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Proc Natl Acad Sci U S A. 2015 Feb 17;112(7):2175-80. doi: 10.1073/pnas.1424775112. Epub 2015 Feb 2.

Age-related immune clearance of hepatitis B virus infection requires the establishment of gut microbiota.

Author information

1
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;
2
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;
3
Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan;
4
Department of Microbiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan;
5
Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University, Taipei 100, Taiwan;
6
Department of Immunology, College of Medicine, National Taiwan University, Taipei 100, Taiwan;
7
Laboratory of Disease Genomics and Individualized Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China;
8
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.
9
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.

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.

KEYWORDS:

Kupffer cells; Toll-like 4 receptor; chronic hepatitis B; liver tolerance; temporal-temperature gel electrophoresis

Comment in

PMID:
25646429
PMCID:
PMC4343154
DOI:
10.1073/pnas.1424775112
[Indexed for MEDLINE]
Free PMC Article

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