The Role of Gut Microbiome-Derived Short-Chain Fatty Acid Butyrate in Hepatobiliary Diseases

Abstract

The short-chain fatty acid butyrate, produced from fermentable carbohydrates by gut microbiota in the colon, has multiple beneficial effects on human health. At the intestinal level, butyrate regulates metabolism, helps in the transepithelial transport of fluids, inhibits inflammation, and induces the epithelial defense barrier. The liver receives a large amount of short-chain fatty acids via the blood flowing from the gut via the portal vein. Butyrate helps prevent nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, inflammation, cancer, and liver injuries. It ameliorates metabolic diseases, including insulin resistance and obesity, and plays a direct role in preventing fatty liver diseases. Butyrate has different mechanisms of action, including strong regulatory effects on the expression of many genes by inhibiting the histone deacetylases and modulating cellular metabolism. The present review highlights the wide range of beneficial therapeutic and unfavorable adverse effects of butyrate, with a high potential for clinically important uses in several liver diseases.

Figure 1

Short-chain fatty acids (SCFAs) produced in the colon by gut microbiota travel mainly to the liver via the portal vein and the various parts of the body. They primarily help in the inhibition of nonalcoholic fatty liver disease (NAFLD) by lessening the process of lipogenesis, free fatty acid (FFA) accumulation, and glucose output. Furthermore, SCFAs also inhibit lipopolysaccharide-induced inflammation as they alleviate IL-1, tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) production in the liver. Butyrate inhibits cell proliferation and cell cycle progression and induces apoptosis in cancer cells. HCC, hepatocellular carcinoma; HDAC, histone deacetylase; TG, triglycerides; TLR4, toll-like receptor 4.

Figure 2

The illustration shows the formation of the short-chain fatty acids, including acetate, propionate, and butyrate, in the colon by the gut microbiota during the fermentation of the dietary fibers. Bacteroids produce propionate and acetate, whereas Eubacteria is responsible for butyrate formation. Butyrate activates G-protein receptor-41 (GPR41) to activate glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), thereby increasing the energy harvest and satiety, which eventually may decrease fat accumulation in the body.

Figure 3

Diverse effects of butyrate in the body are shown. Butyrate is an energy source converted to acetyl-CoA, which enters the tricarboxylic acid (TCA) cycle in mitochondria. It inhibits histone deacetylases (HDACs), inhibiting cell proliferation and cell cycle, and up-regulates apoptosis and autophagy in cancer cells. AMPK, AMP-activated protein kinase; ETC, electron transport chain; mTOR, mammalian target of rapamycin; NAFLD, nonalcoholic fatty liver disease.

Figure 4

The gut microbiota may increase short-chain fatty acid (SCFAs) production as a by-product of the fermentation of dietary fibers, probiotics, or fecal microbiota transplantation. SCFAs are digested and transformed into ATP at the intracellular level, which the cells use as an energy source. The portal circulation receives unmetabolized SCFAs that have crossed the basolateral membrane. SCFAs are used in the liver's production of ATP and glucose. Just a small proportion of SCFAs that are not used by the liver make it to systemic circulation.