A 19F magnetic resonance imaging-based diagnostic test for bile acid diarrhea

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. 75 Selenium 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 19 F magnetic resonance imaging (MRI)-based diagnostic approach. We created 19 F-labeled bile acid analogues whose in vitro and in vivo transport mimics that of naturally occurring bile acids. Using dual 1 H/ 19 F MRI of the gallbladders of live mice fed 19 F-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 19 F-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 19 F signals.

Novel nitroxide-bile acid conjugates inform substrate requirements for human bile acid transporters

“…We have previously reported the synthesis and testing of CA-sar-TFMA and CA-lys-TFMA, in which a fluorinated moiety was conjugated to cholic acid with either a sarcosine analogue or a lysine serving as linker. These conjugates were shown to undergo enterohepatic circulation, enabling their use as imaging agents in studying bile acid transport through 19 F-MRI in vivo ( Felton et al, 2016 ; Metry et al, 2018 ; Raufman et al, 2019 ; Vivian et al, 2014a ; Vivian et al, 2014b ; Vivian et al, 2013 ). CA-Px-1 and CA-Px-2, the NBACs prepared and tested in this study, are based structurally on CA-sar-TFMA and CA-lys-TFMA, respectively.…”

“…The use of bile acid derivatives to assess impaired bile acid transport, particularly in detecting BAD, has been previously characterized in vitro and in vivo . For example, the accumulation of 19 F-labeled bile acid analogues in murine gallbladders was visualized using 1 H/ 19 F magnetic resonance imaging (MRI) ( Felton et al, 2016 ; Metry et al, 2018 ; Raufman et al, 2019 ; Vivian et al, 2014a ; Vivian et al, 2014b ; Vivian et al, 2013 ). Despite the promise of this approach, clinical translation was impeded by the lack of MRI facilities possessing the costly hardware and software necessary to detect fluorine signals or the financial incentive for such facilities to make this costly investment ( Metry et al, 2018 ; Raufman et al, 2019 ).…”

Intestinal Absorption of Bile Acids in Health and Disease

“…These methods are likely insufficient to study dynamic, posttranslational changes in ASBT activity, necessitating the development of real-time methods. Several recent approaches have been developed to quantify the aspects of bile acid physiology in -real time (76,115,263,311,389,392,(397)(398)(399). Additionally, a recent bioluminescence-based approach relying on a CA-luciferin-conjugated probe has shown promising results for measuring real-time ASBT activity in vitro and in isolated intestinal epithelial cells (377).…”

Special issue on fluorine-19 magnetic resonance: technical solutions, research promises and frontier applications

“…This can be compensated by data resampling strategies that improve image quality and suppress background [3]. Quantification of the fluorine MR signal will also be essential for most of the conceivable applications [4][5][6][7][8][9][10][11]. Therefore, the necessary technologies such as B 1 mapping to correct for non-uniform radiofrequency fields [12] or development of new radio frequency coil technologies [13,14] .…”

“…The application of fluorine probes and fluorine MRI in (pre)clinical disease settings continues to expand, particularly in the area of diagnostics such as imaging of inflammation [5,9], tissue oxygenation [7], and assessment of bile acid disorders [10]. This translational research is very encouraging en route to clinical applications and provides expanded knowledge into the distribution of the fluorinated probes in larger animals, particularly during pathology, and while using clinical scanners, thus advancing the opportunities of fluorine MRI for clinical application.…”