Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Critical Care
Published in: Critical Care 1/2020

01-12-2020 | Septicemia | Review

Gut-liver crosstalk in sepsis-induced liver injury

Authors: Jian Sun, Jingxiao Zhang, Xiangfeng Wang, Fuxi Ji, Claudio Ronco, Jiakun Tian, Yongjie Yin

Published in: Critical Care | Issue 1/2020

Login to get access

Abstract

Sepsis is characterized by a dysregulated immune response to infection leading to life-threatening organ dysfunction. Sepsis-induced liver injury is recognized as a powerful independent predictor of mortality in the intensive care unit. During systemic infections, the liver regulates immune defenses via bacterial clearance, production of acute-phase proteins (APPs) and cytokines, and metabolic adaptation to inflammation. Increased levels of inflammatory cytokines and impaired bacterial clearance and disrupted metabolic products can cause gut microbiota dysbiosis and disruption of the intestinal mucosal barrier. Changes in the gut microbiota play crucial roles in liver injury during sepsis. Bacterial translocation and resulting intestinal inflammation lead to a systemic inflammatory response and acute liver injury. The gut-liver crosstalk is a potential target for therapeutic interventions. This review analyzes the underlying mechanisms for the gut-liver crosstalk in sepsis-induced liver injury.
Literature
1.
Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801–10.PubMedPubMedCentralCrossRef
2.
3.
Seymour CW, Gesten F, Prescott HC, Friedrich ME, Iwashyna TJ, Phillips GS, Lemeshow S, Osborn T, Terry KM, Levy MM. Time to treatment and mortality during mandated emergency care for sepsis. N Engl J Med. 2017;376(23):2235–44.PubMedPubMedCentralCrossRef
4.
Vincent JL, Marshall JC, Namendys-Silva SA, Francois B, Martin-Loeches I, Lipman J, Reinhart K, Antonelli M, Pickkers P, Njimi H, et al. Assessment of the worldwide burden of critical illness: the intensive care over nations (ICON) audit. Lancet Respir Med. 2014;2(5):380–6.PubMedCrossRef
5.
Weiss YG, Bellin L, Kim PK, Andrejko KM, Haaxma CA, Raj N, Furth EE, Deutschman CS. Compensatory hepatic regeneration after mild, but not fulminant, intraperitoneal sepsis in rats. Am J Physiol Gastrointest Liver Physiol. 2001;280(5):G968–73.PubMedCrossRef
6.
Strnad P, Tacke F, Koch A, Trautwein C. Liver - guardian, modifier and target of sepsis. Nat Rev Gastroenterol Hepatol. 2017;14(1):55–66.PubMedCrossRef
7.
8.
Cheng B, Xie G, Yao S, Wu X, Guo Q, Gu M, Fang Q, Xu Q, Wang D, Jin Y, et al. Epidemiology of severe sepsis in critically ill surgical patients in ten university hospitals in China. Crit Care Med. 2007;35(11):2538–46.PubMedCrossRef
9.
Brun-Buisson C, Meshaka P, Pinton P, Vallet B, Group ES. EPISEPSIS: a reappraisal of the epidemiology and outcome of severe sepsis in French intensive care units. Intensive Care Med. 2004;30(4):580–8.PubMedCrossRef
10.
Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001;29(7):1303–10.PubMedCrossRef
11.
Lelubre C, Vincent JL. Mechanisms and treatment of organ failure in sepsis. Nat Rev Nephrol. 2018;14(7):417–27.PubMedCrossRef
12.
13.
Schnabl B, Brenner DA. Interactions between the intestinal microbiome and liver diseases. Gastroenterology. 2014;146(6):1513–24.PubMedCrossRef
14.
Ghoshal S, Witta J, Zhong J, de Villiers W, Eckhardt E. Chylomicrons promote intestinal absorption of lipopolysaccharides. J Lipid Res. 2009;50(1):90–7.PubMedCrossRef
15.
Mittal R, Coopersmith CM. Redefining the gut as the motor of critical illness. Trends Mol Med. 2014;20(4):214–23.PubMedCrossRef
16.
17.
McDonald B, Urrutia R, Yipp BG, Jenne CN, Kubes P. Intravascular neutrophil extracellular traps capture bacteria from the bloodstream during sepsis. Cell Host Microbe. 2012;12(3):324–33.PubMedCrossRef
18.
Gustot T, Durand F, Lebrec D, Vincent JL, Moreau R. Severe sepsis in cirrhosis. Hepatology. 2009;50(6):2022–33.PubMedCrossRef
19.
Turner JR. Intestinal mucosal barrier function in health and disease. Nat Rev Immunol. 2009;9(11):799–809.PubMedCrossRef
20.
21.
Nalle SC, Kwak HA, Edelblum KL, Joseph NE, Singh G, Khramtsova GF, Mortenson ED, Savage PA, Turner JR. Recipient NK cell inactivation and intestinal barrier loss are required for MHC-matched graft-versus-host disease. Sci Transl Med. 2014;6(243):243ra287.CrossRef
22.
Bischoff SC, Barbara G, Buurman W, Ockhuizen T, Schulzke JD, Serino M, Tilg H, Watson A, Wells JM. Intestinal permeability--a new target for disease prevention and therapy. BMC Gastroenterol. 2014;14:189.PubMedPubMedCentralCrossRef
23.
24.
Yoseph BP, Klingensmith NJ, Liang Z, Breed ER, Burd EM, Mittal R, Dominguez JA, Petrie B, Ford ML, Coopersmith CM. Mechanisms of intestinal barrier dysfunction in sepsis. Shock. 2016;46(1):52–9.PubMedPubMedCentralCrossRef
25.
Zahs A, Bird MD, Ramirez L, Turner JR, Choudhry MA, Kovacs EJ. Inhibition of long myosin light-chain kinase activation alleviates intestinal damage after binge ethanol exposure and burn injury. Am J Physiol Gastrointest Liver Physiol. 2012;303(6):G705–12.PubMedPubMedCentralCrossRef
26.
Yu D, Marchiando AM, Weber CR, Raleigh DR, Wang Y, Shen L, Turner JR. MLCK-dependent exchange and actin binding region-dependent anchoring of ZO-1 regulate tight junction barrier function. Proc Natl Acad Sci U S A. 2010;107(18):8237–41.PubMedPubMedCentralCrossRef
27.
Alexopoulou A, Agiasotelli D, Vasilieva LE, Dourakis SP. Bacterial translocation markers in liver cirrhosis. Ann Gastroenterol. 2017;30(5):486–97.PubMedPubMedCentral
28.
Lorentz CA, Liang Z, Meng M, Chen CW, Yoseph BP, Breed ER, Mittal R, Klingensmith NJ, Farris AB, Burd EM, et al. Myosin light chain kinase knockout improves gut barrier function and confers a survival advantage in polymicrobial sepsis. Mol Med. 2017;23:155–65.PubMedPubMedCentralCrossRef
29.
Chen C, Wang P, Su Q, Wang S, Wang F. Myosin light chain kinase mediates intestinal barrier disruption following burn injury. PLoS One. 2012;7(4):e34946.PubMedPubMedCentralCrossRef
30.
Neal MD, Sodhi CP, Jia H, Dyer M, Egan CE, Yazji I, Good M, Afrazi A, Marino R, Slagle D, et al. Toll-like receptor 4 is expressed on intestinal stem cells and regulates their proliferation and apoptosis via the p53 up-regulated modulator of apoptosis. J Biol Chem. 2012;287(44):37296–308.PubMedPubMedCentralCrossRef
31.
Mazmanian SK, Round JL, Kasper DL. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature. 2008;453(7195):620–5.PubMedCrossRef
32.
Neal MD, Sodhi CP, Dyer M, Craig BT, Good M, Jia H, Yazji I, Afrazi A, Richardson WM, Beer-Stolz D, et al. A critical role for TLR4 induction of autophagy in the regulation of enterocyte migration and the pathogenesis of necrotizing enterocolitis. J Immunol. 2013;190(7):3541–51.PubMedCrossRef
33.
Dominguez JA, Vithayathil PJ, Khailova L, Lawrance CP, Samocha AJ, Jung E, Leathersich AM, Dunne WM, Coopersmith CM. Epidermal growth factor improves survival and prevents intestinal injury in a murine model of pseudomonas aeruginosa pneumonia. Shock. 2011;36(4):381–9.PubMedPubMedCentralCrossRef
34.
Yang J, Radulescu A, Chen CL, Zhang HY, James IO, Besner GE. Heparin-binding epidermal growth factor-like growth factor improves intestinal barrier function and reduces mortality in a murine model of peritonitis. Surgery. 2013;153(1):52–62.PubMedCrossRef
35.
Chang M, Alsaigh T, Kistler EB, Schmid-Schonbein GW. Breakdown of mucin as barrier to digestive enzymes in the ischemic rat small intestine. PLoS One. 2012;7(6):e40087.PubMedPubMedCentralCrossRef
36.
Hotchkiss RS, Swanson PE, Freeman BD, Tinsley KW, Cobb JP, Matuschak GM, Buchman TG, Karl IE. Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit Care Med. 1999;27(7):1230–51.PubMedCrossRef
37.
Protzer U, Maini MK, Knolle PA. Living in the liver: hepatic infections. Nat Rev Immunol. 2012;12(3):201–13.PubMedCrossRef
38.
Heymann F, Peusquens J, Ludwig-Portugall I, Kohlhepp M, Ergen C, Niemietz P, Martin C, van Rooijen N, Ochando JC, Randolph GJ, et al. Liver inflammation abrogates immunological tolerance induced by Kupffer cells. Hepatology. 2015;62(1):279–91.PubMedCrossRef
39.
Wong CH, Jenne CN, Petri B, Chrobok NL, Kubes P. Nucleation of platelets with blood-borne pathogens on Kupffer cells precedes other innate immunity and contributes to bacterial clearance. Nat Immunol. 2013;14(8):785–92.PubMedPubMedCentralCrossRef
40.
Rauch PJ, Chudnovskiy A, Robbins CS, Weber GF, Etzrodt M, Hilgendorf I, Tiglao E, Figueiredo JL, Iwamoto Y, Theurl I, et al. Innate response activator B cells protect against microbial sepsis. Science. 2012;335(6068):597–601.PubMedPubMedCentralCrossRef
41.
Soji T, Murata Y, Ohira A, Nishizono H, Tanaka M, Herbert DC. Evidence that hepatocytes can phagocytize exogenous substances. Anat Rec. 1992;233(4):543–6.PubMedCrossRef
42.
Deng M, Scott MJ, Loughran P, Gibson G, Sodhi C, Watkins S, Hackam D, Billiar TR. Lipopolysaccharide clearance, bacterial clearance, and systemic inflammatory responses are regulated by cell type-specific functions of TLR4 during sepsis. J Immunol. 2013;190(10):5152–60.PubMedPubMedCentralCrossRef
43.
Wasmuth HE, Kunz D, Yagmur E, Timmer-Stranghoner A, Vidacek D, Siewert E, Bach J, Geier A, Purucker EA, Gressner AM, et al. Patients with acute on chronic liver failure display “sepsis-like” immune paralysis. J Hepatol. 2005;42(2):195–201.PubMedCrossRef
44.
Singal AK, Salameh H, Kamath PS. Prevalence and in-hospital mortality trends of infections among patients with cirrhosis: a nationwide study of hospitalised patients in the United States. Aliment Pharmacol Ther. 2014;40(1):105–12.PubMedCrossRef
45.
Bajaj JS, O'Leary JG, Reddy KR, Wong F, Olson JC, Subramanian RM, Brown G, Noble NA, Thacker LR, Kamath PS, et al. Second infections independently increase mortality in hospitalized patients with cirrhosis: the North American consortium for the study of end-stage liver disease (NACSELD) experience. Hepatology. 2012;56(6):2328–35.PubMedCrossRef
46.
Giannelli V, Di Gregorio V, Iebba V, Giusto M, Schippa S, Merli M, Thalheimer U. Microbiota and the gut-liver axis: bacterial translocation, inflammation and infection in cirrhosis. World J Gastroenterol. 2014;20(45):16795–810.PubMedPubMedCentralCrossRef
47.
Liu Z, Li N, Fang H, Chen X, Guo Y, Gong S, Niu M, Zhou H, Jiang Y, Chang P, et al. Enteric dysbiosis is associated with sepsis in patients. FASEB J. 2019;33(11):12299–310.PubMedPubMedCentralCrossRef
48.
Bloemen JG, Venema K, van de Poll MC, Olde Damink SW, Buurman WA, Dejong CH. Short chain fatty acids exchange across the gut and liver in humans measured at surgery. Clin Nutr. 2009;28(6):657–61.PubMedCrossRef
49.
Bellot P, Frances R, Such J. Pathological bacterial translocation in cirrhosis: pathophysiology, diagnosis and clinical implications. Liver Int. 2013;33(1):31–9.PubMedCrossRef
50.
Dominguez JA, Coopersmith CM. Can we protect the gut in critical illness? The role of growth factors and other novel approaches. Crit Care Clin. 2010;26(3):549–65 x.PubMedPubMedCentralCrossRef
51.
Islam KB, Fukiya S, Hagio M, Fujii N, Ishizuka S, Ooka T, Ogura Y, Hayashi T, Yokota A. Bile acid is a host factor that regulates the composition of the cecal microbiota in rats. Gastroenterology. 2011;141(5):1773–81.PubMedCrossRef
52.
53.
54.
Kalhan SC, Guo L, Edmison J, Dasarathy S, McCullough AJ, Hanson RW, Milburn M. Plasma metabolomic profile in nonalcoholic fatty liver disease. Metab Clin Exp. 2011;60(3):404–13.PubMedCrossRef
55.
Faubion WA, Guicciardi ME, Miyoshi H, Bronk SF, Roberts PJ, Svingen PA, Kaufmann SH, Gores GJ. Toxic bile salts induce rodent hepatocyte apoptosis via direct activation of Fas. J Clin Invest. 1999;103(1):137–45.PubMedPubMedCentralCrossRef
56.
Copple BL, Li T. Pharmacology of bile acid receptors: evolution of bile acids from simple detergents to complex signaling molecules. Pharmacol Res. 2016;104:9–21.PubMedCrossRef
57.
Schaap FG, Trauner M, Jansen PL. Bile acid receptors as targets for drug development. Nat Rev Gastroenterol Hepatol. 2014;11(1):55–67.PubMedCrossRef
58.
Huang F, Zheng X, Ma X, Jiang R, Zhou W, Zhou S, Zhang Y, Lei S, Wang S, Kuang J, et al. Theabrownin from Pu-erh tea attenuates hypercholesterolemia via modulation of gut microbiota and bile acid metabolism. Nat Commun. 2019;10(1):4971.PubMedPubMedCentralCrossRef
59.
Claudel T, Staels B, Kuipers F. The Farnesoid X receptor: a molecular link between bile acid and lipid and glucose metabolism. Arterioscler Thromb Vasc Biol. 2005;25(10):2020–30.PubMedCrossRef
60.
Thomas C, Gioiello A, Noriega L, Strehle A, Oury J, Rizzo G, Macchiarulo A, Yamamoto H, Mataki C, Pruzanski M, et al. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab. 2009;10(3):167–77.PubMedPubMedCentralCrossRef
61.
Ridlon JM, Kang DJ, Hylemon PB. Bile salt biotransformations by human intestinal bacteria. J Lipid Res. 2006;47(2):241–59.PubMedCrossRef
62.
Lorenzo-Zuniga V, Bartoli R, Planas R, Hofmann AF, Vinado B, Hagey LR, Hernandez JM, Mane J, Alvarez MA, Ausina V, et al. Oral bile acids reduce bacterial overgrowth, bacterial translocation, and endotoxemia in cirrhotic rats. Hepatology. 2003;37(3):551–7.PubMedCrossRef
63.
Mouzaki M, Wang AY, Bandsma R, Comelli EM, Arendt BM, Zhang L, Fung S, Fischer SE, McGilvray IG, Allard JP. Bile acids and dysbiosis in non-alcoholic fatty liver disease. PLoS One. 2016;11(5):e0151829.PubMedPubMedCentralCrossRef
64.
Brandl K, Kumar V, Eckmann L. Gut-liver axis at the frontier of host-microbial interactions. Am J Physiol Gastrointest Liver Physiol. 2017;312(5):G413–9.PubMedPubMedCentralCrossRef
65.
Alaish SM, Smith AD, Timmons J, Greenspon J, Eyvazzadeh D, Murphy E, Shea-Donahue T, Cirimotich S, Mongodin E, Zhao A, et al. Gut microbiota, tight junction protein expression, intestinal resistance, bacterial translocation and mortality following cholestasis depend on the genetic background of the host. Gut Microbes. 2013;4(4):292–305.PubMedPubMedCentralCrossRef
66.
Sender R, Fuchs S, Milo R. Are we really vastly outnumbered? Revisiting the ratio of bacterial to host cells in humans. Cell. 2016;164(3):337–40.PubMedCrossRef
67.
Habes QLM, van Ede L, Gerretsen J, Kox M, Pickkers P. Norepinephrine contributes to enterocyte damage in septic shock patients: a prospective cohort study. Shock. 2018;49(2):137–43.PubMedCrossRef
68.
Defazio J, Fleming ID, Shakhsheer B, Zaborina O, Alverdy JC. The opposing forces of the intestinal microbiome and the emerging pathobiome. Surg Clin North Am. 2014;94(6):1151–61.PubMedPubMedCentralCrossRef
69.
70.
Thomson AW, Knolle PA. Antigen-presenting cell function in the tolerogenic liver environment. Nat Rev Immunol. 2010;10(11):753–66.PubMedCrossRef
71.
Ashare A, Monick MM, Powers LS, Yarovinsky T, Hunninghake GW. Severe bacteremia results in a loss of hepatic bacterial clearance. Am J Respir Crit Care Med. 2006;173(6):644–52.PubMedPubMedCentralCrossRef
72.
Arroyo V, Moreau R, Jalan R, Gines P, Study E-CCC. Acute-on-chronic liver failure: a new syndrome that will re-classify cirrhosis. J Hepatol. 2015;62(1 Suppl):S131–43.PubMedCrossRef
73.
Bode JG, Albrecht U, Haussinger D, Heinrich PC, Schaper F. Hepatic acute phase proteins--regulation by IL-6- and IL-1-type cytokines involving STAT3 and its crosstalk with NF-kappaB-dependent signaling. Eur J Cell Biol. 2012;91(6–7):496–505.PubMedCrossRef
74.
Shah C, Hari-Dass R, Raynes JG. Serum amyloid A is an innate immune opsonin for Gram-negative bacteria. Blood. 2006;108(5):1751–7.PubMedCrossRef
75.
Medzhitov R. Recognition of microorganisms and activation of the immune response. Nature. 2007;449(7164):819–26.PubMedCrossRef
76.
77.
Wan J, Benkdane M, Teixeira-Clerc F, Bonnafous S, Louvet A, Lafdil F, Pecker F, Tran A, Gual P, Mallat A, et al. M2 Kupffer cells promote M1 Kupffer cell apoptosis: a protective mechanism against alcoholic and nonalcoholic fatty liver disease. Hepatology. 2014;59(1):130–42.PubMedCrossRef
78.
Kang JW, Lee SM. Resolvin D1 protects the liver from ischemia/reperfusion injury by enhancing M2 macrophage polarization and efferocytosis. Biochim Biophys Acta. 2016;1861(9 Pt A):1025–35.PubMedCrossRef
79.
Xie J, Wu X, Zhou Q, Yang Y, Tian Y, Huang C, Meng X, Li J. PICK1 confers anti-inflammatory effects in acute liver injury via suppressing M1 macrophage polarization. Biochimie. 2016;127:121–32.PubMedCrossRef
80.
Kamada N, Seo SU, Chen GY, Nunez G. Role of the gut microbiota in immunity and inflammatory disease. Nat Rev Immunol. 2013;13(5):321–35.PubMedCrossRef
81.
Fu Y, Moscoso DI, Porter J, Krishnareddy S, Abrams JA, Seres D, Chong DH, Freedberg DE. Relationship between dietary fiber intake and short-chain fatty acid-producing bacteria during critical illness: a prospective cohort study. JPEN J Parenter Enteral Nutr. 2020;44(3):463–71.PubMedCrossRef
82.
Baggs J, Jernigan JA, Halpin AL, Epstein L, Hatfield KM, McDonald LC. Risk of subsequent sepsis within 90 days after a hospital stay by type of antibiotic exposure. Clin Infect Dis. 2018;66(7):1004–12.PubMedCrossRef
83.
DeFilipp Z, Bloom PP, Torres Soto M, Mansour MK, Sater MRA, Huntley MH, Turbett S, Chung RT, Chen YB, Hohmann EL. Drug-resistant E. coli bacteremia transmitted by fecal microbiota transplant. N Engl J Med. 2019;381(21):2043–50.PubMedCrossRef
84.
Manzanares W, Lemieux M, Langlois PL, Wischmeyer PE. Probiotic and synbiotic therapy in critical illness: a systematic review and meta-analysis. Crit Care. 2016;19:262.PubMedCrossRef
85.
Li Q, Wang C, Tang C, He Q, Zhao X, Li N, Li J. Successful treatment of severe sepsis and diarrhea after vagotomy utilizing fecal microbiota transplantation: a case report. Crit Care. 2015;19:37.PubMedPubMedCentralCrossRef
86.
Li Q, Wang C, Tang C, He Q, Zhao X, Li N, Li J. Therapeutic modulation and reestablishment of the intestinal microbiota with fecal microbiota transplantation resolves sepsis and diarrhea in a patient. Am J Gastroenterol. 2014;109(11):1832–4.PubMedCrossRef
87.
Wei Y, Yang J, Wang J, Yang Y, Huang J, Gong H, Cui H, Chen D. Successful treatment with fecal microbiota transplantation in patients with multiple organ dysfunction syndrome and diarrhea following severe sepsis. Crit Care. 2016;20(1):332.PubMedPubMedCentralCrossRef
Metadata
Title
Gut-liver crosstalk in sepsis-induced liver injury
Authors
Jian Sun
Jingxiao Zhang
Xiangfeng Wang
Fuxi Ji
Claudio Ronco
Jiakun Tian
Yongjie Yin
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Critical Care / Issue 1/2020
Electronic ISSN: 1364-8535
DOI
https://doi.org/10.1186/s13054-020-03327-1

Other articles of this Issue 1/2020

Critical Care 1/2020 Go to the issue

Letter

New-onset atrial fibrillation can be falsely associated with increased length of stay in ICU due to immortal time bias

Editorial

Coronavirus: just imagine…

Commentary

Interferon beta-1a for COVID-19: critical importance of the administration route

Research

Nasal high flow higher than 60 L/min in patients with acute hypoxemic respiratory failure: a physiological study

Letter

Risk of harlequin syndrome during bi-femoral peripheral VA-ECMO: should we pay more attention to the watershed or try to change the venous cannulation site?

Viewpoint

Admission decisions to intensive care units in the context of the major COVID-19 outbreak: local guidance from the COVID-19 Paris-region area