Speakers Profiles

1. Exacerbated inflammation of the immature neonatal gut and Necrotizing Enterocolitis The diet of the newborn starts with colostrum for first few days followed with either human milk or formula. Premature birth and formula feeding is highly associated with intestinal inflammation and often developing necrotizing enterocolitis (NEC). This is a devastating inflammatory disease of the gut and causing highest morbidity and mortality in this age group. The etiology of NEC us undefined. Our work had identified key molecules of the innate immune system contributing to NEC. In addition, we have identified ability of key constituents of the human milk to prevents NEC and treat inappropriate mucosal state of the newborn and promotes colonization of health promoting early microbes after birth. Also, these molecules in the milk is able to prevent enteric pathogenic infections. Publications (selected peer-reviewed): (i) Nanthakumar NN, Fusunyan RD, Sanderson I, Walker WA. Inflammation in the developing human intestine: A possible pathophysiologic contribution to necrotizing enterocolitis. Proc Natl Acad Sci U S A., 97:6043-8, 2000. (ii) Fusunyan RD, Nanthakumar NN, Baldeon ME, Walker WA. Evidence for an innate immune response in the immature human intestine: toll-like receptors on fetal enterocytes. Pediatr Res. 49:589-93, 2001. (iii) Nanthakumar NN, Meng D, Goldstein A, Zhu W, Lu L, Uauy R, Llanos A, Claud E, Walker WA. The mechanism of excessive intestinal inflammation in necrotizing enterocolitis: An immature innate immune response. PLoS One, 2011, 6(3): e17776.

2. Develop novel mouse and human models for rare genetic diseases and enteric Infection The mechanisms of few rare genetic diseases and inflammatory diseases are profoundly regulated by the gut microbiome. We have developed a number of animal models and human xenograft models to identify the mechanism and use to evaluate putative therapeutic molecules to define their mode of action. Publications (selected peer-reviewed): (i) Broekaert IJ, Nanthakumar NN, Walker WA. Secreted probiotic factors ameliorate enteropathogenic infection in zinc-deficient human Caco-2 and T84 cell lines. Pediatr Res., 62:139-44, 2007. (ii) Nanthakumar NN, Klopcic CE, Fernandez I, Walker WA. Normal and glucocorticoid-induced development of the human small intestinal xenograft. Am J Physiol Regul Integr Comp Physiol. 285:R162-70, 2003 (iii) Venugopal B, Browning MF, Curcio-Morelli C, Varro A, Michaud N, Nanthakumar NN, Walkley SU, Pickel J, Slaugenhaupt SA. Neurologic, gastric, and opthalmologic pathologies in a murine model of mucolipidosis type IV. Am J Hum Genet. 2007 Nov;81(5):1070-83.

3. Glycosylation of the developing gut and its role in microbial-epithelial crosstalk Initial colonization at birth is followed by establishment of a milk-specific suckling microbiota followed by a succession to a dynamic adult microbiota after weaning. The orderly succession to a healthy microbiome is influenced by mucosal glycan expression and the glycosylation on the intestinal epithelial surface and secreted mucins changes from high sialic acid/low fucose to high fucose/low sialic acid composition at the time of weaning. This transition is mediated by the developmental expression of the intestinal 2,3/6-sialyltransferase and 1,2-fucosyltransferase gene. The underlying mechanisms regulating the expression of these glycosylating enzymes, and how these enzymes contribute to establishing a healthy microbiota, and dysbiotic microbiota of various inflammatory diseases and how glycosylation contribute to infection. Publications (selected peer-reviewed): (i) Nanthakumar NN, Dai D, Newburg DS, Walker WA. The role of indigenous microflora in the development of murine intestinal fucosyl- and sialyltransferases. FASEB J. 17:44-6, 2003. (ii) Meng D, Newburg DS, Young C, Baker A, Tonkonogy SL, Sartor RB, Walker WA, NN Nanthakumar. Bacterial symbionts induce a FUT2-dependent fucosylated niche on colonic epithelium via ERK and JNK signaling. Am J Physiol Gastrointest Liver Physiol., 293: G780-7, 2007. (iii) Nanthakumar NN, Meng D, Newburg DS. Glucocorticoids and microbiota regulate ontogeny of intestinal fucosyltransferase 2 requisite for gut homeostasis. Glycobiology, 23:1131-41, 2013.

4. Probiotic therapy to treat intestinal inflammation and enteric infection A resilient and dynamic microbial ecosystem of the digestive tract is acquired after birth. Colonization by pioneer bacteria at birth is followed by active succession leading to a suckling microbial ecosystem; this process is mediated by the phenotype of the infant mucosa and the composition of the milk. As infants weans, transition from suckling microbiota to a complex adult microbial community is regulated by the mucosal phenotype of the mature gut and the nature of the solid food consumed. In addition, microbial metabolites provide energy (such as short chain fatty acids) and modulate predisposition to many inflammatory diseases. Therefore, the lab is focused on elucidating the impact of probiotic bacteria and how their metabolites regulate the host response to enteric infection and mucosal injury. Publications (selected peer-reviewed): (ii) Chen X, Katchar K, Goldsmith JD, Nanthakumar N, Cheknis A, Gerding DN, Kelly CP. A Mouse Model of Clostridium difficile – Associated Disease. Gastroenterology 135:1984-92, 2008. (ii) Paul L. Beck, E Ihara, Hirota SA, MacDonald JM, Meng D, Nanthakumar NN, DK Podolsky, and RJ Xavier. Exploring the interplay of barrier function and leukocyte recruitment in intestinal inflammation by targeting fucosyltransferase VII and TRF3. Am J Physiol Gastrointest Liver Physiol. 299:G43-53, 2010. (iii) Ganguli K, Meng D, Rautava S, Lu L, Walker WA, Nanthakumar NN. Probiotics prevent necrotizing enterocolitis by modulating enterocyte genes that regulate innate immune-mediated inflammation. Am J Physiol Gastrointest Liver Physiol., 304:G132-41, 2013.

5. Steroids hormone action on the development of the digestive and absorptive functions The mechanisms of the postnatal development of the digestive/absorptive and the role of steroids in this process are unknown. The intrinsic mechanisms that facilitate microbial contribution to the developing digestive functions are fine-tuned by circulating glucocorticoids. Using rodent and human models, the molecular pathways by which steroids accelerate the maturation are being investigated. Publications (selected peer-reviewed): (i) Dai D, Nanthakumar NN, Savidge TC, Newburg DS, Walker WA. Region-specific ontogeny of b2,6-sialyltransferase during normal and cortisone-induced maturation in mouse intestine. Am J Physiol Gastrointest Liver Physiol. 282:G480-90, 2002. (ii) Inui Y, Hausman AM, Nanthakumar NN, Henning SJ, Davidson NO. Apolipoprotein B messenger RNA editing in rat liver: developmental and hormonal modulation is divergent from apolipoprotein A-IV gene expression despite increased hepatic lipogenesis. J Lipid Res. 33:1843-56, 1992. (iii) Nanthakumar NN, Henning SJ. Ontogeny of sucrase-isomaltase gene expression in rat intestine: responsiveness to glucocorticoids. Am J Physiol. 264:G306-11, 1993.

6. Micronutrient supplementation and evaluate their success in human infants Successful microbial colonization also depends upon many environmental factors. Such as access to clean water, sanitary conditions, etc., but orderly colonization can be disrupted by enteric infections, antibiotic treatment, and exposure to animals and livestock. All these factors along with the diet and the human genetics determine the early development of mucosal immune system. We showed Vitamin A and Zinc deficiency disrupt appropriate immune response to infection and delated development of the mucosal immune system. Also, we showed how Vitamin A & Zinc supplementation ameliorated age-specific infection and restored immune responses to infections and reduce infant morbidity. Publications (selected peer-reviewed): (i) Long KZ, Estrada-Garcia T, Rosado JL, Santos JI, Haas M, Firestone M, Bhagwat J, Young C, DuPont HL, Hertzmark E, Nanthakumar NN. The Effect of Vitamin A Supplementation on the Intestinal Immune Response in Mexican Children Is Modified by Pathogen Infections and Diarrhea. J Nutr.136:1365-70, 2006. (ii) Long KZ, Rosado JL, Santos JI, Haas M, Mamun AN, DuPont HL, Nanthakumar NN, and Teresa Estrada-Garcia. Associations between mucosal innate and adaptive immune responses and resolution of diarrheal pathogen infections. Infection and Immunity. 78:1221-8, 2010. (iii) Long KZ, Rosado JL, Santos JI, Estrada-Garcia T, Zhu W, Haas M, Mamun AL, DuPont HL, Nanthakumar NN. Vitamin A Supplementation Modifies the Association between Mucosal Innate and Adaptive Immune Responses and Resolution of Enteric Pathogen Infections. Am. J Clini. Nutri. 93:578-585, 2011.