Gut-liver axis at the frontier of host-microbial interactions

Abstract

Liver and intestine are tightly linked through the venous system of the portal circulation. Consequently, the liver is the primary recipient of gut-derived products, most prominently dietary nutrients and microbial components. It functions as a secondary "firewall" and protects the body from intestinal pathogens and other microbial products that have crossed the primary barrier of the intestinal tract. Disruption of the intestinal barrier enhances microbial exposure of the liver, which can have detrimental or beneficial effects in the organ depending on the specific circumstances. Conversely, the liver also exerts influence over intestinal microbial communities via secretion of bile acids and IgA antibodies. This mini-review highlights key findings and concepts in the area of host-microbial interactions as pertinent to the bilateral communication between liver and gut and highlights the concept of the gut-liver axis.

Fig. 1.

Importance of intestinal barrier in preventing liver exposure to intestinal microbes and their products. The intestinal epithelium serves as a physical and functional barrier that protects the liver from exposure to intestinal bacteria and their products. Multiple mechanisms are involved in protection, including a thick mucus layer (e.g., Muc-2), antimicrobial molecules (e.g., Reg3b) and tight junction molecules (e.g., JAM-A). These protective mechanisms can be compromised by dietary factors, injurious agents, and endogenous factors such as TNF or endocannabinoids. As a consequence, intestinal bacteria and their products can translocate into the portal vein and reach the liver.

Fig. 2.

Beneficial and detrimental effects of bacterial products on liver function. Bacterial products reaching the liver can have beneficial or detrimental functions depending on the physiological circumstances. Stimulation of Kupffer and other liver cells via TLR-Myd88 leads to production of proinflammatory cytokines and chemokines, resulting in the recruitment of inflammatory cells and injury and death of hepatocytes. MyD88-dependent mechanisms can also alter the bile acid (BA) profile and together with other factors (e.g., IgA) modulate microbial composition in the intestine. Cytokines (e.g., IL-6) released by bacterially stimulated Kupffer cells activate cytoprotective mechanisms and promote liver regeneration.