Abstract
In up to 50% of people diagnosed with a common ailment, diarrhea-predominant irritable bowel syndrome, diarrhea results from excess spillage of bile acids into the colon—data emerging over the past decade identified deficient release of a gut hormone, fibroblast growth factor 19 (FGF19), and a consequent lack of feedback suppression of bile acid synthesis as the most common cause. 75Selenium homotaurocholic acid (SeHCAT) testing, considered the most sensitive and specific means of identifying individuals with bile acid diarrhea, is unavailable in many countries, including the United States. Other than SeHCAT, tests to diagnose bile acid diarrhea are cumbersome, non-specific, or insufficiently validated; clinicians commonly rely on a therapeutic trial of bile acid binders. Here, we review bile acid synthesis and transport, the pathogenesis of bile acid diarrhea, the reasons clinicians frequently overlook this disorder, including the limitations of currently available tests, and our efforts to develop a novel 19F magnetic resonance imaging (MRI)-based diagnostic approach. We created 19F-labeled bile acid analogues whose in vitro and in vivo transport mimics that of naturally occurring bile acids. Using dual 1H/19F MRI of the gallbladders of live mice fed 19F-labeled bile acid analogues, we were able to differentiate wild-type mice from strains deficient in intestinal expression of a key bile acid transporter, the apical sodium-dependent bile acid transporter (ASBT), or FGF15, the mouse homologue of FGF19. In addition to reviewing our development of 19F-labeled bile acid analogue-MRI to diagnose bile acid diarrhea, we discuss challenges to its clinical implementation. A major limitation is the paucity of clinical MRI facilities equipped with the appropriate coil and software needed to detect 19F signals.
Highlights
Advances over the past two decades greatly expanded our understanding of how tight regulation of bile acid synthesis and transport maintains homeostasis of the bile acid pool
In concert with these advances, it became apparent that up to one-half of persons diagnosed with a common chronic gastrointestinal ailment, diarrhea-predominant irritable bowel syndrome (IBS-D), have bile acid diarrhea resulting from disruption of that homeostasis [1–3]
Clinicians commonly rely on a therapeutic trial of bile acid binders, which has its own limitations
Summary
Advances over the past two decades greatly expanded our understanding of how tight regulation of bile acid synthesis and transport maintains homeostasis of the bile acid pool. In the absence of feedback repression of hepatic Cyp7A1 activity by the FGF19/FGFR4 axis, increased hepatic production of bile acids and decreased filling of the gallbladder result in excess bile acid levels in the ileum that overwhelm ASBT transport capacity [2, 13, 14]. This mechanism is similar to that underlying the transient diarrhea commonly observed following cholecystectomy; removal of the gallbladder commonly results in the unregulated spillage of bile acids into the small intestine. WT wild-type, bw body weight, KO knockout a Numbers derived from bar graphs in the referenced publications
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