Gut Dysbiosis and Blood-Brain Barrier Alteration in Hepatic Encephalopathy: From Gut to Brain

Abstract

A common neuropsychiatric complication of advanced liver disease, hepatic encephalopathy (HE), impacts the quality of life and length of hospital stays. There is new evidence that gut microbiota plays a significant role in brain development and cerebral homeostasis. Microbiota metabolites are providing a new avenue of therapeutic options for several neurological-related disorders. For instance, the gut microbiota composition and blood-brain barrier (BBB) integrity are altered in HE in a variety of clinical and experimental studies. Furthermore, probiotics, prebiotics, antibiotics, and fecal microbiota transplantation have been shown to positively affect BBB integrity in disease models that are potentially extendable to HE by targeting gut microbiota. However, the mechanisms that underlie microbiota dysbiosis and its effects on the BBB are still unclear in HE. To this end, the aim of this review was to summarize the clinical and experimental evidence of gut dysbiosis and BBB disruption in HE and a possible mechanism.

Keywords: bacterial metabolites; blood-brain barrier; gut microbiome; gut-liver-brain axis; hepatic encephalopathy; inflammation; tight junctions.

Figure 1

The structure of blood–brain barrier. The BBB is formed by endothelial cells, pericytes, basement membrane and perivascular astrocyte end-feet. This barrier strongly restricts paracellular transmission due to the presence of tight junctions between endothelial cells. Tight junctions include two transmembrane proteins claudin and occludin and an intracellular protein zonula occludens-1. AMT: Absorptive-mediated transport; IGF1R: Insulin-like growth factor1 receptor; JAMs: Junctional adhesion molecules; RMT: Receptor-mediated transport; ZO-1: zonula occludens-1. Created with “BioRender.com. (accessed on 2 February 2023)”.

Figure 2

Proposed relationship between the gut microbiome and the structure of blood-brain barrier in health and advanced liver disease. Almost one to two years after birth gut microbiome community is created and its diversity is altered under the influence of age, diet, lifestyle, and geography during life. In healthy, normal gut microbiota-derived metabolites enter circulation and reach the BBB and maintain the integrity of barrier. Advanced liver disease and cirrhosis altered gut microbiota composition. Altered microbiota produces different metabolites that disrupt the intestinal barrier and result in bacterial translocation. Metabolites and products of altered bacteria (i.e., DNA, LPS, etc.) trigger the innate immune system that initiates the production of pro-inflammatory cytokines. Systemic inflammation activates sinusoidal kupffer cells and causes hepatocyte injury that along with gut-derived products and metabolites impair the integrity of the BBB. Leukocyte infiltration, glial activation, oxidative stress, neuroinflammation, and neurodegeneration are the main consequences of BBB damage. BBB: Blood-brain barrier. Created with “BioRender.com. (accessed on 11 February 2023)”.