Retracted and Republished from: “Gut Microbiota Mediates the Therapeutic Effect of Monoclonal Anti-TLR4 Antibody on Acetaminophen-Induced Acute Liver Injury in Mice”

In this study, we found that a monoclonal anti-Toll-like receptor 4 antibody can alleviate APAP-induced acute liver injury through changes in the gut microbiota, metabolic pathways, and gut barrier function. This work suggested that the gut microbiota can be a therapeutic target of APAP-induced acute liver injury, and we performed foundation for further research. ABSTRACT Acetaminophen (APAP) overdose is one of the most common causes of acute liver injury (ALI) in Western countries. Many studies have shown that the gut microbiota plays an important role in liver injury. Currently, the only approved treatment for APAP-induced ALI is N-acetylcysteine; therefore, it is essential to develop new therapeutic agents and explore the underlying mechanisms. We developed a novel monoclonal anti-Toll-like receptor 4 (TLR4) antibody (ATAB) and hypothesized that it has therapeutic effects on APAP-induced ALI and that the gut microbiota may be involved in the underlying mechanism of ATAB treatment. Male C57BL/6 mice were treated with APAP and ATAB, which produced a therapeutic effect on ALI and altered the members of the gut microbiota and their metabolic pathways, such as Roseburia, Lactobacillus, Akkermansia, and the fatty acid pathway, etc. Furthermore, we verified that purified short-chain fatty acids (SCFAs) could alleviate ALI. Moreover, a separate group of mice that received feces from the ATAB group showed less severe liver injury than mice that received feces from the APAP group. ATAB therapy also improved gut barrier functions in mice and reduced the expression of the protein zonulin. Our results revealed that the gut microbiota plays an important role in the therapeutic effect of ATAB on APAP-induced ALI. IMPORTANCE In this study, we found that a monoclonal anti-Toll-like receptor 4 antibody can alleviate APAP-induced acute liver injury through changes in the gut microbiota, metabolic pathways, and gut barrier function. This work suggested that the gut microbiota can be a therapeutic target of APAP-induced acute liver injury, and we performed foundation for further research.

[1]  Yiwen Wang,et al.  Anti-TLR4 IgG2 prevents acetaminophen-induced acute liver injury through the Toll-like receptor 4/MAPKs signaling pathway in mice. , 2022, Current molecular medicine.

[2]  Lanjuan Li,et al.  Akkermansia muciniphila Ameliorates Acetaminophen-Induced Liver Injury by Regulating Gut Microbial Composition and Metabolism , 2022, Microbiology spectrum.

[3]  M. Davari,et al.  The Protective Effects of Live and Pasteurized Akkermansia muciniphila and Its Extracellular Vesicles against HFD/CCl4-Induced Liver Injury , 2021, Microbiology spectrum.

[4]  A. Devlin,et al.  Chains of evidence from correlations to causal molecules in microbiome-linked diseases , 2021, Nature Chemical Biology.

[5]  A. Vella,et al.  What to do about the leaky gut , 2021, Gut.

[6]  N. Everaert,et al.  Intestinal dysbiosis in nonalcoholic fatty liver disease (NAFLD): focusing on the gut–liver axis , 2021, Critical reviews in food science and nutrition.

[7]  L. Lv,et al.  Lactobacillus acidophilus LA14 Alleviates Liver Injury , 2021, mSystems.

[8]  Jun Ren,et al.  Deletion of TLR4 attenuates lipopolysaccharide-induced acute liver injury by inhibiting inflammation and apoptosis , 2021, Acta Pharmacologica Sinica.

[9]  F. Bäckhed,et al.  Gut microbial metabolites as multi-kingdom intermediates , 2020, Nature reviews. Microbiology.

[10]  Xuhui Zhu,et al.  Human monoclonal anti-TLR4 antibody negatively regulates lipopolysaccharide-induced inflammatory responses in mouse macrophages , 2020, Molecular medicine reports.

[11]  A. Grakoui,et al.  Contribution of the Intestinal Microbiome and Gut Barrier to Hepatic Disorders. , 2020, Gastroenterology.

[12]  Jifeng Yu,et al.  How to select IgG subclasses in developing anti-tumor therapeutic antibodies , 2020, Journal of Hematology & Oncology.

[13]  N. Sandhu,et al.  Drug‐Induced Liver Injury in GI Practice , 2020, Hepatology communications.

[14]  A. de Gottardi,et al.  The gut-liver axis in liver disease: pathophysiological basis for therapy. , 2020, Journal of hepatology.

[15]  Juan F Burgueño,et al.  Epithelial Toll-like receptors and their role in gut homeostasis and disease , 2020, Nature Reviews Gastroenterology & Hepatology.

[16]  C. Trautwein,et al.  Intestinal Dysbiosis Amplifies Acetaminophen-Induced Acute Liver Injury , 2020, Zeitschrift für Gastroenterologie.

[17]  J. Sung,et al.  Roseburia Spp. Abundance Associates with Alcohol Consumption in Humans and Its Administration Ameliorates Alcoholic Fatty Liver in Mice. , 2019, Cell host & microbe.

[18]  T. J. Fang,et al.  Protective effects of Lactobacillus plantarum against chronic alcohol-induced liver injury in the murine model , 2019, Applied Microbiology and Biotechnology.

[19]  Byung-Hoon Lee,et al.  Hepatic upregulation of fetuin-A mediates acetaminophen-induced liver injury through activation of TLR4 in mice. , 2019, Biochemical pharmacology.

[20]  T. Karlsen,et al.  EASL Clinical Practice Guidelines: Drug-induced liver injury. , 2019, Journal of hepatology.

[21]  Guan-Jhong Huang,et al.  Salvianolic Acid C against Acetaminophen-Induced Acute Liver Injury by Attenuating Inflammation, Oxidative Stress, and Apoptosis through Inhibition of the Keap1/Nrf2/HO-1 Signaling , 2019, Oxidative medicine and cellular longevity.

[22]  Jian Li,et al.  Lactobacillus rhamnosus GG Ameliorates Liver Injury and Hypoxic Hepatitis in Rat Model of CLP-Induced Sepsis , 2019, Digestive Diseases and Sciences.

[23]  H. Jaeschke,et al.  Acetaminophen Hepatotoxicity , 2019, Seminars in Liver Disease.

[24]  Y. Iwakura,et al.  Macrophage-derived IL-1α promotes sterile inflammation in a mouse model of acetaminophen hepatotoxicity , 2018, Cellular & Molecular Immunology.

[25]  N. Kaplowitz,et al.  Gut microbiota mediates diurnal variation of acetaminophen induced acute liver injury in mice. , 2018, Journal of hepatology.

[26]  A. Hauschild,et al.  PD‐1 Blockade with Cemiplimab in Advanced Cutaneous Squamous‐Cell Carcinoma , 2018, The New England journal of medicine.

[27]  Hongbo Hu,et al.  Mechanisms of acetaminophen-induced liver injury and its implications for therapeutic interventions , 2018, Redox biology.

[28]  Shelly C. Lu,et al.  The mitochondrial negative regulator MCJ is a therapeutic target for acetaminophen-induced liver injury , 2017, Nature Communications.

[29]  P. Nighot,et al.  Lipopolysaccharide-Induced Increase in Intestinal Epithelial Tight Permeability Is Mediated by Toll-Like Receptor 4/Myeloid Differentiation Primary Response 88 (MyD88) Activation of Myosin Light Chain Kinase Expression. , 2017, The American journal of pathology.

[30]  P. Sansonetti,et al.  Lipopolysaccharide from Crypt-Specific Core Microbiota Modulates the Colonic Epithelial Proliferation-to-Differentiation Balance , 2017, mBio.

[31]  Y. Iwakura,et al.  Macrophage-derived IL-1α promotes sterile inflammation in a mouse model of acetaminophen hepatotoxicity , 2017, Cellular & Molecular Immunology.

[32]  H. Jaeschke,et al.  Oxidative stress during acetaminophen hepatotoxicity: Sources, pathophysiological role and therapeutic potential , 2016, Redox biology.

[33]  M. Kutner,et al.  Acetaminophen-Induced Hepatotoxicity: a Comprehensive Update , 2016, Journal of clinical and translational hepatology.

[34]  F. Bäckhed,et al.  From Dietary Fiber to Host Physiology: Short-Chain Fatty Acids as Key Bacterial Metabolites , 2016, Cell.

[35]  Jessica K. Lang,et al.  Intestinal Epithelial Toll-Like Receptor 4 Signaling Affects Epithelial Function and Colonic Microbiota and Promotes a Risk for Transmissible Colitis , 2016, Infection and Immunity.

[36]  F. Tacke,et al.  CX3CR1 is a gatekeeper for intestinal barrier integrity in mice: Limiting steatohepatitis by maintaining intestinal homeostasis , 2015, Hepatology.

[37]  D. McDermott,et al.  Nivolumab for the treatment of cancer , 2015, Expert opinion on investigational drugs.

[38]  F. Tacke,et al.  Immune mechanisms in acetaminophen-induced acute liver failure. , 2014, Hepatobiliary surgery and nutrition.

[39]  Harry J. Flint,et al.  The gut microbiota, bacterial metabolites and colorectal cancer , 2014, Nature Reviews Microbiology.

[40]  R. Wilkinson,et al.  The role of Fc gamma receptors in the activity of immunomodulatory antibodies for cancer , 2014, Journal of Immunotherapy for Cancer.

[41]  J. Tenhunen,et al.  HMGB1 neutralization is associated with bacterial translocation during acetaminophen hepatotoxicity , 2014, BMC Gastroenterology.

[42]  A. Mamalis,et al.  Targeting the PD-1 pathway: a promising future for the treatment of melanoma , 2014, Archives of Dermatological Research.

[43]  R. Jalan,et al.  Role of Toll‐Like Receptor 4 in Mediating Multiorgan Dysfunction in Mice With Acetaminophen Induced Acute Liver Failure , 2013, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[44]  S. Nyberg,et al.  Role of Kupffer cells and toll-like receptor 4 in acetaminophen-induced acute liver failure. , 2013, The Journal of surgical research.

[45]  H. Said,et al.  Lipopolysaccharide causes an increase in intestinal tight junction permeability in vitro and in vivo by inducing enterocyte membrane expression and localization of TLR-4 and CD14. , 2013, The American journal of pathology.

[46]  Charlotte E. Egan,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* , 2012, The Journal of Biological Chemistry.

[47]  Derrick E Fouts,et al.  Bacterial translocation and changes in the intestinal microbiome in mouse models of liver disease. , 2012, Journal of hepatology.

[48]  E. Seki,et al.  Role of innate immunity and the microbiota in liver fibrosis: crosstalk between the liver and gut , 2012, The Journal of physiology.

[49]  S. Akira,et al.  Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. , 2011, Immunity.

[50]  M. Introna,et al.  Mechanism of Action of Type II, Glycoengineered, Anti-CD20 Monoclonal Antibody GA101 in B-Chronic Lymphocytic Leukemia Whole Blood Assays in Comparison with Rituximab and Alemtuzumab , 2011, The Journal of Immunology.

[51]  Manolito Torralba,et al.  Enteric dysbiosis associated with a mouse model of alcoholic liver disease , 2011, Hepatology.

[52]  C. Mayer,et al.  Whole-Genome Transcription Profiling Reveals Genes Up-Regulated by Growth on Fucose in the Human Gut Bacterium “Roseburia inulinivorans” , 2006, Journal of bacteriology.

[53]  Ruslan Medzhitov,et al.  Recognition of Commensal Microflora by Toll-Like Receptors Is Required for Intestinal Homeostasis , 2004, Cell.

[54]  R. Medzhitov,et al.  Innate immune recognition: mechanisms and pathways , 2000, Immunological reviews.

[55]  Jeffrey S. Miller,et al.  Natural killer cell cytotoxicity of breast cancer targets is enhanced by two distinct mechanisms of antibody-dependent cellular cytotoxicity against LFA-3 and HER2/neu. , 1999, Experimental hematology.

[56]  G. Macfarlane,et al.  Bacteria, colonic fermentation, and gastrointestinal health. , 2012, Journal of AOAC International.

[57]  Thomas S. Lin,et al.  FCGR3A and FCGR2A polymorphisms may not correlate with response to alemtuzumab in chronic lymphocytic leukemia. , 2005, Blood.

[58]  P. Schur.  IgG subclasses. A historical perspective. , 1988, Monographs in allergy.