A Potential Link Between Plasma Short-chain Fatty Acids, TNF-α Level and Disease Progression in Non-alcoholic Fatty Liver Disease: A Retrospective Study

The onset and progression of non-alcoholic fatty liver disease (NAFLD) remains unclear, but short-chain fatty acids (SCFAs) in circulation may participate in its pathogenesis by acting as inflammation inhibitors. The aim of this retrospective study was to investigate plasma concentrations of general SCFAs in healthy individuals and in patients with distinct stages of NAFLD. Three main SCFAs (including acetate, propionate and butyrate) were analyzed by gas chromatography. The plasma TNF-α concentration was measured by ELISA. One-way ANOVA, Spearman's correlation and Pearson's correlation analysis were performed to estimate the associations between SCFAs, TNF-α and disease progression. Multiple linear stepwise regression was computed to explore the predictor variables of TNF-α in circulation. A total of 71 patients with NAFLD [including 27 patients with NAFL, 20 patients with non-alcoholic steatohepatitis (NASH) and 24 patients with NAFLD-related cirrhosis (NAFLD-cirrhosis)] and 9 healthy control (HC) subjects were enrolled for analysis. Although not statistically significant, plasma SCFAs were elevated in patients with NAFL compared with HC subjects, whereas the vast majority of SCFAs were statistically reduced in patients with NASH or NAFLD-cirrhosis compared with patients with NAFL. Plasma SCFAs had no significant differences in NASH or NAFLD-cirrhosis patients compared with HC subjects. In addition, significant negative correlations were observed between TNF-α and SCFAs. The progression of NAFLD (β=0.849; P<0.001) and the decline of the total three SCFA concentrations (β=-0.189; P<0.001) were recognized as independent risk variables related to the elevated peripheral TNF-α in the multiple linear stepwise regression model. Plasma SCFA concentrations may alter with the development of NAFLD and may have a potential link to TNF-α and the progression of NAFLD, which may serve a protective role toward disease advancement. Further mechanistic studies, such as analysis of gastrointestinal microecology, signaling pathways and functions involved in TNF-α, need to be performed. Also, therapeutic supplementation of SCFAs for NASH and NAFLD-cirrhosis needs further research and verification.