Novel Insights Into Pathogenesis and Therapeutic Strategies of Hepatic Encephalopathy, From the Gut Microbiota Perspective

Abstract

Since the 1950s, gradual changes in the gut microbiota of patients with hepatic encephalopathy have been observed. Previous research has indicated potential associations between the gut and brain, and the gut microbiota is becoming a hot topic in research on diseases of the nervous system. However, for the past few decades, studies of hepatic encephalopathy have been restricted to controlling the gut microbiota during macroscopic manipulation, such as probiotic intervention, while its clinical use remains controversial, and the cellular mechanisms underlying this condition are still poorly understood. This thesis seeks to comprehensively understand and explain the role of gut microbiota in hepatic encephalopathy as well as analyze the effects of intervention by regulating the gut microbiota. Evidence is presented that shows that dysbiosis of the gut microbiota is the primary pathological driver of hepatic encephalopathy and impacts pathologic progression via complex regulatory networks. As a result, suggestions were identified for future mechanistic research and improvements in therapeutic strategies for hepatic encephalopathy.

Keywords: antibiotics; fecal microbiota transplantation; gut microbiota; gut–liver–brain axis; hepatic encephalopathy; probiotic.

Figure 1

Association between the damaged intestinal mucosa liver failure. Altered immune function such as impaired gut barrier, bacterial products can reach the liver through the portal vein and might lead to a pro-inflammatory response. The pro-inflammatory stimulus facilitates hepatocyte damage and central process that promotes liver inflammation. On the other hand, the defunctionalization of the liver carries on impairing the gut barrier due to the portal hypertension. Left untreated, it can lead to cirrhosis and liver failure.

Figure 2

The healthy gut–liver–brain axis. A healthy gut–liver–brain axis contains gut and its microbiota, the liver, and the brain. In the normal condition, two “shields” including homeostasis of intestinal permeability as physical barrier and the normal hepatic function of amino-metabolism prevent potential pathogens and gut enteroendotoxin from hamming other organs (such as brain) through blood stream.

Figure 3

The collapsed gut–liver–brain in HE. The initial factor of gut microbiota dysbiosis can be liver disease possibly with relevant or irrelevant changes of intestinal barrier and portal system. Altered intestinal permeability, bacterial translocation, systemic and local inflammation, modified the microbiota composition, with reduction of commensal bacteria and their metabolites such as short-chain fatty acids, excessive amino and gamma-aminobutyric acid. The abnormal status finally affects liver function such as ammonia metabolism. Besides, liver disease can also cause portal-system shunt and let ammonia escape from the liver. Therefore, ammonia entering the body circulation and then the blood brain barrier, leading to neuropsychiatric complications such as hepatic encephalopathy.

Figure 4

The molecular mechanisms involved in FMT intervention. The process includes limiting the systemic inflammatory response by reducing the expression of interleukin (IL)-1β, IL-6 and TNF-α through toll-like receptor (TLR)4 and TLR9 (two effective inflammatory mediators) via NF-κB signal and restoring the tight junction proteins (Claudin-1, Claudin-6, and Occludin) that was lost due to HE.