Modulation of serotonin in the gut–liver neural axis ameliorates the progression of nonalcoholic fatty liver

Backgrounds & Aims: The etiology of nonalcoholic fatty liver disease (NAFLD) consists of various factors, including inter-organ crosstalk through autonomic neural signal pathways. However, the mechanisms of the pathways influencing NAFLD progression have not been elucidated. Therefore, we examined the involvement of the gut–liver neural axis in NAFLD aiming at developing the novel therapeutics.
Methods: To test the contribution of the axis, we examined body weight, hepatic steatosis, fibrosis, intestinal tight junction, microbiota, and short-chain fatty acid in NAFLD models of choline-deficient defined L-amino-acid and high-fat diet-fed mice with or without blockades of autonomic nerves from the liver.
Results: Blockade of the neural signal in these NAFLD models ameliorated the disease progression by modulating serotonin expression in the small intestine and its receptor in the liver. It was related to the severity of the liver pathology, the lipid metabolism-related gene expression in the liver, the intestinal tight junction protein expression, and microbiota diversity. These effects were reproduced by administrating serotonin antagonist, and it ameliorated the NAFLD progression. 
Conclusions: Our study demonstrated that the gut–liver neural axis is involved in the NAFLD progression and that serotonin is the key factor of this axis. Therefore, the axis and serotonin can be a novel therapeutic target of NAFLD.