Pediatric Surgery Research

Eric Strauch, MD

The Role of Critical Bile Salts: Intestinal Mucosal Integrity and Renewal

Injury to the intestinal mucosa is a common and clinically significant problem that results in impairment of intestinal function, translocation of bacteria, and significantly affects systemic health. We have shown that bile salts have beneficial effects in the small intestine, including stimulating restitution after injury, increasing proliferation after injury, and increases resistance to apoptosis after injury. The overall objective of this proposal is to establish physiologically and molecularly the beneficial effects bile salts have on intestinal mucosal maintenance of integrity and intestinal mucosal renewal. We will achieve these goals by testing the hypothesis that bile salts are critical to intestinal mucosal health and integrity during critical illness and injury through cell signaling pathways that stimulate intestinal mucosal renewal through an increase in mucosal proliferation and an increase in mucosal resistance increasing survival after intestinal injury and critical illness. These specific aims are proposed to test this hypothesis. Aim 1: Determine how bile salts maintain intestinal mucosal integrity after critical illness and how this increase in mucosal integrity results in improved systemic health and survival. Aim 2: Determine how bile salts stimulate mucosal renewal through FXR-regulated and HuR-induced c-Myc expression. Aim 3: Determine how bile salts increase survival and diminish injury to the intestine during NEC through an increase in intestinal mucosal proliferation and resistance to apoptosis. We will determine both in vitro and in vivo, the effect of bile salts on enterocyte resistance to apoptosis, XIAP activation, enterocyte proliferation, and c-myc expression. We will determine how bile salts regulate protein translation through HuR, and how bile salts regulate transcription the FXR. This proposal has great relevance to public health as mucosal injury and loss is caused by ischemia, inflammation, necrotizing enterocolitis, short gut syndrome, obstruction, and other sources is a common source of morbidity and mortality in the surgical population. The pediatric surgical community has seen the devastation of the common surgical disease necrotizing enterocolitis which results from mucosal injury and inadequate mucosal repair in premature infants whose liver is incapable of secreting the appropriate levels of these beneficial bile salts into the intestinal lumen. Short gut syndrome results from a variety of pathologies leading to death and lifelong impairment of organ function, need of IV nutrition and intestinal transplant. These data will be used to develop plans to translate this research to the clinical setting for development of therapeutic uses for bile salts in critical illness and intestinal injury in a variety of pathologic conditions including: premature infants with a diminished capacity to synthesize and secrete bile salts; critically ill patients with cholestasis; loss of bile salts secondary to intestinal injury; and in patients with liver injury who are unable to synthesize bile salts.

• Sponsor: NIH-National Institutes of Health

The Critical Role of Bile Salts: Gut Protection in Critical Illness

Our objective of this supplement is to accelerate the tempo of our research on the beneficial effects of bile salts on the intestinal mucosa. Maintenance of mucosal integrity is important of normal digestive and barrier functions. Normal mucosal epithelial integrity depends on a dynamic balance between cell proliferation, growth arrest and apoptosis. Changing this balance in any direction alters intestinal mucosal homeostasis and has significant pathologic consequences. Bile salts are multifunctional molecules consistently found within the intestinal lumen. The intestinal mucosa requires the presence of luminal contents including bile salts to maximize the adaptive response. Our data show that enteral supplementation of bile salts protect the intestinal mucosa in vivo from intestinal injury. Enteral Supplementation of bile salts stimulates intestinal mucosal renewal through an increase in RNA binding Hu antigen R (HuR) -regulated c-Myc-induced enterocyte proliferation. We hypothesize that bile salts are critical to intestinal mucosal health and regulate important intestinal and systemic functions through cell signaling pathways that are crucial to the maintenance of intestinal mucosal integrity. To test this hypothesis, these Specific Aims are proposed; Aim 1: To determine how bile salt-regulated intestinal mucosal integrity affects survival after intestinal injury. Aim 2: To determine how bile salts stimulate enterocyte proliferation through HuR-induced c-Myc. We will study the effects of enteral supplementation of bile salts on murine survival after lipopolysaccharide induced injury resulting in intestinal injury, pulmonary inflammation, and death. We will delineate how bile salt-induced HuR regulates c-Myc expression.

• Sponsor: NIH-National Insititutes of Health