Short gut syndrome (SGS) is one of the most lethal conditions in infancy and childhood. One in four who develops this condition will not survive. SGS arises in infants with developmental defects of the intestine (atresia, in utero volvulus) or conditions that develop in the newborn period which require the removal of significant intestinal length, namely neonatal necrotizing enterocolitis (NEC) or midgut volvulus. After resection, the remaining intestine adapts by increasing its surface area and caliber, lengthening villi, and forming deeper crypts. Evidence suggests the intestinal microbial environment (microbiome) contributes to these alterations through microbe-driven increased energy harvest. Progress in characterizing the intestinal microbiome demonstrates correlations between microbial shifts and the presence of disease in conditions such as malnutrition, obesity and Crohns disease. The role of the intestinal microbiome in the pathogenesis of epithelial and metabolic responses to massive small bowel resection (SBR) is unknown. Our preliminary studies confirm the presence of significant differences in gut microbiome after SBR compared to sham operation in mice. Using quantitative nuclear magnetic resonance imaging, we have determined there are significant differences in body composition between mice after SBR versus sham operation. We propose to test the hypothesis that short gut syndrome perturbs the gut microbial community which is necessary for compensatory, adaptive structural and metabolic changes in the host.
In Aim 1, we will investigate whether resection-induced shifts in the gut microbiome regulate the metabolic phenotype. We will compare adaptation, body composition, and the microbiome constituents between germ-free (GF) mice after SBR in a GF environment and GF mice after fecal transplant from standard mice that underwent SBR or sham operation.
For Aim 2, we will determine the contribution of the gut microbiome to the mechanism behind enhanced adaptation responses associated with a high-fat (HF) diet. We will compare the effects of HF diet on body composition and intestinal morphology in GF mice colonized with SBR stool to germ-free mice after SBR fed a HF diet. These results will lay the foundation for understanding the relationship between the intestinal microbiome and intestinal adaptation. During this two year tenure, I will learn isolation of DNA, RNA, protein, and microbial DNA. I will learn PCR, Western blotting, intestinal resection procedures in mice and perioperative care of small animals. These methods, standard in the Warner laboratory, have been taught to over 30 residents in the past 20 years. I will also take courses in molecular cell biology and and microbiology to supplement my background knowledge. Participation in weekly journal clubs, lab meetings, one-on-one meetings with Dr. Warner, daily lab supervision by Dr. Erwin, quarterly meetings with my advisory committee and attendance at monthly GI research seminars will contribute greatly to my education. This program will be fundamental goal to be an academic pediatric surgeon, leading a research program directed toward a significant clinical problem in pediatric surgery.
Short gut syndrome is a condition resulting from the removal of a large portion of bowel due to malformation, disease, or trauma. As the bowel adapts o this change, a shift is seen in the bacterial environment within the bowel as well as in the bod composition of the host. Understanding how the bacterial environment augments the host's ability to harvest energy for adaptation will present a novel, cost effective approach to treating the malnutrition in patients suffering from massive intestinal loss.