pathways in premature gut;and (3) probiotic factors prevent the onset of NEC by accelerating the maturation of the TLR signaling pathways in premature gut. The successful completion of this project will provide novel basic information on the ontogeny of the control elements of TLR signaling pathways, and their modulation by steroids and probiotics. This mechanistic understanding of the effect of steroids and probiotics in preventing inflammation in premature infants could be used to design effective therapeutic strategies to prevent the onset of NEC. This is important since NEC is an important public health issue facing premature infants and accounts for 10% of all deaths in the US.
Despite the recent advances of neonatal intensive care, necrotizing enterocolitis (NEC) remains a major health complication for the premature infants and an important cause of neonatal morbidity and mortality. The major risk factors for NEC are prematurity and bacterial colonization. The proposal is designed to determine the mechanism of inflammation in the premature infants that leads to necrotizing enterocolitis. The proposed TLR-mediated signaling in the immature intestine and the steroids and probiotic therapy may accelerate the maturation of innate immune response preventing the onset of necrotizing enterocolitis. The identification of the mechanism and factors involved in this suppression of inflammation could be of tremendous benefit in understanding and preventing NEC in infants.
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