Maturation of intestinal innate immunity and NEC
Principal Investigator: NADARAJAH NANDA NANTHAKUMAR
Affiliation: Harvard University
Abstract: 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. PUBLIC HEALTH RELEVANCE: 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.
Funding Period: 2009-06-01 - 2010-10-31
more information: NIH RePORT
- Conditioned medium from Bifidobacteria infantis protects against Cronobacter sakazakii-induced intestinal inflammation in newborn miceMeiqian Weng
Mucosal Immunology and Biology Research Center, Division of Pediatric Gastroenterology, Harvard Medical School, Boston, Massachusetts and Mass General Hospital for Children, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts
Am J Physiol Gastrointest Liver Physiol 306:G779-87. 2014..This study suggests that an active component(s) released into the culture medium by B. infantis may prevent ileal damage by a pathogen linked to NEC. ..
- The role of gut microbiota in programming the immune phenotypeM Weng
Mucosal Immunology Laboratory, Division of Gastroenterology, Department of Pediatrics, Massachusetts General Hospital for Children, Harvard Medical School, Boston, MA, USA
J Dev Orig Health Dis 4:203-14. 2013..This has been shown to prevent debilitating diseases such as NEC. Thus, understanding the role of gut microbiota in programming of the immune phenotype may be important in preventing disease expression in later childhood and adulthood. ..
- Glucocorticoids and microbiota regulate ontogeny of intestinal fucosyltransferase 2 requisite for gut homeostasisN Nanda Nanthakumar
Biomedical Sciences and Pathobiology, Virginia Polytechnic Institute and State University, Blacksburg, VA 24060, USA
Glycobiology 23:1131-41. 2013..Fut2-dependent recovery from inflammation may explain the high incidence of inflammatory disease (Crohn's and necrotizing enterocolitis) in populations with mutant FUT2 polymorphic alleles. ..
- Probiotics prevent necrotizing enterocolitis by modulating enterocyte genes that regulate innate immune-mediated inflammationKriston Ganguli
Mucosal Immunology Laboratory, Division of Pediatric Gastroenterology, Massachusetts General Hospital for Children, 114 16th St 114 3503, Charlestown, MA 02192 4404, USA
Am J Physiol Gastrointest Liver Physiol 304:G132-41. 2013..We conclude that PCM promotes maturation of innate immune response gene expression, potentially explaining the protective effects of probiotics in clinical NEC...
- Immune factors in breast milk and the development of atopic diseaseShuba R Iyengar
Pediatric Allergy Immunology Division, Massachusetts General Hospital for Children, Boston, MA, USA
J Pediatr Gastroenterol Nutr 55:641-7. 2012..In this overview, we explore the potential role of immune factors in the breast milk, as well as selected probiotics, in the development of allergy...
- TGF-β2 induces maturation of immature human intestinal epithelial cells and inhibits inflammatory cytokine responses induced via the NF-κB pathwaySamuli Rautava
Division of Pediatric Gastroenterology, Massachusetts General Hospital for Children, Charlestown, MA 02192 4404, USA
J Pediatr Gastroenterol Nutr 54:630-8. 2012..We sought to investigate whether conditioning with TGF-β2 may result in a more mature immune responder phenotype in immature human intestinal epithelial cells (IECs)...
- The mechanism of excessive intestinal inflammation in necrotizing enterocolitis: an immature innate immune responseNanda Nanthakumar
Developmental Gastroenterology Laboratory, Harvard Medical School, Boston, Massachusetts, United States of America
PLoS ONE 6:e17776. 2011..We conclude that the excessive inflammatory response of the immature intestine, a hallmark of NEC, is due to a developmental immaturity in innate immune response genes...
- Breast milk-transforming growth factor-β₂ specifically attenuates IL-1β-induced inflammatory responses in the immature human intestine via an SMAD6- and ERK-dependent mechanismSamuli Rautava
Developmental Gastroenterology Laboratory, Division of Pediatric Gastroenterology, Massachusetts General Hospital for Children, Charlestown, Mass, USA
Neonatology 99:192-201. 2011..Breast milk is known to protect the infant against infectious and immuno-inflammatory diseases, but the mechanisms of this protection are poorly understood...
- Exploring the interplay of barrier function and leukocyte recruitment in intestinal inflammation by targeting fucosyltransferase VII and trefoil factor 3P L Beck
Gastrointestinal Research Group, University of Calgary, Calgary, Alberta, Canada T2N 4N1
Am J Physiol Gastrointest Liver Physiol 299:G43-53. 2010..These studies highlight the importance of the interplay between factors involved in the innate immune response, mucosal barrier function, and genes involved in regulating leukocyte recruitment and other aspects of the immune response...
- A mouse model of Clostridium difficile-associated diseaseXinhua Chen
Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
Gastroenterology 135:1984-92. 2008..The aim of this study was to establish a mouse model of antibiotic-induced C. difficile-associated disease (CDAD) that more closely resembles human disease...