title: Age-related immune clearance of hepatitis B virus infection requires the establishment of gut microbiota.
abstract: A unique feature of hepatitis B virus (HBV) infection in humans is that viral clearance heavily depends on the age of exposure. However, the reason for this remains unclear. Here we show that gut microbiota contribute to the age dependence of HBV immunity in a hydrodynamic transfection mouse model. Although adult (12-wk-old) C3H/HeN mice cleared HBV within 6 wk postinjection (wpi), their young (6-wk-old) counterparts remained HBV-positive at 26 wpi. Sterilization of gut microbiota from 6 to 12 wk of age using antibiotics prevented adult mice from rapidly clearing HBV. Young mice with the Toll-like-receptor (TLR) 4 mutation (C3H/HeJ) exhibited rapid HBV clearance. The results suggest that an immuno-tolerating pathway to HBV prevailed in young mice, before the establishment of gut bacteria, through a TLR4-dependent pathway and that the maturation of gut microbiota in adult mice stimulated liver immunity, resulting in rapid HBV clearance.
authors: Department of Microbiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan;
authors: Han-Hsuan
authors: HH
authors: Chou
authors: Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan; Department of Medical Education, Chung-Shan Medical University Hospital and School of Medicine, Chung-Shan Medical University, Taichung 402, Taiwan;
authors: Wei-Hung
authors: WH
authors: Chien
authors: Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan;
authors: Li-Ling
authors: LL
authors: Wu
authors: Department of Microbiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan;
authors: Chi-Hung
authors: CH
authors: Cheng
authors: Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan;
authors: Chen-Han
authors: CH
authors: Chung
authors: Department of Microbiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan;
authors: Jau-Haw
authors: JH
authors: Horng
authors: Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University, Taipei 100, Taiwan;
authors: Yen-Hsuan
authors: YH
authors: Ni
authors: Department of Immunology, College of Medicine, National Taiwan University, Taipei 100, Taiwan;
authors: Hong-Tai
authors: HT
authors: Tseng
authors: Laboratory of Disease Genomics and Individualized Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China;
authors: Dafei
authors: D
authors: Wu
authors: Laboratory of Disease Genomics and Individualized Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China;
authors: Xuemei
authors: X
authors: Lu
authors: Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan; Institute of Ecology and Evolution, National Taiwan University, Taipei 106, Taiwan; Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei 100, Taiwan; and chends@ntu.edu.tw hurngyi@ntu.edu.tw.
authors: Hurng-Yi
authors: HY
authors: Wang
authors: Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan;
authors: Pei-Jer
authors: PJ
authors: Chen
authors: Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan; Genomics Research Center, Academia Sinica, Taipei 115, Taiwan chends@ntu.edu.tw hurngyi@ntu.edu.tw.
authors: Ding-Shinn
authors: DS
authors: Chen
mesh_terms: D000818:Animals; D006509:Hepatitis B / Q000276:immunology*; D006801:Humans; D007422:Intestines / Q000382:microbiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D064307:Microbiota
keywords: Kupffer cells; Toll-like 4 receptor; chronic hepatitis B; liver tolerance; temporal-temperature gel electrophoresis
references: J Hepatol. 1995 Feb;22(2):226-9
references: 7790711
references: N Engl J Med. 1995 Apr 20;332(16):1065-9
references: 7898524
references: Clin Exp Immunol. 1998 Dec;114(3):427-33
references: 9844054
references: Hepatology. 2005 Jun;41(6):1383-90
references: 15915462
references: Hepatology. 2005 Jul;42(1):193-9
references: 15962311
references: Proc Natl Acad Sci U S A. 2006 Nov 21;103(47):17862-7
references: 17095599
references: Nat Genet. 2009 May;41(5):591-5
references: 19349983
references: Hepatology. 2009 May;49(5 Suppl):S13-21
references: 19399811
references: Infect Immun. 2009 Jul;77(7):2741-53
references: 19380465
references: Cell. 2009 Oct 30;139(3):485-98
references: 19836068
references: PLoS One. 2010;5(2):e9085
references: 20140211
references: Hum Mol Genet. 2011 Oct 1;20(19):3884-92
references: 21750111
references: Semin Immunol. 2012 Feb;24(1):58-66
references: 22178452
references: Annu Rev Immunol. 2012;30:271-94
references: 22224770
references: Am J Pathol. 2013 Jan;182(1):180-91
references: 23159949
references: Nat Immunol. 2013 Jun;14(6):574-83
references: 23584070
references: Nat Immunol. 2013 Jul;14(7):646-53
references: 23778791
references: Nature. 2013 Jul 4;499(7456):97-101
references: 23803760
references: J Clin Invest. 2013 Sep;123(9):3728-39
references: 23925290
references: Antivir Ther. 2013;18(8):953-4
references: 23756458
references: Hepatology. 2014 Feb;59(2):443-52
references: 23929689
references: J Clin Invest. 1995 Jul;96(1):447-55
references: 7615817
references: Nat Med. 2000 Dec;6(12):1348-54
references: 11100119
references: J Microbiol Methods. 2001 Apr;44(3):253-62
references: 11240048
references: Antiviral Res. 2001 Nov;52(2):113-6
references: 11672820
references: Am J Gastroenterol. 2003 Jan;98(1):144-50
references: 12526950
references: N Engl J Med. 2004 Mar 11;350(11):1118-29
references: 15014185
references: Immunol Lett. 2004 May 15;93(2-3):199-204
references: 15158617
references: Cell. 2004 Jul 23;118(2):229-41
references: 15260992
references: J Virol. 2004 Oct;78(20):11258-62
references: 15452244
references: Anticancer Res. 1989 May-Jun;9(3):737-41
references: 2764519
references: Proc Natl Acad Sci U S A. 1990 Sep;87(17):6599-603
references: 2395863
references: Science. 1993 Oct 15;262(5132):369-70
references: 8211155
references: J Immunother Emphasis Tumor Immunol. 1993 Oct;14(3):226-33
references: 8297904