Role of gut microbiota in the pathogenesis and therapeutics of minimal hepatic encephalopathy via the gut-liver-brain axis

Abstract

Minimal hepatic encephalopathy (MHE) is a frequent neurological and psychiatric complication of liver cirrhosis. The precise pathogenesis of MHE is complicated and has yet to be fully elucidated. Studies in cirrhotic patients and experimental animals with MHE have indicated that gut microbiota dysbiosis induces systemic inflammation, hyperammonemia, and endotoxemia, subsequently leading to neuroinflammation in the brain via the gut-liver-brain axis. Related mechanisms initiated by gut microbiota dysbiosis have significant roles in MHE pathogenesis. The currently available therapeutic strategies for MHE in clinical practice, including lactulose, rifaximin, probiotics, synbiotics, and fecal microbiota transplantation, exert their effects mainly by modulating gut microbiota dysbiosis. Microbiome therapies for MHE have shown promised efficacy and safety; however, several controversies and challenges regarding their clinical use deserve to be intensively discussed. We have summarized the latest research findings concerning the roles of gut microbiota dysbiosis in the pathogenesis of MHE via the gut-liver-brain axis as well as the potential mechanisms by which microbiome therapies regulate gut microbiota dysbiosis in MHE patients.

Keywords: Gut microbiota; Gut-liver-brain axis; Minimal hepatic encephalopathy; Pathogenesis; Therapeutics.

Figure 1

On the background of liver cirrhosis with hepatic dysfunction, dysbiotic gut microbiota and its byproducts including ammonia and endotoxin cross the impaired intestinal barrier, stimulate innate immune responses in the liver, and lead to systemic inflammation, hyperammonemia, and endotoxemia. TNF-α: Tumor necrosis factor-alpha; ILs: Interleukins; IFN: Interferon.

Figure 2

Systemic inflammation, hyperammonemia, and endotoxemia influence the permeability of the blood-brain barrier, resulting in neuroinflammation and low-grade cerebral edema, contributing to the pathogenesis of minimal hepatic encephalopathy. TNF-α: Tumor necrosis factor-alpha.