Abstract
Background/ObjectivesNon-alcoholic fatty liver disease (NAFLD) causes a wide spectrum of liver damage, from simple steatosis (SS) to cirrhosis. SS and non-alcoholic steatohepatitis (NASH) cannot be distinguished by clinical or laboratory features. Dysregulation of the gut microbiota is involved in NASH pathogenesis. The aim of this study was to assess the relationship between microbiota-derived metabolites and the degrees of NAFLD; also, to investigate whether these metabolites could be included in a panel of NASH biomarkers.Subjects/MethodsWe used liquid chromatography coupled to triple-quadrupole-mass spectrometry (LC-QqQ) analysis to quantify choline and its derivatives, betaine, endogenous ethanol, bile acids, short-chain fatty acids and soluble TLR4 in serum from women with normal weight (n = 29) and women with morbid obesity (MO) (n = 82) with or without NAFLD. We used real-time polymerase chain reaction (RT-PCR) analysis to evaluate the hepatic and intestinal expression level of all genes studied (TLR2, TLR4, TLR9, LXRα, SREBP1C, ACC1, FAS, PPARα, CPT1α, CROT, SREBP2, ABCA1, ABCG1 and FXR in the liver; TLR2, TLR4, TLR5, TLR9, GLP-1R, DPP-4, FXR and PPARɣ in the jejunum) in 82 women with MO with normal liver histology (NL, n = 29), SS (n = 32), and NASH (n = 21).ResultsHepatic FAS, TLR2, and TLR4 expression were overexpressed in NAFLD patients. TLR2 was overexpressed in NASH patients. In women with MO with NAFLD, we found upregulation of intestinal TLR9 expression and downregulation of intestinal FXR expression in women with NASH. Circulating TMAO, glycocholic acid and deoxycholic acid levels were significantly increased in NAFLD patients. Endogenous circulating ethanol levels were increased in NASH patients in comparison to those in SS patients.ConclusionsThese findings suggest that the intestine participates in the progression of NAFLD. Moreover, levels of certain circulating microbiota-related metabolites are associated with NAFLD severity and could be used as a “liquid biopsy” in the noninvasive diagnosis of NASH.
Highlights
IntroductionNon-alcoholic fatty liver disease (NAFLD) is a complicated metabolic disease with pathophysiological interactions between genetic and environmental factors [4]
Non-alcoholic fatty liver disease (NAFLD) is a health problem expanding in parallel with the global increase in Supplementary information The online version of this article contains supplementary material, which is available to authorized users.non-alcoholic steatohepatitis (NASH) is biopsy-mediated, and it has become essential to improve the accuracy in its noninvasive diagnosis because biopsy is limited by cost, sampling error, and procedurerelated morbidity and mortality [3].NAFLD is a complicated metabolic disease with pathophysiological interactions between genetic and environmental factors [4]
We studied the circulating levels of choline, betaine, endogenous ethanol, primary and secondary bile acid (BA), short-chain fatty acids (SCFAs) and soluble TLR4 in relation to the hepatic expression of farnesoid X receptor (FXR), hepatic lipid metabolism genes (LXRα, SREBP1C, ACC1, FAS, PPARα, CPT1α, CROT, SREBP2, ABCA1, and ABCG1) and Toll-like receptors (TLRs) (TLR2, TLR4, and TLR9), and in relation to the intestinal expression of FXR, TLRs, GLP-1, and dipeptidyl peptidase-4 (DPP-4) receptors and PPARγ in a cohort of patients with morbid obesity (MO) and NAFLD
Summary
NAFLD is a complicated metabolic disease with pathophysiological interactions between genetic and environmental factors [4]. In this regard, the most generally accepted hypothesis at present to explain the progression from simple steatosis (SS) to the concomitant presence of inflammation and ballooning, which defines NASH, is the “multiple hit” hypothesis. The most generally accepted hypothesis at present to explain the progression from simple steatosis (SS) to the concomitant presence of inflammation and ballooning, which defines NASH, is the “multiple hit” hypothesis This hypothesis considers multiple insults acting together, including hormones/adipokines secreted from the adipose tissue, lipotoxicity, oxidative stress, mitochondrial dysfunction, genetic and epigenetic factors, and gut microbiota [5]. The dysregulation of gut microbiota has been found to be involved in a variety of metabolic diseases, such as diabetes, insulin resistance, obesity, and NAFLD [6]
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