MON-260 - In Vivo Visualization of Bile Acids Transport with A Click from Intestines to the Liver using Confocal Microscopy

Bile acids (BAs)—signaling molecules which are key aspects of lipid absorption—transit via enterohepatic circulation (gut to liver transport). Additionally, BAs act as ligands for many nuclear receptors (NRs), including small heterodimer partner (SHP) and farnesoid X receptor (FXR), whose regulations are sex-specific. Once secreted into the intestine, BAs transiting through the gut are deconjugated and transformed by microbiota, further modifying their metabolism and transit. Thus, gut microbes-bile acid interactions affect this enterohepatic axis, such that they are altered in many diseases, including liver and colon cancer. A major limitation until now has been the inability to image the BA transit and its kinetics. Previous techniques have successfully measured individual BA concentrations in homogenized tissues but have been unable to visualize BAs and receptors localized together using confocal microscopy. We show that by gavaging wild-type C57BL/6 mice with Clickable-Taurocholic acid (TCA) or Clickable-Taurochenodeoxycholic acid (TCDCA), we can use a Copper-Catalyzed Azide-Alkyne Cycloaddition reaction (click reaction) to visualize them within the tissues. In addition, we can perform immunofluorescence co-staining in the same sample as the click reaction to visualize the localization of bile acids in tissues in relation with receptors and transport proteins. Our findings with clickable TCA and TCDCA show their presence throughout the entire enterohepatic loop—in the duodenum, jejunum, ileum, colon, and the liver. This is exciting, as until now most bile acid interactions were thought to primarily occur in the ileum or the colon—not the entire length of the intestine. We validated that these clickable TCA and TCDCA in mice are reliably transported and detectable in both portal vein and systemic serum samples, completing the enterohepatic loop. This technique enables us to differentiate between newly synthesized BAs and recirculated BAs and allows for further visualization of the localization and interaction of BAs within tissues.

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