title: Oral ampicillin inhibits liver regeneration by breaking hepatic innate immune tolerance normally maintained by gut commensal bacteria.
abstract: Commensal bacteria have been proposed to play a role in liver repair after partial (67%) hepatectomy. However, the underlying immune mechanisms remain elusive. Here, we show that liver regeneration was impaired in antibiotic (Atb) water-treated mice and this impairment strongly correlated with commensal bacterial load. Among the various Atbs used in our cocktail, ampicillin-sensitive commensal bacterial was associated with normal liver regeneration. The number of CD1d-dependent natural killer T (NKT) cells in Atb-treated hepatectomized mice was markedly increased, and these NKT cells were functionally overactivated to produce higher interferon-γ. Deficiency of NKT cells or antibody blockade of the CD1d-NKT interaction increased hepatocyte proliferation, which improved liver regeneration. Importantly, an increased number of Kupffer cells were observed in Atb-treated mice, and these Kupffer cells produced higher interleukin-12, which then functioned to activate hepatic NKT cells. Interleukin-12p40 deficiency or treatment with an anti-interleukin-12 antibody significantly inhibited NKT cell overactivation and recovered liver regeneration in Atb-treated mice.
  
  
  CONCLUSIONS
  Commensal bacteria play a critical role in maintaining Kupffer cells in a tolerant state, preventing subsequent NKT cell overactivation during liver regeneration. Moreover, our data suggest that long-term Atb use, which can impair the gut microbiota, may influence liver function by retarding liver regeneration.
authors.affiliation: Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui, China.
authors.forename: Xunyao
authors.initials: X
authors.lastname: Wu
authors.affiliation: Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui, China.|Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Sun
authors.affiliation: Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui, China.
authors.forename: Yongyan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui, China.|Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui, China.
authors.forename: Li
authors.initials: L
authors.lastname: Bai
authors.affiliation: Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui, China.|Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui, China.
authors.forename: Zhexiong
authors.initials: Z
authors.lastname: Lian
authors.affiliation: Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui, China.|Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui, China.
authors.forename: Haiming
authors.initials: H
authors.lastname: Wei
authors.affiliation: Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui, China.|Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui, China.|Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Tian
mesh_terms: D000667:Ampicillin / Q000009:adverse effects*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000009:adverse effects*; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000276:immunology / Q000382:microbiology*; D007108:Immune Tolerance / Q000187:drug effects*; D007113:Immunity, Innate / Q000187:drug effects; D007728:Kupffer Cells / Q000187:drug effects; D008115:Liver Regeneration / Q000187:drug effects* / Q000276:immunology; D008297:Male; D008810:Mice, Inbred C57BL; D064307:Microbiota / Q000187:drug effects / Q000276:immunology; D055611:Natural Killer T-Cells / Q000187:drug effects; D013559:Symbiosis / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D000667:Ampicillin