Our objective is to show that bile salts have significant beneficial effects on the intestinal mucosa, through the activation of the transcription factors c-myc and NF-:B. Maintenance of mucosal integrity is important for preservation 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. Oral administration of sodium taurocholate improves anastomotic healing after bile duct ligation. We have shown that bile salts have beneficial effects on the small intestinal mucosa by stimulating intestinal epithelial cell proliferation through an increase in c-myc expression, and that bile salts stimulate intestinal epithelial restitution through the activation of nuclear factor-kappaB (NF-:B), a transcription factor that is the central regulator of various genes involved in apoptosis. We hypothesize that at physiologic conditions bile salts are critical to intestinal mucosal integrity by means of NF-:B-induced resistance to apoptosis and c-myc-induced enterocyte proliferation.
These specific aims are proposed to test this hypothesis.
Aim 1 : To determine how bile salt-induced NF-:B activation regulates intestinal mucosal apoptosis.
Aim 2 : Determine how bile salts protect the intestinal mucosa during disease processes in vivo. We will study, both in vivo and in vitro, the effect of bile salts on enterocyte resistance to apoptosis, NF-:B activation, enterocyte proliferation, and c-myc expression. We will study the down stream regulators of apoptosis including the Inhibitor of apoptosis and Bcl-2 family of proteins, and how bile salts induce c-myc expression. These experiments will be performed using exposure to and elimination of bile salts from the mucosal environment. We will use genetic manipulation to determine the role of these factors on bile salt-induced resistance to apoptosis. 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.
| Perrone, Erin E; Liu, Lan; Turner, Douglas J et al. (2012) Bile salts increase epithelial cell proliferation through HuR-induced c-Myc expression. J Surg Res 178:155-64 |
| Huo, Xiaofang; Zhang, Hui Ying; Zhang, X I et al. (2010) Acid and bile salt-induced CDX2 expression differs in esophageal squamous cells from patients with and without Barrett's esophagus. Gastroenterology 139:194-203.e1 |
| Perrone, Erin E; Chen, Chen; Longshore, Shannon W et al. (2010) Dietary bile acid supplementation improves intestinal integrity and survival in a murine model. J Pediatr Surg 45:1256-65 |
| Greenspon, Jose; Li, Ruiyun; Xiao, Lan et al. (2009) Sphingosine-1-phosphate protects intestinal epithelial cells from apoptosis through the Akt signaling pathway. Dig Dis Sci 54:499-510 |
