Scientific Abstract
Proposal No. IBD-0300
Principal Investigator: Julian Walters, MA, MB
Applicant Organization: Imperial College London (England)
Project Title: Diarrhea in Crohn's: investigating the role of the novel ileal hormone fibroblast growth factor 19 (FGF19) in disease assessment and pathogenesis of diarrhea
Period of Award: October 1, 2010 – September 30, 2011
Diarrhea is a major symptom in Crohn’s disease and causes significant concern in patients with inflammatory activity and also in surgically-treated patients. It is a key component of the Crohn’s Disease Activity Index used in most studies of drug efficacy. There are multiple mechanisms that lead to diarrhea, including impaired absorption and secretion of electrolytes and water in the inflamed parts of the intestinal tract. Bile acids, which are normally absorbed in the ileum as part of an entero-hepatic circulation, may be implicated as they will produce a secretory diarrhea in the colon if ileal function is abnormal, as is usually the case in Crohn’s. Many studies have demonstrated secondary bile acid malabsorption in most Crohn’s patients with diarrhea, whether or not they have undergone ileal resection. Corticosteroids increase expression of bile acid transporters and improve diarrhea. Therapy with bile acid sequestrants can be beneficial.
Another potential mechanism for bile acid diarrhea has become apparent recently. It has been shown that the ileum produces a secreted hormone, fibroblast growth factor 19 (FGF19), which inhibits hepatic bile acid synthesis. In our pilot data, we have measured the expression of FGF19 in human ileum and in blood, and have found very low levels in some patients who have undergone ileal resection for Crohn’s disease. This is proposed to result in increased hepatic bile acid synthesis, which in the presence of sub-optimal ileal reabsorption of bile acids, will further worsen the secretory effects of bile acids in the colon, producing diarrhea.
We hypothesize that FGF19 production is altered in patients with Crohn’s disease and so may serve as a marker for functioning ileal tissue and for disease activity. Reduced FGF19 may contribute as a novel, unappreciated cause of the diarrheal symptoms.
We seek funding for studies to investigate: (1) whether an inverse relationship is found between FGF19 and the length of ileal resection, (2) the relationship between ileal inflammation and FGF19 in patients treated with corticosteroids and other anti-inflammatory agents, using clinical markers (CDAI) and established biochemical markers (calprotectin), and (3) the mechanisms affecting FGF19 synthesis in normal and inflamed ileal tissue, obtained at ileo-colonoscopy. Studies of this new system in Crohn’s patients should lead to an improved understanding of diarrhea in Crohn’s disease and may indicate novel treatments for this neglected symptom.
Diarrhea is a major symptom in Crohn’s disease and causes significant concern in patients with inflammatory activity and also in surgically-treated patients. It is a key component of the Crohn’s Disease Activity Index used in most studies of drug efficacy. There are multiple mechanisms that lead to diarrhea, including impaired absorption and secretion of electrolytes and water in the inflamed parts of the intestinal tract. Bile acids, which are normally absorbed in the ileum as part of an entero-hepatic circulation, may be implicated as they will produce a secretory diarrhea in the colon if ileal function is abnormal, as is usually the case in Crohn’s. Many studies have demonstrated secondary bile acid malabsorption in most Crohn’s patients with diarrhea, whether or not they have undergone ileal resection. Corticosteroids increase expression of bile acid transporters and improve diarrhea. Therapy with bile acid sequestrants can be beneficial.
Another potential mechanism for bile acid diarrhea has become apparent recently. It has been shown that the ileum produces a secreted hormone, fibroblast growth factor 19 (FGF19), which inhibits hepatic bile acid synthesis. In our pilot data, we have measured the expression of FGF19 in human ileum and in blood, and have found very low levels in some patients who have undergone ileal resection for Crohn’s disease. This is proposed to result in increased hepatic bile acid synthesis, which in the presence of sub-optimal ileal reabsorption of bile acids, will further worsen the secretory effects of bile acids in the colon, producing diarrhea.
We hypothesize that FGF19 production is altered in patients with Crohn’s disease and so may serve as a marker for functioning ileal tissue and for disease activity. Reduced FGF19 may contribute as a novel, unappreciated cause of the diarrheal symptoms.
We seek funding for studies to investigate: (1) whether an inverse relationship is found between FGF19 and the length of ileal resection, (2) the relationship between ileal inflammation and FGF19 in patients treated with corticosteroids and other anti-inflammatory agents, using clinical markers (CDAI) and established biochemical markers (calprotectin), and (3) the mechanisms affecting FGF19 synthesis in normal and inflamed ileal tissue, obtained at ileo-colonoscopy. Studies of this new system in Crohn’s patients should lead to an improved understanding of diarrhea in Crohn’s disease and may indicate novel treatments for this neglected symptom.