Inflammatory gut-liver crosstalk: mechanisms and therapeutic targets

The gut has a profound influence on the liver through their anatomical connection via the portal vein. During acute inflammation, gut tissue injury leads to increased barrier permeability, allowing the translocation of external contents that can affect hepatic function. Gut-liver crosstalk contributes to the pathophysiology of acute inflammatory disorders, such as sepsis, intestinal ischaemia-reperfusion, hepatitis and drug-induced liver injury. This organ-to-organ crosstalk is mediated by the microbiome, pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs) and various proinflammatory mediators. Different types of gut and liver resident cells as well as circulating cells also facilitate inflammatory gut-liver crosstalk. These cell types include intestinal epithelial and myeloid cells, Kupffer cells, sinusoidal endothelial cells, hepatic stellate cells, hepatocytes, lymphocytes and neutrophils. PAMPs and DAMPs activate pattern recognition receptors, such as Toll-like receptors, on various cells, leading to proinflammatory signal transduction, including NFκB activation, cytokine and chemokine production, and NETosis. Collectively, these soluble and cellular factors exacerbate acute inflammation and tissue injury via the gut-liver axis, leading to poor outcomes in critically ill patients. Potential therapeutic interventions for this deadly clinical condition include modulation of the microbiome and pharmacological inhibition of proinflammatory mediators and cellular interactions. In this article we review the pathophysiology of inflammatory gut-liver crosstalk and potential therapeutic interventions.