Bile acid overproduction is implicated in diarrhea associated with several GI disorders such as inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). Bile acids in the ileum stimulate the expression and secretion of ileal Fibroblast Growth Factor 19 (FGF15 in mice), which circulates to the liver to suppress CYP7A1 enzyme that mediates the rate-limiting step of bile acid synthesis. Recent studies showed that the levels of FGF15/19 are decreased in mouse model of intestinal inflammation and in patients with IBD along with an increase in the rate of hepatic bile acid synthesis. These observations provided evidence for the key role of FGF15/19 in the pathogenesis of diarrhea during intestinal inflammation, albeit the mechanisms underlying this decrease are not fully understood. Our preliminary data provided evidence demonstrating a decrease in FGF15/19 expression and promoter activity by TNF suggesting a direct effect of proinflammatory cytokines on FGF15/19 expression. In this regards, dietary compounds that increase ileal FGF15/19 expression could be exploited to reduce the excessive production of bile acids. Our novel preliminary findings showed that lysophosphatidic acid (LPA), normally found in foods such as soy and egg yolk, induced the expression of FGF15/19 providing a new lead to novel therapeutic interventions to treat bile acid-induced diarrhea. Based on these data, we hypothesized that ileal FGF15/19 expression is decreased by pro-inflammatory cytokines via transcriptional mechanisms leading to subsequent increase in hepatic CYP7A1 and exacerbating diarrhea associated with intestinal inflammation. We further hypothesized that the activation of LPA-receptors in intestinal epithelial cells triggers specific signaling pathways that lead to an increase in FGF15/19 expression and could be exploited as a therapy for bile acid-induced diarrhea. The proposed studies will utilize advanced in vitro models including intestinal organoids and human epithelial Caco2 cells cultured in 3 dimensional matrigel. FGF15 knockout mice and transgenic mice with hepatic overexpression of CYP7A1 with overproduction of bile acids will be used to investigate the impact of disrupting FGF15/19-CYP7A1 axis on diarrhea and intestinal inflammation. Studies in Aim 1 will determine the molecular mechanisms involved in the inhibition of FGF15/19 by cytokines. Proposed studies in Aim 2 will investigate the mechanisms underlying the upregulation of FGF15/19 expression and secretion by LPA and determine the LPA receptor subtype involved utilizing LPA receptor knockout mice.
Aim 3 is designed to investigate the effects of LPA on bile acid homeostasis and examine the contribution of disrupting ileal FGF15-hepatic CYP7A1 to diarrhea and deregulation of intestinal ion transport in mouse models of intestinal inflammation (DSS and TNBS-induced intestinal inflammation). Unraveling the molecular mechanisms controlling crosstalk between the gut and liver will provide the basis for future clinical studies to design novel therapy for bile acid-induced diarrhea.
The increase in the amount of bile acids secreted from the liver into the intestine represents a major factor contributing to diarrhea associated with gut disorders. Bile acid production in the liver is under the control of a hormone secreted from the small intestine called FGF19. Patients with inflammatory bowel disease (IBD) have low levels of FGF19 with subsequent excessive production of bile acids that leads to harmful effects in the intestine. The studies proposed in this grant application seek to introduce new therapeutic agents that induce the expression of FGF19 to alleviate diarrhea associated with intestinal inflammation. The proposed studies are crucial to support future clinical trials to investigate the therapeutic efficacy of beneficial compounds to enhance ileal FGF19 expression and treat bile acid-induced diarrhea.
