Advances in the Involvement of Gut Microbiota in Pathophysiology of NAFLD

Abstract

Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis and progresses to non-steatohepatitis (NASH) when the liver displays overt inflammatory damage. Increasing evidence has implicated critical roles for dysbiosis and microbiota-host interactions in NAFLD pathophysiology. In particular, microbiota alter intestine absorption of nutrients and intestine permeability, whose dysregulation enhances the delivery of nutrients, endotoxin, and microbiota metabolites to the liver and exacerbates hepatic fat deposition and inflammation. While how altered composition of gut microbiota attributes to NAFLD remains to be elucidated, microbiota metabolites are shown to be involved in the regulation of hepatocyte fat metabolism and liver inflammatory responses. In addition, intestinal microbes and circadian coordinately adjust metabolic regulation in different stages of life. During aging, altered composition of gut microbiota, along with circadian clock dysregulation, appears to contribute to increased incidence and/or severity of NAFLD.

Gut Microbiota in Metabolic-associated Fatty Liver Disease and in Other Chronic Metabolic Diseases

“…It is also important to highlight the importance of Kupffer cell activation and lymphocyte recruitment, because apart from the effects mentioned before, leukocyte presence in the liver tissue is a classic histopathological sign of metabolic steatohepatitis. 72 Increasing evidence suggests that the gut-liver axis can take part in the onset of hepatocellular carcinoma, particularly due to the dysbiosis-induced endotoxemia. For example, gut microbial metabolites that act as antigens, like lipoteichoic acids in the case of Gram-positive bacteria or LPS in Gram-negative bacteria, can induce synthesis of the prostaglandin E2 PGE2 by hepatic stellate cells, which reduces the antitumoral activity of CD8+ lymphocytes.…”

“…The mechanisms behind these protective effects are the reduction of hepatic lipid accumulation, less endotoxemia, oxidative stress and activation of anti-inflammatory pathways through the modulation of NF-κB and TNF production, as well as the regulation of collagen production. 72,75,76 For example, a study conducted by Xin et al 75 showed prevention of the onset of hepatic steatosis and cellular apoptosis in mice fed with a high-fat diet through the administration of the probiotic Lactobacillus johnsonii BS15; the end result was an improvement in hepatic inflammation and oxidative stress. A more recent study by Liang et al 77 gave a compound of probiotics to a group of mice fed with a high-fat diet and Fig.…”

Treatments for NAFLD: State of Art

“…Indeed, bariatric surgery can increase circulating levels of glucagon-like peptide-1 (GLP-1), which, in turn, decreases appetite, slows gastric emptying, and improves insulin sensitivity [ 47 ]. In addition, GLP-1 modulates bile acid signaling via the farnesoid X receptor (FXR), which can alter the gut microbiome and promote NAFLD [ 48 , 49 ]. With these premises, current guidelines indicate that bariatric surgery can be a potential option in patients with T2DM or in those with severe obesity (i.e., BMI >35 kg/m 2 ) [ 1 , 2 ].…”

Different Effects of Leucine Supplementation and/or Exercise on Systemic Insulin Sensitivity in Mice

“…The liver plays an important role in metabolism and interacts with all tissues and organs ( 31 ). Histological examination showed that compared with the LFD group, HFD increased liver fat accumulation ( Supplementary data and Figures S2A, B ), but the treatment of exercise and/or leucine had not shown effects on elimination of adiposity in the liver ( Supplementary Data and Figures S2A, B ), which was consistent with the results of tissue weight.…”