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1. Circulating Bile Acids in Liver Failure Activate TGR5 and Induce Monocyte DysfunctionSummary

Author

Julia Leonhardt, Raphael S. Haider, Christoph Sponholz, Silke Leonhardt, Julia Drube, Katrin Spengler, Diana Mihaylov, Sophie Neugebauer, Michael Kiehntopf, Nevin A. Lambert, Andreas Kortgen, Tony Bruns, Frank Tacke, Carsten Hoffmann, Michael Bauer, and Regine Heller

Subjects
Liver Failure, Bile Acids, TGR5, GPBAR1, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Background & Aims: Retention of bile acids in the blood is a hallmark of liver failure. Recent studies have shown that increased serum bile acid levels correlate with bacterial infection and increased mortality. However, the mechanisms by which circulating bile acids influence patient outcomes still are elusive. Methods: Serum bile acid profiles in 33 critically ill patients with liver failure and their effects on Takeda G-protein–coupled receptor 5 (TGR5), an immunomodulatory receptor that is highly expressed in monocytes, were analyzed using tandem mass spectrometry, novel highly sensitive TGR5 bioluminescence resonance energy transfer using nanoluciferase (NanoBRET, Promega Corp, Madison, WI) technology, and in vitro assays with human monocytes. Results: Twenty-two patients (67%) had serum bile acids that led to distinct TGR5 activation. These TGR5-activating serum bile acids severely compromised monocyte function. The release of proinflammatory cytokines (eg, tumor necrosis factor α or interleukin 6) in response to bacterial challenge was reduced significantly if monocytes were incubated with TGR5-activating serum bile acids from patients with liver failure. By contrast, serum bile acids from healthy volunteers did not influence cytokine release. Monocytes that did not express TGR5 were protected from the bile acid effects. TGR5-activating serum bile acids were a risk factor for a fatal outcome in patients with liver failure, independent of disease severity. Conclusions: Depending on their composition and quantity, serum bile acids in liver failure activate TGR5. TGR5 activation leads to monocyte dysfunction and correlates with mortality, independent of disease activity. This indicates an active role of TGR5 in liver failure. Therefore, TGR5 and bile acid metabolism might be promising targets for the treatment of immune dysfunction in liver failure.

Published
2021
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2. What does critical illness do to the liver?

Author

Michael Bauer and Andreas Kortgen

Subjects
medicine.diagnostic_test, Bilirubin, business.industry, Acute-phase protein, Inflammation, Systemic inflammation, Bioinformatics, chemistry.chemical_compound, chemistry, Pharmacokinetics, Shock (circulatory), medicine, Liver function, medicine.symptom, Liver function tests, business
Abstract

Common pathophysiologic states in critically ill patients, such as systemic inflammation or shock, lead to profound alterations in liver function with a reprogramming of protein synthesis referred to as ‘acute phase response’. In parallel, a disruption of phase I and II biotransformation and bile transport is frequently observed. Complex mechanisms to regulate liver blood flow might be impaired, leading to hypoperfusion, shunting and ultimately to cell death primarily in the pericentral region. The incidence and severity of liver impairment is underestimated when exclusively traditional “static” biomarkers, such as bilirubin and serum transaminases, are used while “dynamic” tests evaluating excretory or metabolic functions, such as plasma disappearance rate of indocyanine green or methacetin breath test, are more sensitive. Nevertheless, even slight elevations of bilirubin are associated with worse outcome in critical care patients. Changes in liver function lead to unpredictable changes in pharmacokinetics and pharmacodynamics, particularly in multidrug therapy frequently initiated in the critically ill. For some drugs, such as sedatives or analgesics, careful clinical assessment might be sufficient. Whenever possible, therapeutic monitoring should be performed. Sometimes, liver function tests and scoring systems can be helpful to adapt dosage. In principal, drugs solely metabolized via phase II metabolism should be preferred as this pathway is often less impaired. In contrast, the hepatobiliary excretory machinery appears exceptionally sensitive to inflammation. Hepatotoxic drugs should be avoided whenever possible to prevent additional liver damage.

Published
2020

3. Contributors

Author

Gareth L. Ackland, Adeel Rafi Ahmed, Djillali Annane, Eman Ansari, Hubertus Axer, Jan Bakker, Ian J. Barbash, John James Bates, Michael Bauer, Amy L. Bellinghausen, William S. Bender, Matthew R. Biery, Alexandra Binnie, Thomas P. Bleck, Christina Boncyk, Jason C. Brainard, Scott C. Brakenridge, Frank Martin Brunkhorst, Tara Cahill, BSc(Physio), Christina Campbell, Jonathan Dale Casey, Jean-Marc Cavaillon, Maurizio Cereda, David J. Cooper, Craig M. Coopersmith, Jennifer Cruz, Cheston B. Cunha, Gerard F. Curley, Allison Dalton, Daniel De Backer, Clifford S. Deutschman, David Devlin, Claudia C. Dos, Tomas Drabek, Laura Dragoi, Martin Dres, Anne M. Drewry, Stephen Duff, Philip A. Efron, Sinéad Egan, MB, Ali A. El, E. Wesley Ely, Laura Evans, Jessica Falco-Walter, Jonathan K. Frogel, Niall D. Ferguson, Joseph S. Fernandez-Moure, Jakub Furmaga, David Foster Gaieski, Ognjen Gajic, Alice Gallo De, Kelly R. Genga, Pierce Geoghegan, Evangelos J. Giamarellos-Bourboulis, Rick Gill, Ewan C. Goligher, Emily K. Gordon, W. Robert Grabenkort, Garima Gupta, Jacob T. Gutsche, Goksel Guven, Paige Guyatt, Nicholas Heming, Cheralyn J. Hendrix, McKenzie K. Hollen, Steven M. Hollenberg, Vivien Hong Tuan Ha, Shahd Horie, Catherine L. Hough, Can Ince, Theodore J. Iwashyna, Judith Jacobi, Marc Jeschke, Nicholas J. Johnson, Jeremy M. Kahn, Lewis J. Kaplan, Mark T. Keegan, Jordan Anthony Kempker, Leo G. Kevin, Yasin A. Khan, Ruth Kleinpell, Kurt Kleinschmidt, Michael Klompas, Patrick M. Kochanek, W. Andrew Kofke, Benjamin Kohl, Andreas Kortgen, David Kung, John G. Laffey, Joel Lage, David William Lappin, Francois Lamontagne, Daniel E. Leisman, Ron Leong, Joshua M. Levine, Andrew T. Levinson, Mitchell M. Levy, Ariane Lewis, Ariel Tamara Slavin, Olivier Lheureux, Vincent X. Liu, Craig Lyons, Jason H. Maley, Atul Malhotra, Joshua A. Marks, Greg S. Martin, Niels D. Martin, Claire Masterson, Yunis Mayasi, Virginie Maxime, Bairbre Aine McNicholas, Jakob McSparron, Maureen O. Meade, Mark E. Mikkelsen, Alicia M. Mohr, Peter Moran, Stephanie Royer Moss, Patrick T. Murray, Patrick J. Neligan, Larry X. Nguyen, Alistair D. Nichol, Katherine Lyn Nugent, Mark E. Nunnally, Michael F. O’Connor, Yewande Odeyemi, Steven M. Opal, Anthony O’Regan, John O’Regan, Michelle O’Shaughnessy, Robert L. Owens, Pratik Pandharipande, Ithan D. Peltan, Anders Perner, Michael R. Pinsky, Greta Piper, Lauren A. Plante, Ariella Pratzer, Jean-Charles Preiser, Hallie C. Prescott, Megan T. Quintana, Lindsay Raab, Jason S. Radowsky, Jesse M. Raiten, Bryan T. G. Reidy, Patrick M. Reilly, Kenneth E. Remy, Emanuele Rezoagli, Zaccaria Ricci, Lisbi Rivas, Bram Rochwerg, Kristen Carey Rock, Claudio Ronco, James A. Russell, Danielle K. Sandsmark, Joshua Iokepa Santos, Babak Sarani, Damon C. Scales, Michael Scully, Jon Sevransky, Sam D. Shemie, Carrie A. Sims, Brian P. Smith, Audrey E. Spelde, Robert David Stevens, B. Taylor Thompson, Samuel A. Tisherman, Mark Trinder, Isaiah R. Turnbull, Ida-Fong Ukor, MBBS, Tom van der Poll, Tjitske S.R. van Engelen, Charles R. Vasquez, Michael A. Vella, William J. Vernick, Gianluca Villa, Jean-Louis Vincent, Amy C. Walker, Keith R. Walley, Lorraine B. Ware, Stuart J. Weiss, Anna E. Garcia, and Pauline Whyte

Published
2020

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