Lay Summary
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
Chronic diarrhea is extremely common in people with Crohn’s disease. It is often the symptom that leads to diagnosis of the condition, and signals the onset of a relapse. Drug treatment may improve symptoms, but surgery for Crohn’s can often make the symptoms of diarrhea worse, although it may relieve pain, bleeding, and infection. Diarrhea is a major component of the Crohn’s Disease Activity Index, used in studies to assess the severity of the disease and any response to novel therapeutic agents.
Several different mechanisms can cause diarrhea. One of these is related to impaired absorption of bile acids by the ileum – the part of the small intestine most commonly affected in Crohn’s. Bile acids are produced by the liver and used in digestion, and are recycled by being absorbed by the last part of the small intestine (the ileum). If the absorption by the ileum is reduced following surgery or by inflammation, the excess bile acids enter the large intestine (the colon) and cause diarrhea. Drugs, such as cholestyramine, bind the unabsorbed bile acid salts in the colon and can be effective treatment for this sort of diarrhea. Previous studies have shown that most patients with Crohn’s and diarrhea have abnormal bile acid absorption and retention.
However, the homeostatic pathways involving bile acids are more complex, as the ileum also produces a hormone, Fibroblast Growth Factor 19 (FGF19), which normally signals back to the liver how the ileum is functioning, and regulates the production of bile acids. In our preliminary work, we have shown that this hormone is very low in patients with intestinal resection for Crohn’s, and this is associated with excessive bile acid production.
We propose to study blood levels of FGF19 in a full range of patients with Crohn’s, to determine if these levels can indicate the function of the ileum in disease. We propose to relate this to measures of inflammation, and to the amount of bowel remaining after surgical resection. We will explore how therapeutic interventions used in treatment of Crohn’s affect the production of FGF19 in the intestine. The long-term aim of these studies will be to see if it may be possible to modify this system to produce benefits in the treatment of the diarrhea in Crohn’s.
Chronic diarrhea is extremely common in people with Crohn’s disease. It is often the symptom that leads to diagnosis of the condition, and signals the onset of a relapse. Drug treatment may improve symptoms, but surgery for Crohn’s can often make the symptoms of diarrhea worse, although it may relieve pain, bleeding, and infection. Diarrhea is a major component of the Crohn’s Disease Activity Index, used in studies to assess the severity of the disease and any response to novel therapeutic agents.
Several different mechanisms can cause diarrhea. One of these is related to impaired absorption of bile acids by the ileum – the part of the small intestine most commonly affected in Crohn’s. Bile acids are produced by the liver and used in digestion, and are recycled by being absorbed by the last part of the small intestine (the ileum). If the absorption by the ileum is reduced following surgery or by inflammation, the excess bile acids enter the large intestine (the colon) and cause diarrhea. Drugs, such as cholestyramine, bind the unabsorbed bile acid salts in the colon and can be effective treatment for this sort of diarrhea. Previous studies have shown that most patients with Crohn’s and diarrhea have abnormal bile acid absorption and retention.
However, the homeostatic pathways involving bile acids are more complex, as the ileum also produces a hormone, Fibroblast Growth Factor 19 (FGF19), which normally signals back to the liver how the ileum is functioning, and regulates the production of bile acids. In our preliminary work, we have shown that this hormone is very low in patients with intestinal resection for Crohn’s, and this is associated with excessive bile acid production.
We propose to study blood levels of FGF19 in a full range of patients with Crohn’s, to determine if these levels can indicate the function of the ileum in disease. We propose to relate this to measures of inflammation, and to the amount of bowel remaining after surgical resection. We will explore how therapeutic interventions used in treatment of Crohn’s affect the production of FGF19 in the intestine. The long-term aim of these studies will be to see if it may be possible to modify this system to produce benefits in the treatment of the diarrhea in Crohn’s.