Butyrate: A Double-Edged Sword for Health?

Abstract

Butyrate, a four-carbon short-chain fatty acid, is produced through microbial fermentation of dietary fibers in the lower intestinal tract. Endogenous butyrate production, delivery, and absorption by colonocytes have been well documented. Butyrate exerts its functions by acting as a histone deacetylase (HDAC) inhibitor or signaling through several G protein-coupled receptors (GPCRs). Recently, butyrate has received particular attention for its beneficial effects on intestinal homeostasis and energy metabolism. With anti-inflammatory properties, butyrate enhances intestinal barrier function and mucosal immunity. However, the role of butyrate in obesity remains controversial. Growing evidence has highlighted the impact of butyrate on the gut-brain axis. In this review, we summarize the present knowledge on the properties of butyrate, especially its potential effects and mechanisms involved in intestinal health and obesity.

Keywords: G protein–coupled receptors; butyrate; gut-brain axis; histone deacetylase; inflammation; intestinal barrier; intestinal microbiota; obesity.

FIGURE 1

Butyrate biosynthesis and absorption in the large intestine and subsequent metabolism. Two pathways of endogenous butyrate production from butyryl-CoA in bacteria have been reported. The letter “A” indicates that butyryl-CoA is phosphorylated to butyryl-phosphate and converted to butyrate via butyrate kinase. The letter “B” shows that the CoA moiety of butyryl-CoA is transferred to external acetate via butyryl-CoA:acetate CoA transferase, leading to the formation of butyrate and acetyl-CoA. Several receptors for butyrate have been identified, including GPR41, GPR43, and GPR109A. GPR41 is found in adipose tissues and immune cells. The highest expression of GPR43 has been found in immune cells, whereas GPR109A is essential for butyrate-mediated induction of IL-18 in colonic epithelium. A small portion of butyrate is transported to the liver and metabolized to produce ATP. GPR, orphan G protein–coupled receptor.

FIGURE 2

Schematic overview of the mechanisms by which butyrate affects glucose and lipid metabolism. MCTs are involved in butyrate transport in colonic luminal membrane. For glucose metabolism, butyrate increases PYY and GLP-1 expression in the colon via GPR41 and GPR43. GLP-1 increases insulin and decreases glucagon production in the pancreas, and PYY increases glucose uptake in the muscle and adipose tissue. Meanwhile, butyrate decreases hepatic gluconeogenesis. For lipid metabolism, butyrate increases FA oxidation in the muscle and decreases lipolysis via the GPR43 pathway in white adipose tissue. In addition, butyrate is converted to FAs, cholesterol, and ketone bodies in the liver. GLP-1, glucagon-like peptide 1; GPR, orphan G protein–coupled receptor; MCT, monocarboxylate transporter; PYY, peptide YY.