Role of obesity related peptides in gastrointestinal health and disease
Our current work focuses on the role of gut derived obesity peptides such as leptin and ghrelin in gastrointestinal health and disease. The prevalence of obesity continues to rise along with its associated adverse effects on health. Epidemiologic studies have demonstrated a link between obesity and gastroesophageal reflux, Barrett’s esophagus, esophageal adenocarcinoma, as well as colon cancer. Our goal is to try to understand the development of these diseases within the context of the interplay between hosts, environmental, and bacterial factors that may be associated energy homeostasis.
It is estimated that 44% of adults in the U.S. have monthly heartburn symptoms. In 2000, the estimated direct and indirect cost of treating reflux disease in the United States exceeded $9.8 billion. There is a need to better understand the factors involved in the GERD landscape in order to better predict who will develop complications. We hypothesized that changes in the gastric microbiota at a population level might influence the observed trends in reflux disease (K23CA107123). To begin to test this hypothesis we have evaluated the relationship between H. pylori and the prevalence of esophageal pathology among adults undergoing upper endoscopy for any indicated reason. This approach aims to provide direct access to the gastric and esophageal mucosa while avoiding the selection bias associated with recruiting only those individuals referred with heartburn symptoms. Manometric and pH-metric evaluation of the esophagus allows for further characterization of underlying esophageal pathology.
Although heartburn is a hallmark of GERD, its presence alone is not predictive of esophageal mucosal injury. The complications associated with GERD (esophagitis, Barrett’s esophagus, and esophageal adenocarcinoma), are considered to result from an imbalance between exposure to injurious elements such as acid, pepsin, and bile, and esophageal epithelial protective mechanisms. Although esophageal epithelial proliferation and restitution are critical in limiting erosions following acid-pepsin exposure, proliferation leading to a metaplastic epithelium increases oncogenic risk. Although salivary epidermal growth factor (EGF) stimulates esophageal repair, the role of other luminal peptides such as leptin in esophageal epithelial homeostasis has not been examined.
Leptin is the 167-amino acid hormone product of the (ob) gene, that is produced primarily by adipocytes, and plays a role in appetite regulation as well as in energy homeostasis. Both leptin and its receptor (ob-R) are expressed by the gastric epithelium. Leptin administration inhibits gastric ulcer formation in rats, and stimulates growth of esophageal adenocarcinoma cells; gastric leptin thus may contribute to both mucosal homeostasis and to abnormal proliferation. We hypothesized that leptin of gastric origin, present in the gastric refluxate, may participate in the maintenance of the normal (non-inflamed) esophageal mucosa, or of the more acid-resistant Barrett’s epithelium.
We have tested this hypothesis by comparing plasma and regional gastric leptin levels among groups of individuals with either normal, inflamed, or Barrett’s (American College of Gastroenterology Clinical Research Grant).
Ghrelin is another peptide that is known to play a role in appetite and energy expenditure. The gastric mucosa is the primary source of ghrelin. Since inflammation has been shown to modulate the levels of gastric leptin and ghrelin, we hypothesized that H. pylori colonization may influence both fasting and post-prandial levels of these peptides. We have evaluated pre and post meal levels of leptin and ghrelin in individuals before and at least 8 weeks after H. pylori treatment. The use of a prospective eradication study has provided an ideal model to study the long-term effects of changes in the gastric flora on nutritional status.
As an extension of this work we have also begun to evaluate the association of leptin with colon adenomas (the precursor lesion to colon adenocarcinoma). Colon cancer remains the second leading cause of cancer related death and there is gender and ethnic/racial variation in both the incidence and mortality of the disease. We have hypothesized that some of these differences may be due to cytokine polymorphisms which in turn might influence the amount of leptin produced or the degree of colonic leptin receptor expression. Our approach has been to evaluate a large asymptomatic diverse colon cancer screening population for cytokine polymorphisms (IL-1, IL-8, TNF, IL-10) and to assess the relationship of the various alleles to the prevalence of adenomas and advanced adenomas.
We hope to continue to evaluate these and other questions that have arisen through patient interactions at the bedside, in order to further the diagnostic and therapeutic offerings to our patients.