Neurobehavioral dysfunction in non-alcoholic steatohepatitis is associated with hyperammonemia, gut dysbiosis, and metabolic and functional brain regional deficits.

Sara G Higarza,Miguel Gueimonde,Silvia Arboleya,Natalia Arias,Jorge L Arias,Eneritz Gómez-Lázaro,Florian Reichmann

doi:10.1371/journal.pone.0223019

Abstract

Non-alcoholic steatohepatitis (NASH) is one of the most prevalent diseases worldwide. While it has been suggested to cause nervous impairment, its neurophysiological basis remains unknown. Therefore, the aim of this study is to unravel the effects of NASH, through the interrelationship of liver, gut microbiota, and nervous system, on the brain and human behavior. To this end, 40 Sprague-Dawley rats were divided into a control group that received normal chow and a NASH group that received a high-fat, high-cholesterol diet. Our results show that 14 weeks of the high-fat, high-cholesterol diet induced clinical conditions such as NASH, including steatosis and increased levels of ammonia. Rats in the NASH group also demonstrated evidence of gut dysbiosis and decreased levels of short-chain fatty acids in the gut. This may explain the deficits in cognitive ability observed in the NASH group, including their depressive-like behavior and short-term memory impairment characterized in part by deficits in social recognition and prefrontal cortex-dependent spatial working memory. We also reported the impact of this NASH-like condition on metabolic and functional processes. Brain tissue demonstrated lower levels of metabolic brain activity in the prefrontal cortex, thalamus, hippocampus, amygdala, and mammillary bodies, accompanied by a decrease in dopamine levels in the prefrontal cortex and cerebellum and a decrease in noradrenalin in the striatum. In this article, we emphasize the important role of ammonia and gut-derived bacterial toxins in liver-gut-brain neurodegeneration and discuss the metabolic and functional brain regional deficits and behavioral impairments in NASH.

Highlights

Non-Alcoholic Fatty Liver disease (NAFLD) is one of the most prevalent diseases in the world
The high-fat, high-cholesterol animal model reported in this study was previously described in a publication documenting a rat Non-alcoholic steatohepatitis (NASH) model [6,7] which demonstrated the typical features of NAFLD pathology, including hepato- and splenomegaly, early NASH histopathology, hypercholesterolemia, increased serum liver enzymes, and increased pro-inflammatory cytokines [6,8,9,10]
The purpose of this study was to investigate the consequences of HFHC consumption in an animal model that reflects some of the pathophysiological processes characteristic of human

Summary

Introduction

Non-Alcoholic Fatty Liver disease (NAFLD) is one of the most prevalent diseases in the world. It is defined by the presence of steatosis in a minimum of 5% of hepatocytes, in the absence of significant alcohol consumption [1]. NAFLD includes a spectrum of conditions, ranging from simple steatosis to steatohepatitis (NASH). The high-fat, high-cholesterol animal model reported in this study was previously described in a publication documenting a rat NASH model [6,7] which demonstrated the typical features of NAFLD pathology, including hepato- and splenomegaly, early NASH histopathology, hypercholesterolemia, increased serum liver enzymes, and increased pro-inflammatory cytokines [6,8,9,10]

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