Intrahepatic microbes govern liver immunity by programming NKT cells

Area of Science:

• Immunology
• Microbiology
• Hepatology

Background:

• The liver has traditionally been considered a sterile organ.
• The gut microbiome's role in systemic immunity is well-established, but the liver's microbial composition remains unexamined.
• Understanding the liver's microbial environment is crucial for comprehending hepatic immunity.

Purpose of the Study:

• To investigate the existence and characteristics of a hepatic microbiome in mice and humans.
• To determine the relationship between the liver microbiome and hepatic immunity.
• To elucidate the mechanisms by which the liver microbiome influences immune responses.

Main Methods:

• Comparative analysis of liver and gut microbiome composition in mice and humans.
• Fecal microbial transfer experiments to assess microbiome seeding.
• Antibiotic targeting of specific bacterial species (Bacteroidetes) to evaluate immune effects.
• Analysis of immune cell populations, antigen-presenting cell (APC) maturation, and adaptive immunity markers.
• Investigation of molecular pathways involving glycosphingolipids, NKT cells, and CCL5 signaling.

Main Results:

• A distinct liver microbiome was identified, differing from the gut microbiome and enriched in Proteobacteria.
• The liver microbiome composition changes with age and is influenced by environmental and host factors.
• Fecal microbial transfer demonstrated selective colonization of the liver from the gut.
• Targeting Bacteroidetes with antibiotics significantly reduced hepatic immune cells, impaired APC maturation, and diminished adaptive immunity.
• A microbial/glycosphingolipid/NKT/CCL5 axis was identified as a key regulator of hepatic immunity.

Conclusions:

• The liver harbors a unique microbiome that plays a critical role in regulating hepatic immunity.
• Hepatic immunity is dependent on specific gut-derived bacteria, particularly Bacteroidetes.
• The findings reveal a novel axis involving microbial components, immune cells, and signaling pathways that govern liver immune responses.