Omega-3 Fatty Acids and Gut Microbiota: A Reciprocal Interaction in Nonalcoholic Fatty Liver Disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease characterized with the spectrum of hepatic steatosis, inflammation, and fibrosis. The etiology of NAFLD remains incompletely understood. Numerous studies have implied that the gut microbiota (GM) is involved in the development of NAFLD, as it particularly mediating the interaction between nutrient intake and the gut-liver function. Meanwhile, the omega-3 and omega-6 polyunsaturated fatty acids (n-3/n-6 PUFA) as essential fatty acids have been linked to NAFLD. Increasing studies in the past decades have indicated that there is a reciprocal interaction between GM and n-3/n-6 PUFA, which may be underlying at least in part, the pathogenesis of NAFLD. In this review, we will discuss: (1) How GM is linked to NAFLD by interacting with various nutrients; (2) How imbalanced dietary n-3/n-6 PUFA is linked to NAFLD; (3) How n-3/n-6 PUFA may affect the GM balance, leading to altered nutrients release to the liver; and (4) How GM may modify ingested n-3/n-6 PUFA and alter their absorption, bioavailability, and biotransformation.

Keywords: Gut microbiota; NAFLD; Nutrient; n-3/n-6 PUFA.

Figure 1:

Schematic explanation for the influence of different effectors on GM and its relation on the development of NAFLD. Microbiome-derived metabolites cause liver damage via several pathways including pro-inflammatory signaling, alteration in gene expression, and metabolic modification and toxicity. Bile acids interact with Farnesoid-X receptor (FXR) in the intestine releasing β-Klotho that enters liver via portal vein then binds FGFR4 on the surface of hepatocytes and leads to metabolic changes. Bile acids also stimulate the TGR5 receptor leading to the production of pro-inflammatory cytokines. Short-chain fatty acids (e.g. acetate) bind to their receptors (GPR43) and remodel metabolism; while butyrate inhibits histone deacetylase (HDAC) and regulates gene expression by changing overall chromatin state. Microbial products, i.e., peptidoglycan and LPS, cause pro-inflammatory signaling via Toll like receptors (TLR2 and TLR4). Phenylacetate increases gene expression of Fatty acid synthase (FASN) and lipoprotein lipase (LPL) by unknown receptors leading to metabolic changes. Ethanol is oxidized to acetaldehyde aggravates oxidative stress on the hepatocytes. Dextran increases gut permeability lead to over release of LPS to blood.

Figure 2:

Cross-link between PUFA and GM and their effect on development and progression of NASH. Abbreviations: GM, Gut microbiota; LA, Linoleic acid; ALA, α-linolenic acid; CLA, Conjugated linoleic acid; CALA, Conjugated α-linolenic acid; RA, Retinoic acid; FFA, Free fatty acid; RXRα, Retinoid X receptor alpha; PPAR, peroxisome proliferator-activated receptor; BCMO1, Beta-carotene oxygenase 1; SCFAs, Short chain fatty acids.