Gail A Cresci1,2,3,4, Bryan Glueck1, Megan R McMullen1, Wei Xin5, Daniella Allende6, Laura E Nagy1,7. 1. Department of Pathobiology, Cleveland Clinic, Cleveland, Ohio, USA. 2. Department of Gastroenterology/Hepatology, Cleveland Clinic, Cleveland, Ohio, USA. 3. Pediatric Research Center, Cleveland Clinic, Cleveland, Ohio, USA. 4. Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA. 5. Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA. 6. Department of Pathology, Cleveland Clinic, Cleveland, Ohio, USA. 7. Department of Molecular Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
Abstract
BACKGROUND AND AIM: Impaired gut-liver axis is a potential factor contributing to alcoholic liver disease. Ethanol depletes intestinal integrity and causes gut dysbiosis. Butyrate, a fermentation byproduct of gut microbiota, is altered negatively following chronic ethanol exposure. This study aimed to determine whether prophylactic tributyrin could protect the intestinal barrier and liver in mice during combined chronic-binge ethanol exposure. METHODS: C57BL/6J mice exposed to 5% v/v ethanol-containing diet for 10 days received a single ethanol gavage (5 g/kg) 9 h before euthanasia. Control mice were isocalorically pair-fed maltose dextrin for ethanol. Diets were supplemented (5 mM) with tributyrin or glycerol. Intestine and liver disease activity was assessed histologically. Protein and mRNA expression of tight junction (TJ) proteins, toll-like receptors, and tumor necrosis factor-alpha were assessed. Caco-2 monolayers with or without ethanol exposure and/or sodium butyrate were used to test butyrate's direct effects on intestinal integrity. RESULTS: Chronic-binge ethanol feeding impaired intestinal TJ protein co-localization staining; however, tributyrin co-treatment mitigated these effects. Ethanol depleted TJ and transepithelial electrical resistance in Caco-2 monolayers, but butyrate co-treatment reduced these effects. Hepatic toll-like receptor mRNA expression and tumor necrosis factor-alpha protein expression was induced by ethanol; however, the response was significantly dampened in mice co-treated with tributyrin. Tributyrin altered localization of both neutrophils and single hepatocyte death: Leukocytes and apoptotic hepatocytes localized predominantly around the portal tract in ethanol-only treated mice, whereas localization predominated around the central vein in ethanol-tributyrin mice. CONCLUSIONS: Prophylactic tributyrin supplementation mitigated effects of combined chronic-binge ethanol exposure on disruption of intestinal TJ localization and intestinal permeability and liver injury.
BACKGROUND AND AIM: Impaired gut-liver axis is a potential factor contributing to alcoholic liver disease. Ethanol depletes intestinal integrity and causes gut dysbiosis. Butyrate, a fermentation byproduct of gut microbiota, is altered negatively following chronic ethanol exposure. This study aimed to determine whether prophylactic tributyrin could protect the intestinal barrier and liver in mice during combined chronic-binge ethanol exposure. METHODS: C57BL/6J mice exposed to 5% v/v ethanol-containing diet for 10 days received a single ethanol gavage (5 g/kg) 9 h before euthanasia. Control mice were isocalorically pair-fed maltose dextrin for ethanol. Diets were supplemented (5 mM) with tributyrin or glycerol. Intestine and liver disease activity was assessed histologically. Protein and mRNA expression of tight junction (TJ) proteins, toll-like receptors, and tumor necrosis factor-alpha were assessed. Caco-2 monolayers with or without ethanol exposure and/or sodium butyrate were used to test butyrate's direct effects on intestinal integrity. RESULTS: Chronic-binge ethanol feeding impaired intestinal TJ protein co-localization staining; however, tributyrin co-treatment mitigated these effects. Ethanol depleted TJ and transepithelial electrical resistance in Caco-2 monolayers, but butyrate co-treatment reduced these effects. Hepatic toll-like receptor mRNA expression and tumor necrosis factor-alpha protein expression was induced by ethanol; however, the response was significantly dampened in mice co-treated with tributyrin. Tributyrin altered localization of both neutrophils and single hepatocyte death: Leukocytes and apoptotic hepatocytes localized predominantly around the portal tract in ethanol-only treated mice, whereas localization predominated around the central vein in ethanol-tributyrinmice. CONCLUSIONS: Prophylactic tributyrin supplementation mitigated effects of combined chronic-binge ethanol exposure on disruption of intestinal TJ localization and intestinal permeability and liver injury.
Authors: Megan R McMullen; Michele T Pritchard; Qifang Wang; Carrie A Millward; Colleen M Croniger; Laura E Nagy Journal: Gastroenterology Date: 2005-06 Impact factor: 22.682
Authors: Jose Antonio López-Moreno; Miguel Marcos; Javier Calleja-Conde; Victor Echeverry-Alzate; Kora M Bühler; Pilar Costa-Alba; Edgar Bernardo; Francisco-Javier Laso; Fernando Rodríguez de Fonseca; Roser Nadal; Maria Paz Viveros; Rafael Maldonado; Elena Giné Journal: Alcohol Clin Exp Res Date: 2015-09-13 Impact factor: 3.455
Authors: Ece Mutlu; Ali Keshavarzian; Phillip Engen; Christopher B Forsyth; Masoumeh Sikaroodi; Patrick Gillevet Journal: Alcohol Clin Exp Res Date: 2009-07-23 Impact factor: 3.455
Authors: Sophie Leclercq; Sébastien Matamoros; Patrice D Cani; Audrey M Neyrinck; François Jamar; Peter Stärkel; Karen Windey; Valentina Tremaroli; Fredrik Bäckhed; Kristin Verbeke; Philippe de Timary; Nathalie M Delzenne Journal: Proc Natl Acad Sci U S A Date: 2014-10-06 Impact factor: 11.205
Authors: Gary D Wu; Jun Chen; Christian Hoffmann; Kyle Bittinger; Ying-Yu Chen; Sue A Keilbaugh; Meenakshi Bewtra; Dan Knights; William A Walters; Rob Knight; Rohini Sinha; Erin Gilroy; Kernika Gupta; Robert Baldassano; Lisa Nessel; Hongzhe Li; Frederic D Bushman; James D Lewis Journal: Science Date: 2011-09-01 Impact factor: 47.728
Authors: Carlos Sanz-Garcia; Kyle L Poulsen; Damien Bellos; Han Wang; Megan R McMullen; Xiaoxia Li; Saurabh Chattopadhyay; Ganes Sen; Laura E Nagy Journal: J Hepatol Date: 2019-01-31 Impact factor: 25.083
Authors: Zdenek Dvorak; Max Klapholz; Thomas P Burris; Benjamin P Willing; Antimo Gioiello; Roberto Pellicciari; Francesco Galli; John March; Stephen J O'Keefe; R Balfour Sartor; Chang H Kim; Maayan Levy; Sridhar Mani Journal: Mol Pharmacol Date: 2020-08-06 Impact factor: 4.436
Authors: Garth R Swanson; Joel Siskin; Annika Gorenz; Maliha Shaikh; Shohreh Raeisi; Louis Fogg; Christopher Forsyth; Ali Keshavarzian Journal: Transl Res Date: 2020-05-05 Impact factor: 7.012
Authors: Matias A Avila; Jean-François Dufour; Alexander L Gerbes; Fabien Zoulim; Ramon Bataller; Patrizia Burra; Helena Cortez-Pinto; Bin Gao; Ian Gilmore; Philippe Mathurin; Christophe Moreno; Vladimir Poznyak; Bernd Schnabl; Gyongyi Szabo; Maja Thiele; Mark R Thursz Journal: Gut Date: 2019-12-26 Impact factor: 23.059