The gut-liver axis in sepsis: interaction mechanisms and therapeutic potential

Abstract

Sepsis is a potentially fatal condition caused by dysregulation of the body's immune response to an infection. Sepsis-induced liver injury is considered a strong independent prognosticator of death in the critical care unit, and there is anatomic and accumulating epidemiologic evidence that demonstrates intimate cross talk between the gut and the liver. Intestinal barrier disruption and gut microbiota dysbiosis during sepsis result in translocation of intestinal pathogen-associated molecular patterns and damage-associated molecular patterns into the liver and systemic circulation. The liver is essential for regulating immune defense during systemic infections via mechanisms such as bacterial clearance, lipopolysaccharide detoxification, cytokine and acute-phase protein release, and inflammation metabolic regulation. When an inappropriate immune response or overwhelming inflammation occurs in the liver, the impaired capacity for pathogen clearance and hepatic metabolic disturbance can result in further impairment of the intestinal barrier and increased disruption of the composition and diversity of the gut microbiota. Therefore, interaction between the gut and liver is a potential therapeutic target. This review outlines the intimate gut-liver cross talk (gut-liver axis) in sepsis.

Fig. 1

During sepsis, several mechanisms contribute to disruption of the gut barrier, including IEC apoptosis, alteration of the mucus layer, and disruption of intercellular junctions, resulting in translocation of intestinal PAMPs into the liver via the lymphatic vessels, portal circulation, or biliary tract. The liver is essential to the regulation of immune defense, with effector cells such as LSECs, macrophages, stellate cells, and hepatocytes immediately identifying and engaging pathogens, clearing bacteria, and releasing cytokines. When an inappropriate immune response or overwhelming inflammation occurs with high levels of DAMPs and proinflammatory cytokine production in the liver, the normal structure of the hepatic sinus is disrupted, and such cells are damaged through apoptosis and autophagy, leading to bacterial clearance dysfunction and metabolic disorders. As a result, the gut barrier is further damaged, gut microbiota dysbiosis is exacerbated, and distal organs are injured due to the spread of PAMPs and DAMPs and systemic inflammation. IECs, intestinal epithelial cells; DAMPs, damage-associated molecular patterns; LSECs, liver sinusoidal endothelium; PAMPs, pathogen-associated molecular patterns

Fig. 2

An overview of the signaling pathway of TLR4 activated by LPS. LPS recognition, as facilitated by LBP and CD14, is mediated by TLR4 and the MD-2 receptor complex. Activation of TLR4 signaling, classified into MyD88 dependent, MyD88-independent, and TRIF-dependent pathways, mediates activation of proinflammatory cytokines (TNF-α, IL-6, etc.) and type I interferon genes. IL, interleukin; LBP, LPS-binding protein; LPS, lipopolysaccharide; MD-2, myeloid differentiation-2; MyD88, myeloid differentiation factor 88; TLR4, toll-like receptor 4; TRIF, Toll/IL-1R domain-containing adaptor-inducing IFN-β; TNF, tumor necrosis factor

Fig. 3

When gut-derived PAMPs are exposed to hepatic macrophages, the macrophages are polarized and form large numbers of M1-like macrophages that mainly produce proinflammatory cytokines such as IL-1β, TNF, and IL-6; some M2-like macrophages typically produce IL-10 and play a role in anti-inflammatory reactions. Inflammasomes are activated in hepatic macrophages and in response to pathogen infections and tissue injury. Moreover, neutrophils are attracted to the liver by chemotactic factors, such as CXCL1 and CXCL2 derived from KCs, and released NETs participate in removal of pathogens and toxins. Platelet recruitment is also critical for limiting bacterial infection, and platelets that interact with KCs play a crucial role in fighting against bacterial infection. However, when an inappropriate immune response or overwhelming inflammation occurs with high levels of DAMP formation and proinflammatory cytokine production in the liver, notable hepatocyte injury, macrophage autophagy, and apoptosis occur. Hepatic macrophages are supplemented by KC proliferation and circulating monocyte recruitment and differentiation. CXCL, chemokine (C-X-C motif) ligand; DAMPs, damage-associated molecular patterns; IL, interleukin; KCs, Kupffer cells; NETs, neutrophil extracellular traps; PAMPs, pathogen-associated molecular patterns; TNF, tumor necrosis factor