The Liver May Act as a Firewall Mediating Mutualism Between the Host and Its Gut Commensal Microbiota

The liver forms a firewall that protects against vascular-borne gut microbes and is commonly impaired in liver disease. Breaching Barriers Premature death from chronic liver disease is a rising global trend. Opportunistic bacterial infections caused by beneficial microbes that have breached the gut and its immune barrier often lead to death in liver cirrhosis patients. Balmer et al. now show that the liver forms a second vascular barrier for eliminating commensal bacteria that have escaped from the gut. In animal models of liver disease and gut dysfunction and in patients with nonalcoholic steatohepatitis, the liver is unable to capture escaped gut commensal bacteria, which then leak into the systemic circulation, resulting in a robust host nonmucosal immune response and the breakdown of mutualism between the host and its gut microbiota. Mutualism breakdown is an important complication of liver disease. A prerequisite for establishment of mutualism between the host and the microbial community that inhabits the large intestine is the stringent mucosal compartmentalization of microorganisms. Microbe-loaded dendritic cells trafficking through lymphatics are arrested at the mesenteric lymph nodes, which constitute the firewall of the intestinal lymphatic circulation. We show in different mouse models that the liver, which receives the intestinal venous blood circulation, forms a vascular firewall that captures gut commensal bacteria entering the bloodstream during intestinal pathology. Phagocytic Kupffer cells in the liver of mice clear commensals from the systemic vasculature independently of the spleen through the liver’s own arterial supply. Damage to the liver firewall in mice impairs functional clearance of commensals from blood, despite heightened innate immunity, resulting in spontaneous priming of nonmucosal immune responses through increased systemic exposure to gut commensals. Systemic immune responses consistent with increased extraintestinal commensal exposure were found in humans with liver disease (nonalcoholic steatohepatitis). The liver may act as a functional vascular firewall that clears commensals that have penetrated either intestinal or systemic vascular circuits.