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Circulating Bile Acids in Liver Failure Activate TGR5 and Induce Monocyte DysfunctionSummary
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 s...
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Published in: | Cellular and molecular gastroenterology and hepatology 2021-01, Vol.12 (1), p.25-40 |
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creator | 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 Regine Heller |
description | 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. |
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fullrecord | <record><control><sourceid>doaj</sourceid><recordid>TN_cdi_doaj_primary_oai_doaj_org_article_f2898bb220504471a55ccd6030fbf158</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><doaj_id>oai_doaj_org_article_f2898bb220504471a55ccd6030fbf158</doaj_id><sourcerecordid>oai_doaj_org_article_f2898bb220504471a55ccd6030fbf158</sourcerecordid><originalsourceid>FETCH-doaj_primary_oai_doaj_org_article_f2898bb220504471a55ccd6030fbf1583</originalsourceid><addsrcrecordid>eNqtjM1KAzEUhYNYsGjf4b5AIZOZdMalVqsFu9EuXBTCnfyUW9JEkklh3t5WXPgArs7hOx_nik1FLcW8buTn9Z9-w2Y5HzjnVdMuWi6nbLekpIvHgcIeHslbeNBkMlCANzrZBCskX9IFD3TCwcL25V0CBgPrYIq2sIkh6vE8PI3ZlXDWYvgoxyOm8Y5NHPpsZ795y9ar5-3ydW4iHtRXooukIpL6ATHtFaaBtLfKie6-63shuORN01YopdZmwWvuelfJrv7Pr2_xoF4k</addsrcrecordid><sourcetype>Open Website</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Circulating Bile Acids in Liver Failure Activate TGR5 and Induce Monocyte DysfunctionSummary</title><source>Open Access: PubMed Central</source><source>ScienceDirect®</source><creator>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 ; Regine Heller</creator><creatorcontrib>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 ; Regine Heller</creatorcontrib><description>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.</description><identifier>ISSN: 2352-345X</identifier><identifier>EISSN: 2352-345X</identifier><language>eng</language><publisher>Elsevier</publisher><subject>Bile Acids ; GPBAR1 ; Liver Failure ; TGR5</subject><ispartof>Cellular and molecular gastroenterology and hepatology, 2021-01, Vol.12 (1), p.25-40</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784</link.rule.ids></links><search><creatorcontrib>Julia Leonhardt</creatorcontrib><creatorcontrib>Raphael S. Haider</creatorcontrib><creatorcontrib>Christoph Sponholz</creatorcontrib><creatorcontrib>Silke Leonhardt</creatorcontrib><creatorcontrib>Julia Drube</creatorcontrib><creatorcontrib>Katrin Spengler</creatorcontrib><creatorcontrib>Diana Mihaylov</creatorcontrib><creatorcontrib>Sophie Neugebauer</creatorcontrib><creatorcontrib>Michael Kiehntopf</creatorcontrib><creatorcontrib>Nevin A. Lambert</creatorcontrib><creatorcontrib>Andreas Kortgen</creatorcontrib><creatorcontrib>Tony Bruns</creatorcontrib><creatorcontrib>Frank Tacke</creatorcontrib><creatorcontrib>Carsten Hoffmann</creatorcontrib><creatorcontrib>Michael Bauer</creatorcontrib><creatorcontrib>Regine Heller</creatorcontrib><title>Circulating Bile Acids in Liver Failure Activate TGR5 and Induce Monocyte DysfunctionSummary</title><title>Cellular and molecular gastroenterology and hepatology</title><description>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.</description><subject>Bile Acids</subject><subject>GPBAR1</subject><subject>Liver Failure</subject><subject>TGR5</subject><issn>2352-345X</issn><issn>2352-345X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>DOA</sourceid><recordid>eNqtjM1KAzEUhYNYsGjf4b5AIZOZdMalVqsFu9EuXBTCnfyUW9JEkklh3t5WXPgArs7hOx_nik1FLcW8buTn9Z9-w2Y5HzjnVdMuWi6nbLekpIvHgcIeHslbeNBkMlCANzrZBCskX9IFD3TCwcL25V0CBgPrYIq2sIkh6vE8PI3ZlXDWYvgoxyOm8Y5NHPpsZ795y9ar5-3ydW4iHtRXooukIpL6ATHtFaaBtLfKie6-63shuORN01YopdZmwWvuelfJrv7Pr2_xoF4k</recordid><startdate>20210101</startdate><enddate>20210101</enddate><creator>Julia Leonhardt</creator><creator>Raphael S. Haider</creator><creator>Christoph Sponholz</creator><creator>Silke Leonhardt</creator><creator>Julia Drube</creator><creator>Katrin Spengler</creator><creator>Diana Mihaylov</creator><creator>Sophie Neugebauer</creator><creator>Michael Kiehntopf</creator><creator>Nevin A. Lambert</creator><creator>Andreas Kortgen</creator><creator>Tony Bruns</creator><creator>Frank Tacke</creator><creator>Carsten Hoffmann</creator><creator>Michael Bauer</creator><creator>Regine Heller</creator><general>Elsevier</general><scope>DOA</scope></search><sort><creationdate>20210101</creationdate><title>Circulating Bile Acids in Liver Failure Activate TGR5 and Induce Monocyte DysfunctionSummary</title><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 ; Regine Heller</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-doaj_primary_oai_doaj_org_article_f2898bb220504471a55ccd6030fbf1583</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Bile Acids</topic><topic>GPBAR1</topic><topic>Liver Failure</topic><topic>TGR5</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Julia Leonhardt</creatorcontrib><creatorcontrib>Raphael S. Haider</creatorcontrib><creatorcontrib>Christoph Sponholz</creatorcontrib><creatorcontrib>Silke Leonhardt</creatorcontrib><creatorcontrib>Julia Drube</creatorcontrib><creatorcontrib>Katrin Spengler</creatorcontrib><creatorcontrib>Diana Mihaylov</creatorcontrib><creatorcontrib>Sophie Neugebauer</creatorcontrib><creatorcontrib>Michael Kiehntopf</creatorcontrib><creatorcontrib>Nevin A. Lambert</creatorcontrib><creatorcontrib>Andreas Kortgen</creatorcontrib><creatorcontrib>Tony Bruns</creatorcontrib><creatorcontrib>Frank Tacke</creatorcontrib><creatorcontrib>Carsten Hoffmann</creatorcontrib><creatorcontrib>Michael Bauer</creatorcontrib><creatorcontrib>Regine Heller</creatorcontrib><collection>DOAJ Directory of Open Access Journals</collection><jtitle>Cellular and molecular gastroenterology and hepatology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Julia Leonhardt</au><au>Raphael S. Haider</au><au>Christoph Sponholz</au><au>Silke Leonhardt</au><au>Julia Drube</au><au>Katrin Spengler</au><au>Diana Mihaylov</au><au>Sophie Neugebauer</au><au>Michael Kiehntopf</au><au>Nevin A. Lambert</au><au>Andreas Kortgen</au><au>Tony Bruns</au><au>Frank Tacke</au><au>Carsten Hoffmann</au><au>Michael Bauer</au><au>Regine Heller</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Circulating Bile Acids in Liver Failure Activate TGR5 and Induce Monocyte DysfunctionSummary</atitle><jtitle>Cellular and molecular gastroenterology and hepatology</jtitle><date>2021-01-01</date><risdate>2021</risdate><volume>12</volume><issue>1</issue><spage>25</spage><epage>40</epage><pages>25-40</pages><issn>2352-345X</issn><eissn>2352-345X</eissn><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.</abstract><pub>Elsevier</pub><oa>free_for_read</oa></addata></record> |
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subjects | Bile Acids GPBAR1 Liver Failure TGR5 |
title | Circulating Bile Acids in Liver Failure Activate TGR5 and Induce Monocyte DysfunctionSummary |
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