Douglas Burrin Lab

Master
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About the Lab

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The Translational Pediatric Nutrition laboratory led by Dr. Douglas Burrin works on basic and translational projects designed to establish how nutritional support, enteral versus parenteral, effects gut and liver function and susceptibility to disease in early neonatal infant development. We use the neonatal piglet in unique models of parenteral nutrition-associated liver disease (PNALD), necrotizing enterocolitis (NEC) to address clinically-relevant problems in pediatric gastroenterology.

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Clinical and nutritional challenges of preterm infants. Shown is an overview of the fundamental choices of how and what to feed preterm compared to term infants. These choices include intravenous parenteral nutrition (i.e., TPN) or enteral nutrition composed of infant formula or breast milk)
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Clinical and nutritional challenges of preterm infants. This is an overview of the fundamental choices of how and what to feed preterm compared to term infants. These choices include intravenous parenteral nutrition (i.e., TPN) or enteral nutrition composed of infant formula or breast milk. The combination of immature intestinal digestive and immune function increases the risk for NEC, which can lead to intestinal resection and SBS. Prolonged parenteral nutrition resulting from GI disease (SBS) or other clinical morbidities increases the risk for PNALD. Abbreviations: GI, gastrointestinal; NEC, necrotizing enterocolitis; PN, parenteral nutrition; PNALD, parenteral nutrition–associated liver disease; SBS, short bowel syndrome; TPN, total parenteral nutrition.

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Translational relevance and advantages of the pig to investigate human pediatric nutrition and GI diseases. The similarities of the newborn pig to human infants in terms of body size, anatomy, and physiology provide a well-suited animal model to test questions that are not feasible or ethically possible in human infants.
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Translational relevance of the pig to investigate human pediatric nutrition and GI diseases. The similarities of the newborn pig to human infants in terms of body size, anatomy, and physiology provide a well-suited animal model to test questions that are not feasible or ethically possible in human infants. The pig also enables the use of clinical procedures and therapies (e.g., TPN, orogastric tube feeding, surgical intestinal resection) used in human infants that more closely simulate current medical practices. The advantages of newborn mice are lower cost and widely available genetic mouse models to test specific gene effects on GI and liver disease. Abbreviations: GI, gastrointestinal; NEC, necrotizing enterocolitis; PN, parenteral nutrition; SBS, short bowel syndrome; TPN, total parenteral nutrition.

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Parenteral Nutrition and Cholestatic Liver Disease
Current projects in the laboratory seek to identify the cellular and molecular mechanism that lead to PNALD and metabolic dysfunction associated with prematurity and neonatal parenteral nutrition (PN) support. Our work has shown that chronic PN induces hepatic steatosis, cholestasis and insulin resistance in both term and premature neonatal piglets. We are exploring how nutrients affect inter-organ and local cellular signaling pathways involved in hepatic lipid metabolism and bile acid homeostasis. Studies led by former fellow and CNRC faculty, Greg Guthrie, Ph.D., have shown how specific nutrients in commercial lipid emulsions (Intralipid, Omegaven, SMOF) alter the susceptibility to PNALD. These studies showed that new generation fish oil-based lipid emulsions (Omegaven and SMOFlipid) markedly reduce the incidence of cholestatic liver injury and steatosis compared to Intralipid. Phytosterols are a key ingredient in soybean lipid emulsions and our recent studies in a model of preterm piglets provide evidence that the amount of phytosterols present in intravenous soybean oil–based emulsion is directly associated with increased serum markers of cholestasis.

Biology of Fibroblast Growth Factor 19 in Infancy
A major area of study in the laboratory centers on the secretion of a key enterokine, fibroblast growth factor 19 (FGF19), involved in bile acid homeostasis. Research studies led by former Pedi GI fellow, Ajay Jain, M.D., we were first to show that plasma FGF19 secretion is suppressed in piglets nourished by TPN. We also showed that minimal enteral bile acid feeding restores FGF19 secretion and prevents cholestasis in TPN fed piglets. More recent studies by Caitlin Vonderohe have discovered a novel developmental program in FGF19 biology that describes the molecular and cellular mechanisms that trigger upregulation of FGF19 expression and secretion in late gestation fetal life. She has also shown now a key stress hormone, cortisol, triggers the secretion of FGF19 at birth.

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Fibroblast Growth Factor-19 pre- and post-natal secretion and target tissues at physiologic and supraphysiologic levels.
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Shaping The Gut Microbiome Using Nutrition To Prevent NEC
Another important research area uses our clinically relevant, premature piglet model of NEC to establish the critical elements of pathogenesis and strategies for prevention. Our previous studies with long-time collaborator, Per Sangild, Ph.D. at University of Copenhagen established that prematurity, microbial colonization and diet are necessary elements in the pathogenesis of NEC.

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Possible differences between effects of maternal colostrum/milk and formula on the neonatal gut.
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The figure illustrates some of the proposed functional effects of maternal colostrum/milk bioactive factors on the dominant gut microbiota communities, mucosal epithelium, and immune cells, relative to formula diets. Enterobacteriaceae, Bifidobacteraceae, and Clostridiaceae families represent common bacteria groups found in the developing neonatal gut. The bacterial community composition can be affected by maternal milk factors, such as Igs (IgA and IgG), LF, bovine and human oligosaccharides (BMO/HMO), and a number of growth factors (e.g., EGF). Igs and LF have antimicrobial properties that function to limit epithelial inflammation and apoptosis resulting from activation of Toll-like receptor 4 (TLR4) by Enterobacteriaceae. BMO/HMO may serve as a substrate for growth and colonization of Bifidobacteraceae, a family of bacteria associated with gut health. The figure also illustrates that key peripheral organs, including the brain and lungs, directly or indirectly may be impacted by colostrum/milk-induced improved gut microbial activity and gut mucosal immune defense.

More recent studies by BCM graduate student, Lee Call, Ph.D. have shown that malabsorption of carbohydrates, namely maltodextrins, in infant formula can trigger bacterial overgrowth and promote the onset of NEC. Current studies led by Valeria Melendez Hebib are aimed at establishing how the components of infant formula and human milk shapes the microbiome-metabolomic interaction with the host immune function and prevents NEC.

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Nutritional and bioactive components present in bovine colostrum and human milk
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The figure shows some of the key biological functions of bovine colostrum components related to their partially overlapping nutritional, immunomodulatory, antimicrobial, and cell-growth functions.

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Enteral Nutrition in Neonatal Intestinal Adaptation
Past projects in the laboratory have been aimed at establishing the cellular and physiological functions of enteral nutrition and the secretion of glucagon-like peptide 2 (GLP-2), an FDA-approved gut hormone for treatment of adult short-bowel syndrome. Several of our studies described how TPN results in intestinal atrophy and loss of function. We also were first to show the trophic and vasoactive actions of GLP-2 in the neonatal gut. We identified the cellular co-localization of the GLP-2 receptor in enteric neurons with neurotransmitters.

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Intestinal mucosal adaptation to TPN and intestinal resection
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Illustrated is the influence of TPN, a common clinical practice in hospitalized preterm infants, which deprives the gut lumen of enteral nutrition and results in mucosal villus atrophy, deterioration of intestinal barrier function, and infiltration of immune cells. Also shown is the influence of surgical resection of intestine, which occurs due to congenital and acquired GI diseases, that results in activation of adaptive processes that promote mucosal growth, such as increased GLP-2 secretion, crypt cell proliferation, and blood flow. GLP-2 is a key gut hormone that functions to activate mucosal enteric neuron release of NO and VIP as well as subepithelial fibroblast release of EGF and IGF-1. Abbreviations: EGF, epidermal growth factor; GI, gastrointestinal; GLP-2, glucagon-like peptide 2; GLP-2R, glucagon-like peptide 2 receptor; IGF-1, insulin-like growth factor 1; NO, nitric oxide; TPN, total parenteral nutrition; VIP, vasoactive intestinal peptide.

Research projects in the laboratory take an integrative experimental approach that is driven by scientific or clinical question to address relevant functions at the whole animal, tissue, cellular or molecular level. We use sophisticated metabolic, cell biological and molecular approaches, such as stable isotope metabolomics, laser-capture micro-dissection, gene microarray, and confocal microscopic imaging to identify the cellular localization of specific signals involved in the metabolism, proliferation and survival of relevant cell types, including gut enteroids, mucosal epithelial cells and hepatocytes.