Name: using multi-fluorinated bile acids and in vivo magnetic resonance imaging to measure bile acid transport
Uploaded: 2016-11-27T14:00:00
Description: Watch this Scientific Journal Video about Using Multi-fluorinated Bile Acids and In Vivo Magnetic Resonance Imaging to Measure Bile Acid Transport at JoVE.com

This work was supported by the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (grant numbers R21 DK093406 and T32 DK067872 to J-P.R.) and a VA Merit award (grant number 1BX002129 to J-P.R.).

The following protocol adheres to guidelines approved by the Institutional Animal Care and Use Committee (IACUC) at the University of Maryland School of Medicine (IACUC Protocol #0415011, approved June 18, 2015).
1. Gavaging Mice with 19F-Labeled Bile Acids
<ol>
	<li>Gavage mice with 150 mg/kg body weight 19F-labeled bile acids. Fill a 1-ml syringe to the necessary volume with 19F-labeled bile acid stock solution [cholic acid-trifluoro-acetyl lysine (CA-lys-TFA; in 1:1 polyethyle...

<ol>
	<li>Thomas, C., Pellicciari, R., Pruzanski, M., Auwerx, J., Schoonjans, K. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Targeting+bile-acid+signalling+for+metabolic+diseases.">Targeting bile-acid signalling for metabolic diseases.</a> Nat Rev Drug Discov. 7, 678-693 (2008).</li><li>Vallim, T. Q., Edwards, P. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Bile+acids+have+the+gall+to+function+as+hormones.">Bile acids have the gall to function as hormones.</a> Cell Metab. 10, 162-164 (2009).</li><li>Dawson, P. A., Karpen, S. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Thematic+Review+Series:+Intestinal+Lipid+Metabolism:+New+Developments+and+Current+Insights+Intestinal+transport+and+metabolism+of+bile+acids.">Thematic Review Series: Intestinal Lipid Metabolism: New Developments and Current Insights Intestinal transport and metabolism of bile acids.</a> Journal of Lipid Research. 56, 1085-1099 (2015).</li><li>Dawson, P. A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Targeted+deletion+of+the+ileal+bile+acid+transporter+eliminates+enterohepatic+cycling+of+bile+acids+in+mice.">Targeted deletion of the ileal bile acid transporter eliminates enterohepatic cycling of bile acids in mice.</a> J Biol Chem. 278, 33920-33927 (2003).</li><li>Pattni, S., Walters, J. R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Recent+advances+in+the+understanding+of+bile+acid+malabsorption.">Recent advances in the understanding of bile acid malabsorption.</a> Br Med Bull. 92, 79-93 (2009).</li><li>Walters, J. R., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+new+mechanism+for+bile+acid+diarrhea:+defective+feedback+inhibition+of+bile+acid+biosynthesis.">A new mechanism for bile acid diarrhea: defective feedback inhibition of bile acid biosynthesis.</a> Clin Gastroenterol Hepatol. 7, 1189-1194 (2009).</li><li>Hofmann, A. F., Mangelsdorf, D. J., Kliewer, S. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Chronic+diarrhea+due+to+excessive+bile+acid+synthesis+and+not+defective+ileal+transport:+a+new+syndrome+of+defective+fibroblast+growth+factor+19+release.">Chronic diarrhea due to excessive bile acid synthesis and not defective ileal transport: a new syndrome of defective fibroblast growth factor 19 release.</a> Clin Gastroenterol Hepatol. 7, 1151-1154 (2009).</li><li>Flynn, C., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Deoxycholic+acid+promotes+the+growth+of+colonic+aberrant+crypt+foci.">Deoxycholic acid promotes the growth of colonic aberrant crypt foci.</a> Mol Carcinog. 46, 60-70 (2007).</li><li>Glinghammar, B., Rafter, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Carcinogenesis+in+the+colon:+interaction+between+luminal+factors+and+genetic+factors.">Carcinogenesis in the colon: interaction between luminal factors and genetic factors.</a> Eur J Cancer Prev. 8, S87-S94 (1999).</li><li>Bernstein, C., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Carcinogenicity+of+deoxycholate,+a+secondary+bile+acid.">Carcinogenicity of deoxycholate, a secondary bile acid.</a> Arch Toxicol. 85, 863-871 (2011).</li><li>Zheng, X., Ekins, S., Raufman, J. P., Polli, J. E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Computational+models+for+drug+inhibition+of+the+human+apical+sodium-dependent+bile+acid+transporter.">Computational models for drug inhibition of the human apical sodium-dependent bile acid transporter.</a> Mol Pharm. 6, 1591-1603 (2009).</li><li>Vivian, D., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Design+and+characterization+of+a+novel+fluorinated+magnetic+resonance+imaging+agent+for+functional+analysis+of+bile+Acid+transporter+activity.">Design and characterization of a novel fluorinated magnetic resonance imaging agent for functional analysis of bile Acid transporter activity.</a> Pharm Res. 30, 1240-1251 (2013).</li><li>Vivian, D., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Design+and+evaluation+of+a+novel+trifluorinated+imaging+agent+for+assessment+of+bile+acid+transport+using+fluorine+magnetic+resonance+imaging.">Design and evaluation of a novel trifluorinated imaging agent for assessment of bile acid transport using fluorine magnetic resonance imaging.</a> J Pharm Sci. 103, 3782-3792 (2014).</li><li>Vivian, D., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=In+vivo+performance+of+a+novel+fluorinated+magnetic+resonance+imaging+agent+for+functional+analysis+of+bile+acid+transport.">In vivo performance of a novel fluorinated magnetic resonance imaging agent for functional analysis of bile acid transport.</a> Mol Pharm. 11, 1575-1582 (2014).</li><li>Raufman, J. P., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=In+Vivo+Magnetic+Resonance+Imaging+to+Detect+Biliary+Excretion+of+19F-Labeled+Drug+in+Mice.">In Vivo Magnetic Resonance Imaging to Detect Biliary Excretion of 19F-Labeled Drug in Mice.</a> Drug Metab Dispos. 39, 736-739 (2011).</li><li>Ridlon, J. M., Kang, D. J., Hylemon, P. B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Bile+salt+biotransformations+by+human+intestinal+bacteria.">Bile salt biotransformations by human intestinal bacteria.</a> J Lipid Res. 47, 241-259 (2006).</li><li>Frisch, K., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=N-methyl-11C]cholylsarcosine,+a+novel+bile+acid+tracer+for+PET/CT+of+hepatic+excretory+function:+radiosynthesis+and+proof-of-concept+studies+in+pigs.">N-methyl-11C]cholylsarcosine, a novel bile acid tracer for PET/CT of hepatic excretory function: radiosynthesis and proof-of-concept studies in pigs.</a> J Nucl Med. 53, 772-778 (2012).</li></ol>

The synthesis of CA-lys-TFA and CA-sar-TFMA and the in vitro analysis of their transport using stably transfected Madin-Darby canine kidney cells expressing ASBT and human embryonic kidney cells expressing the sodium/taurocholate co-transporting polypeptide (NTCP) are detailed elsewhere13,14. Here, the focus is on oral administration of MFBA by gavage to live animals, followed by harvest of the gallbladder, liver, and blood for analysis of MFBA content, and, notably, imaging MFBA in the gallbladder by...

Along with their classical role as detergents that facilitate fat absorption from the gut, bile acids have emerged as potent signaling molecules affecting multiple organs in addition to those associated with their enterohepatic circulation1,2. In addition to controlling their own metabolism, bile acids modulate several aspects of gastrointestinal physiology (e.g., gut motility and incretin hormone production, colon physiology, and cancer susceptibility) and have systemic effects on vascular tone, glucose and lipid metabolism, and energy utilization. While some of these effects are mediated in the gut, others are due to postprandial changes in systemic bile acid levels, as noted in obese patients or after gastric by-pass surgery. To elucidate the complex metabolic actions of bile acids new technology is required that permits simultaneous monitoring of bile acid levels in different anatomical compartments, in the gastrointestinal tract and metabolic tissues (liver, pancreas, skeletal muscle and adipose). Obtaining such temporal and spatial information requires innovative technology - in vivo imaging using novel bile acid tracers as described here is such a novel approach.
Bile acid composition and distribution in anatomical compartments are regulated by factors that modulate their hepatic synthesis and ileal uptake, including diet, surgery, antibiotic use and changes in gut flora. A key regulator of intestinal bile acid uptake for their enterohepatic circulation3 (Figure 1) is the ileal Apical Sodium-dependent Bile Acid Transporter (ASBT; SLC10A2). Although passive absorption occurs throughout the intestines, ASBT mediates uptake of 95% of intestinal bile acids so that normally there is limited spillage of bile acids into the feces. Asbt-deficient (Slc10a2-/-) mice have increased fecal bile acids and a diminished bile acid pool4.
<img alt="Figure 1" src="/files/ftp_upload/54597/54597fig1.jpg" /> 
Figure 1: Enterohepatic Circulation of Bile Acids. 
Illustration of Enterohepatic Circulation whereby Bile Acids are Synthesized in the Liver, Excreted into the Biliary Tree, Stored in the Gallbladder, Released into the Proximal Small Intestine with Meals, and Actively taken up via ASBT in the Distal Ileum. Whereas small amounts of bile acids are absorbed passively throughout the gut, approximately 95% of intestinal bile acids are transported actively by ASBT resulting in minimal (approximately 5%) loss in the stool which is compensated by a similar amount of new bile acid synthesis in the liver, thereby maintaining a steady-state bile acid pool. The arrows on the right identify factors that may impact native and fluorine-labeled bile acid stability, including gastric acid, pancreatic and intestinal mucosal enzymes, and, most importantly, hydrolytic enzymes released by Clostridial species that colonize the distal small bowel and colon. (Modified with permission16) <a href="http://cloudflare.jove.com/files/ftp_upload/54597/54597fig1large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
Bile acid malabsorption can be categorized into three types, each of which increases fecal dihydroxy bile acids, thereby causing intermittent or chronic diarrhea. Type 1 results from gross ileal pathology (e.g., resection, Crohn disease)5. Type 3 results from cholecystectomy, vagotomy, celiac disease, bacterial overgrowth, and pancreatic insufficiency. In contrast, persons with &#39;primary&#39; (Type 2) bile acid malabsorption pose a formidable diagnostic challenge because they lack such antecedent conditions and do not have evidence of pathology in the ileum. Hence, primary bile acid malabsorption is commonly misdiagnosed as diarrhea-predominant irritable bowel syndrome (IBS-D), perhaps the most common reason for gastroenterology-related out-patient visits. It has been estimated that one-third of patients with IBS-D have primary bile acid malabsorption; in the U.S., this may represent several million persons5. Recent insights indicate that primary BAM derives from impaired feedback inhibition of hepatic bile acid synthesis by intestinal fibroblast growth factor-19 (FGF19), not from reduced expression or function of ASBT.
In primary bile acid malabsorption, low plasma levels of FGF19 fail to shut off hepatic bile acid synthesis - the resulting increase in intestinal bile acids saturates bile acid transporters, including ASBT, and the augmented spillage of bile acids into the feces causes diarrhea6 (Figure 2). Mice deficient in Fgf15 (murine FGF19) have an expanded bile acid pool and increased fecal bile acids7.
<img alt="Figure 2" src="/files/ftp_upload/54597/54597fig2.jpg" /> 
Figure 2: Mechanisms of Intestinal Bile Acid Malabsorption. 
Normally, as shown in panel A, approximately 95% of intestinal bile acids are absorbed by active transport in the distal ileum via ASBT. When ASBT expression or activity is diminished (panel B), impaired intestinal bile acid uptake results in spillage of bile acids into the colon. With impaired FGF19 signaling (panel C), the lack of feedback inhibition of hepatic bile acid synthesis results in increased concentrations of intestinal bile acids that overwhelm ASBT transport capacity with spillage of bile acids into the colon. <a href="http://cloudflare.jove.com/files/ftp_upload/54597/54597fig2large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
Long-term, chronic elevation in fecal bile acids may promote colon neoplasia. Colon neoplasia arises from progressive mucosal dysplasia associated with somatic gene mutations, but environmental factors that increase fecal bile acids may accelerate and augment this process. In rodents, increased fecal bile acids either as a consequence of exogenous administration or Asbt deficiency promote colon dysplasia and tumor formation8-10.
Notably, provocative findings indicate that commonly-used drugs approved by the Food and Drug Administration (FDA) potently inhibit bile acid transport by ASBT in vitro11. If these drugs reduce small intestinal bile acid transport in vivo and increase fecal bile acid levels, the potential impact on colon pathology would be concerning. Even a small increase in colon pathology attributed to use of such a drug could have a major health impact. A toolkit which can assess the plausibility of these in vitro findings and epidemiologic observations would spur additional research, including post-marketing safety studies.
Despite the need, practical assays to identify people with bile acid malabsorption are lacking. Direct measurement of fecal bile acids was rejected years ago as cumbersome, impractical, and unreliable5. Alternative approaches include measuring retention of a radioactive selenium-labeled cholic acid derivative (75SeHCAT) and plasma levels of 7&#945;-hydroxy-4-cholesten-3-one (C4), or a therapeutic trial of bile acid binders. 75SeHCAT testing has limited availability in Europe and is not FDA-approved or available for use in the U.S. Moreover, even modest radiation exposure (0.26 mSv/75SeHCAT test) from diagnostic testing raises concerns, and bacterial overgrowth and advanced liver disease may confound 75SeHCAT results. C4 testing is potentially attractive since only plasma is required, but it has low positive-predictive value and testing is not widely available. Measuring serum levels of FGF19 has similar limitations. Frequently clinicians resort to a therapeutic trial of bile acid sequestrants, but this approach cannot provide a definitive diagnosis of bile acid malabsorption5.
For these reasons, a novel MRI approach was conceived to measure bile acid transport and distribution in vivo using innovative multi-fluorinated bile acids (MFBA-MRI). MFBA containing three atoms of fluorine (19F), a stable isotope of 100% natural abundance, are transported similarly to native bile acids12, and can be used to visualize bile acid transport with a combination of proton (1H) and fluorine (19F) MRI, a sensitive, safe method without ionizing radiation exposure13,14.

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>Duall size-21 all glass tissue grinder</td>
			<td>Kimble Chase Life Science, Vineland, NJ</td>
			<td>885351-0022</td>
			<td></td>
		</tr>
		<tr>
			<td>Bruker BioSpec 70/30USR Avance III 7T horizontal bore MR Scanner</td>
			<td>Bruker Biospin MRI GmbH, Germany</td>
			<td></td>
			<td>Use companion Paravision Version 5.1 software (see step 3.5)</td>
		</tr>
		<tr>
			<td>Bruker 40 mm 19F/1H dual-tuned linerar volume coil</td>
			<td>Bruker Biospin MRI GmbH, Germany</td>
			<td></td>
			<td>Use companion Paravision Version 5.1 software (see step 3.5)</td>
		</tr>
		<tr>
			<td>Waters Acquity UPLC System with Quadrupole Detector</td>
			<td>Waters Corporation, Milford, MA</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Waters Acquity UPLC ethylene bridged hybrid C8 1.7 &#956;m 2.1 X 50 mm column</td>
			<td>Waters Corporation, Milford, MA</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Gavage Needle</td>
			<td>Braintree Scientific, INC.</td>
			<td>N-010</td>
			<td>20 G-1.5&#34; curved 2.25mm ball</td>
		</tr>
		<tr>
			<td>2 Stainless Steel Hemostats&#160;</td>
			<td>VWR</td>
			<td>10755-018</td>
			<td>4 and 5 inch, straight</td>
		</tr>
		<tr>
			<td>Ketamine</td>
			<td>MWI Veterinary Supply</td>
			<td>501090</td>
			<td>Ketamin zetamine 100 mg / ml</td>
		</tr>
		<tr>
			<td>Xylazine</td>
			<td>Akorn, Inc.</td>
			<td></td>
			<td>20 mg/ml</td>
		</tr>
		<tr>
			<td>Intraperitoneal Catheter</td>
			<td>Abbott</td>
			<td>AbbocathTM-T.I.V. G720-A01 4535-42</td>
			<td>24-G x 0.75&#34;</td>
		</tr>
	</tbody>
</table>

using multi-fluorinated bile acids and in vivo magnetic resonance imaging to measure bile acid transport

Along with their traditional role as detergents that facilitate fat absorption, emerging literature indicates that bile acids are potent signaling molecules that affect multiple organs; they modulate gut motility and hormone production, and alter vascular tone, glucose metabolism, lipid metabolism, and energy utilization. Changes in fecal bile acids may alter the gut microbiome and promote colon pathology including cholerrheic diarrhea and colon cancer. Key regulators of fecal bile acid composition are the small intestinal Apical Sodium-dependent Bile Acid Transporter (ASBT) and fibroblast growth factor-19 (FGF19). Reduced expression and function of ASBT decreases intestinal bile acid up-take. Moreover, in vitro data suggest that some FDA-approved drugs inhibit ASBT function. Deficient FGF19 release increases hepatic bile acid synthesis and release into the intestines to levels that overwhelm ASBT. Either ASBT dysfunction or FGF19 deficiency increases fecal bile acids and may cause chronic diarrhea and promote colon neoplasia. Regrettably, tools to measure bile acid malabsorption and the actions of drugs on bile acid transport in vivo are limited. To understand the complex actions of bile acids, techniques are required that permit simultaneous monitoring of bile acids in the gut and metabolic tissues. This led us to conceive an innovative method to measure bile acid transport in live animals using a combination of proton (1H) and fluorine (19F) magnetic resonance imaging (MRI). Novel tracers for fluorine (19F)-based live animal MRI were created and tested, both in vitro and in vivo. Strengths of this approach include the lack of exposure to ionizing radiation and translational potential for clinical research and practice.

The use of MFBA for in vivo MRI to &#39;see&#39; bile acid transport in real time has great potential for both research and clinical use. Moreover, the methods described here for resection of the gallbladder and biochemical analysis of its contents using liquid chromatography and mass spectrometry provide a means of confirming imaging results. However, the validity of these methods requires precise dosing, timing of assays, and localization of the gallbladder for imaging or surgi...

Watch this Scientific Journal Video about Using Multi-fluorinated Bile Acids and In Vivo Magnetic Resonance Imaging to Measure Bile Acid Transport at JoVE.com

Using Multi-fluorinated Bile Acids and In Vivo Magnetic Resonance Imaging to Measure Bile Acid Transport

Tools to diagnose bile acid malabsorption and measure bile acid transport in vivo are limited. An innovative approach in live animals is described that utilizes combined proton (1H) plus fluorine (19F) magnetic resonance imaging; this novel methodology has translational potential to screen for bile acid malabsorption in clinical practice.

Using Multi-fluorinated Bile Acids and In Vivo Magnetic Resonance Imaging to Measure Bile Acid Transport

Along with their traditional role as detergents that facilitate fat absorption, emerging literature indicates that bile acids are potent signaling ...

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