@article{798b7f6e29fb454bb5bbb1a8b94dcc20,
title = "Intrahepatic microbes govern liver immunity by programming NKT cells",
abstract = "The gut microbiome shapes local and systemic immunity. The liver is presumed to be a protected sterile site. As such, a hepatic microbiome has not been examined. Here, we showed a liver microbiome in mice and humans that is distinct from that of the gut and is enriched in Proteobacteria. It undergoes dynamic alterations with age and is influenced by the environment and host physiology. Fecal microbial transfer experiments revealed that the liver microbiome is populated from the gut in a highly selective manner. Hepatic immunity is dependent on the microbiome, specifically the bacteroidetes species. Targeting bacteroidetes with oral antibiotics reduced hepatic immune cells by approximately 90%, prevented antigen-presenting cell (APC) maturation, and mitigated adaptive immunity. Mechanistically, our findings are consistent with presentation of bacteroidetes-derived glycosphingolipids to NKT cells promoting CCL5 signaling, which drives hepatic leukocyte expansion and activation, among other possible host-microbe interactions. Collectively, we reveal a microbial/glycosphingolipid/NKT/CCL5 axis that underlies hepatic immunity.",
author = "Leinwand, {Joshua C.} and Bidisha Paul and Ruonan Chen and Fangxi Xu and Sierra, {Maria A.} and Paluru, {Madan M.} and Sumant Nanduri and Alcantara, {Carolina G.} and Shadaloey, {Sorin A.A.} and Fan Yang and Adam, {Salma A.} and Qianhao Li and Michelle Bandel and Inderdeep Gakhal and Lara Appiah and Yuqi Guo and Mridula Vardhan and Zia Flaminio and Grodman, {Emilie R.} and Ari Mermelstein and Wei Wang and Brian Diskin and Berk Aykut and Mohammad Khan and Gregor Werba and Smruti Pushalkar and Mia McKinstry and Zachary Kluger and Park, {Jaimie J.} and Brandon Hsieh and Kristen Dancel-Mannin and Liang, {Feng Xia} and Park, {James S.} and Anjana Saxena and Xin Li and Theise, {Neil D.} and Deepak Saxena and George Miller",
note = "Funding Information: This work was supported by the Americas Hepato-Pancreato-Biliary Association Research Fellowship (to JCL) and NIH grants CA168611, CA203105, CA215471, CA19311, and DK106025 (all to GM). We thank the NYU Langone Health Genome Technology Center (GTC) for expert library preparation and sequencing, the Experimental Pathology (ExpPath) Laboratory for expert tissue processing and equipment support, and the Microscopy Laboratory (Micros) for consultation and assistance with TEM work. Mouse liver tissue was prepared and provided by David Levy and Daniel Gough (NYUGSM), with support from the NIH (R01AI28900). GTC, ExpPath, and Micros are partially supported by Cancer Center support grant P30CA016087 at the Laura and Isaac Perlmutter Cancer Center. Publisher Copyright: {\textcopyright} 2022, Leinwand et al.",
year = "2022",
month = apr,
day = "15",
doi = "10.1172/JCI151725",
language = "English (US)",
volume = "132",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "8",
}