Mechanistic insights into the pleiotropic effects of butyrate as a potential therapeutic agent on NAFLD management: A systematic review

Abstract

Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic diseases worldwide. As a multifaceted disease, NAFLD's pathogenesis is not entirely understood, but recent evidence reveals that gut microbiota plays a significant role in its progression. Butyrate, a gut microbiota metabolite, has been reported to have hepato-protective effects in NAFLD animal models. The purpose of this systematic review is to determine how butyrate affects the risk factors for NAFLD. Searches were conducted using relevant keywords in electronic databases up to March 2022. According to the evidence presented in this study, butyrate contributes to a wide variety of biological processes in the gut-liver axis. Its beneficial properties include improving intestinal homeostasis and liver health as well as anti-inflammatory, metabolism regulatory and anti-oxidative effects. These effects may be attributed to butyrate's ability to regulate gene expression as an epigenetic modulator and trigger cellular responses as a signalling molecule. However, the exact underlying mechanisms remain unclear. Human trials have not been performed on the effect of butyrate on NAFLD, so there are concerns about whether the results of animal studies can be translated to humans. This review summarises the current knowledge about the properties of butyrate, particularly its potential effects and mechanisms on liver health and NAFLD management.

Keywords: NAFLD; butyrate; gut microbiota; insulin resistance; obesity.

FIGURE 1

A flow chart showing the process of literature searching and selecting studies.

FIGURE 2

Butyrate’s beneficial effects on NAFLD. It has been proved that butyrate inhibits HDAC and binds to specific GPCRs, which hereby interferes with the expression of several genes. It downregulates TLR 4/MyD88/NF-kB pathways (inhibits NF-kB translocation) and upregulates PPAR-related pathways. Butyrate, mainly through these mechanisms, contributes to the management of NAFLD. Clinical manifestation of butyrate effects on the liver, gut, and brain pictured in this figure: (1) in the liver: butyrate improves liver enzymes, lipid metabolism, glycemic control, mitochondrial thermogenesis, oxidative status, hepatic lipid accumulation, and inflammatory markers, (2) in the gut: butyrate modifies dysbiosis and microbiota, reduces endotoxemia, increases intestinal integrity, increases anorexic hormones such as PYY and GLP-1 and modulates tight junction proteins, and (3) in the brain: as a positive effect of butyrate on managing obesity, it may suppress appetite and food intake. AMPK, adenosine monophosphate-activated protein kinase; GLP1, glucagon-like peptide-1; GPCR, G-protein coupled receptor; HDAC, histone deacetylase; MyD88, myeloid differentiation factor 88; NAFLD, non-alcoholic fatty liver disease; NF-kB, nuclear factor kappa-light-chain enhancer of activated B cells; PPAR, peroxisome proliferator-activated receptor; TJs, tight junctions; TLR-4, toll-like receptor-4.