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.
Conclusion: 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.
© 2015 by the American Association for the Study of Liver Diseases.