Short-chain fatty acids in diseases

Abstract

Short-chain fatty acids (SCFAs) are the main metabolites produced by bacterial fermentation of dietary fibre in the gastrointestinal tract. The absorption of SCFAs is mediated by substrate transporters, such as monocarboxylate transporter 1 and sodium-coupled monocarboxylate transporter 1, which promote cellular metabolism. An increasing number of studies have implicated metabolites produced by microorganisms as crucial executors of diet-based microbial influence on the host. SCFAs are important fuels for intestinal epithelial cells (IECs) and represent a major carbon flux from the diet, that is decomposed by the gut microbiota. SCFAs play a vital role in multiple molecular biological processes, such as promoting the secretion of glucagon-like peptide-1 by IECs to inhibit the elevation of blood glucose, increasing the expression of G protein-coupled receptors such as GPR41 and GPR43, and inhibiting histone deacetylases, which participate in the regulation of the proliferation, differentiation, and function of IECs. SCFAs affect intestinal motility, barrier function, and host metabolism. Furthermore, SCFAs play important regulatory roles in local, intermediate, and peripheral metabolisms. Acetate, propionate, and butyrate are the major SCFAs, they are involved in the regulation of immunity, apoptosis, inflammation, and lipid metabolism. Herein, we review the diverse functional roles of this major class of bacterial metabolites and reflect on their ability to affect intestine, metabolic, and other diseases. Video Abstract.

Keywords: Gut microbiota; Immunity; Inflammation; Metabolism; Short-chain fatty acids.

Fig. 1

Schematic diagram of carbohydrate fermentation pathways producing acetate, propionate and butyrate

Fig. 2

Impact of intestinal microbes on human diseases. T2D: type 2 diabetes; NAFLD: non-alcoholic fatty liver disease; IBD: inflammatory bowel disease; CRC: colorectal cancer; HTN: hypertension; and CKD: chronic kidney disease

Fig. 3

SCFAs alleviate IBD and CRC by increasing intestinal barrier function and reducing endotoxin levels in the blood. SCFAs increase the intestinal barrier function, reduce the entry of lipopolysaccharide (LPS) into the blood, induces naive T cells to differentiate into Tregs, inhibit the production of tumour necrosis factor-alpha (TNF-α) and interleukin (IL)-6 by intestinal macrophages, and inhibit the production of IL-8 by normal intestinal epithelial cells (IECs) to alleviate inflammation. Butyrate promotes CRC cell apoptosis by inhibiting C-AMP/P38-MAPK and increasing Bax/Bcl-2 ratio. Other abbreviations are: SCFA: short-chain fatty acid; GPCR: G protein-coupled receptor; FFAR: free fatty acid receptor; IBD: inflammatory bowel disease; CRC: colorectal cancer; AKT: protein kinase B; TLR4: Toll-like receptors 4; and HDACi: histone deacetylase inhibitor

Fig. 4

Intestinal microbiota metabolites acetate, propionate, and butyrate alleviates obesity, non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D). Short-chain fatty acids (SCFAs) increase the intestinal barrier function by elevating the expression of zonula occludens-1 (ZO-1) and claudin-1 in IECs, preventing lipopolysaccharide (LPS) from entering the blood from the intestine, and further inhibiting adipose tissue inflammation. SCFAs promote the production of glucagon-like peptide-1 (GLP-1) in L cells; GLP-1 enters the liver and binds to the GLP-1 receptor on the surface of hepatocytes, promoting hepatic β-oxidation by activation of AMPK, thereby relieving fatty liver. GLP-1 activates PI3K/AKT signalling in pancreatic islets, inhibits apoptosis, and alleviates T2D. Other abbreviations are: GPCR: G protein-coupled receptors; FFAR: free fatty acid receptor; NF-κB: nuclear factor kappa-B; TG: triacylglycerol; TLR4: Toll-like receptor 4; p-ACC: phospho-acetyl-CoA carboxylase; p-AMPK: phospho-adenosine monophosphate-activated protein kinase; PYY: Peptide YY; and IECs: intestinal epithelial cells

Fig. 5

Beneficial and detrimental effects of SCFAs on pneumonia and other respiratory diseases. Short-chain fatty acids (SCFAs) promote the phagocytosis of Klebsiella. pneumoniae by pulmonary macrophages to clear lung bacteria. SCFAs can also inhibit lung immune cell function and promote inflammation. Other abbreviations are: GPCR: G protein-coupled receptors; FFAR: free fatty acid receptor; p-ERK: phosphorylated extracellular signal-regulated kinase; TNF-α: tumour necrosis factor-alpha; MAPK: mitogen-activated protein kinase

Fig. 6

Short-chain fatty acids (SCFAs) alleviate hypertension, neurologic disorders, and chronic kidney disease (CKD) by modulating immunity. SCFAs alleviates hypertension by reducing lipopolysaccharide (LPS) entry into the blood and inhibiting cardiac Treg cells. SCFAs can also alleviate neurological diseases by reducing axonal damage via the inhibition of the c-Jun N-terminal kinase 1 (JNK-1)/p-38 pathway. In addition, SCFAs alleviate renal fibrosis by inhibiting the phosphorylation of JNK-1/p-38 pathway. Other abbreviations are: GPCR: G protein-coupled receptors; FFAR: free fatty acid receptor; and MCP-1: monocyte chemotactic protein-1