In a recent review published within the journal Nutrients, researchers review existing data on short-chain fatty acids (SCFAs), reminiscent of butyrate, acetate, and propionate, as critical constituents of the human intestinal microbiome.
Study: Short-Chain Fatty-Acid-Producing Bacteria: Key Components of the Human Gut Microbiota. Image Credit: mi_viri / Shutterstock.com
The intestinal microbiota plays critical roles in preserving health, including barrier effects against pathogenic organisms, immune system maturation and functioning, dietary intake regulation, and nutrient absorption. Gut microbial dysbiosis has been observed in several disorders, with quite a few gut microbiota-based therapeutics currently being investigated for managing chronic medical disorders. A clinically relevant pathway for modulating the gut microbiota involves restoring SCFA levels for improved cardiometabolic health.
In the current review, researchers presented an outline of the association between SCFA levels and human health.
SCFAs in human health
SCFA transporters present on the epithelial surface of the colon including monocarboxylate transporter-1 (MCT-1) and MCT-4, sodium-coupled MCT-1 (SMCT-1), and breast cancer resistance protein (BCRP) mediate the results of SCFA on the intestines.
SCFAs increase the permeability and integrity of the intestinal barrier. Butyrate, for instance, increases the concentrations of tight junction proteins reminiscent of occludin, claudin-1, and zona occludens-1 by upregulating genes coding for the respective proteins.
Butyrate also strengthens the intestinal epithelial mucus layer by elevating mucin 2 (MUC-2) expression, modulating oxidative stress levels, reducing hydrogen peroxide-induced deoxyribonucleic acid (DNA) damage, reducing reactive oxygen species (ROS) production, and restoring glutathione levels. SCFAs also induce cellular differentiation and/or apoptosis to forestall cancer.
SCFAs can even regulate intestinal gluconeogenesis induced by the brain. Particularly, propionate prompts free fatty acid receptors-3 (FFAR-3) situated on the outermost layer of afferent-type periportal neuronal cells.
SCFAs have also been shown to inhibit histone deacetylase (HDAC) activity and, because of this, may influence the pathophysiology of neuropsychiatric disorders reminiscent of Alzheimer’s disease, schizophrenia, and depression.
Furthermore, SCFAs regulate neuro- and systemic inflammation by modulating microglia cell structure and performance, in addition to emotion and cognitive functions. SCFAs can also influence brain barrier integrity by inducing tryptophan 5-hydroxylase 1 enzymatic production, thereby increasing serotonin synthesis.
SCFAs reminiscent of acetate lower appetite by moderating dietary intake and increasing the degrees of satiety hormones reminiscent of peptide YY (PYY) and Glucagon-like peptide-1 (GLP-1) through G protein-coupled receptor (GPR)-41 and GPR-43 activity and HDAC inhibition.
Propionate lowers gluconeogenesis within the liver, whereas butyrate and acetate increase leptin levels and reduce lipogenesis, weight, and serological triglyceride levels. Propionate and butyrate lower blood pressure levels by binding with GPR-41 and vasodilatation, along with stopping thrombosis by lowering plasminogen activator inhibitor-1 (PAI-1) expression.
Moreover, SCFAs lower myeloperoxidase (MPO) levels and reduce inflammatory cell chemotaxis by decreasing monocyte chemoattractant protein-1 (MCP-1) and vascular cell adhesion molecule-1 (VCAM-1) levels. SCFAs also increase regulatory T cell (Treg) counts and reduce intestinal inflammation by lowering nuclear factor-kappa B (NF-κB) activity and associated cytokine release.
How SCFA production pertains to human diseases
Gut microbes, particularly Firmicutes species including Lactobacillaceae, Ruminococcaceae, and Lachnospiraceae produce SCFA from complex polysaccharides through hydrolysis. As well as, Actinobacteria, Proteobacteria, and Fusobacteria can produce butyrate.
Acute inflammation protects the gut from injurious stimuli like viruses and bacteria. If unresolved, these injuries can progress to chronic inflammation, which has been related to disorders reminiscent of inflammatory bowel disease (IBD).
IBD patients often present with a lowered abundance of butyrate-producing microbes reminiscent of Roseburia species and Faecalibacterium prausnitzii, thereby leading to lower SCFA production. Acetate controls tissue homeostasis through NLR family pyrin domain containing-3 (NLRP-3) activation. Comparatively, butyrate regulates the intestinal barrier, which is impaired in IBD, through increased claudin-1, amphiregulin (AREG), and interleukin-22 (IL-22) levels.
In colorectal cancer, an increased abundance of pathogenic microbes reminiscent of Fusobacterium nucleatum and a decreased abundance of butyrate-producing bacteria, with resultant lowered SCFA levels and enhanced inflammation, have been observed.
Butyrate enhances tumor cell apoptosis by altering the redox states and D-glucose metabolic pathways. In hypertension, lowered butyrate-producing gut microbial counts and deficient intestinal absorption of SCFA have been observed.
SCFAs, particularly butyrate, regulate cardiac inflammation and stabilize plaques by decreasing matrix metalloproteinase-2 (MMP-2), VCAM-1, and chemokine ligand-2 (CCL-2) levels, thereby lowering macrophage migration and increasing collagen deposition.
Obesity is related to intestinal microbial dysbiosis and an altered Firmicutes/Bacteroidetes ratio. Moreover, type 2 diabetes is related to reduced butyrate-producing microbial counts and lower circulating SCFA levels.
SCFAs improve glucose homeostasis through adenine monophosphate (AMP)-activated patient kinase (AMPK)-dependent and peroxisome proliferator-activated receptor gamma (PPARγ)-regulated effects. SCFAs also inhibit lipolysis and increase lipogenesis.
SCFAs are essential components of the gut microbiota that preserve cardiometabolic health. Microbiota-dependent SCFA production might be enhanced by consuming high-fiber diets reminiscent of the Mediterranean, vegan, or vegetarian food regimen. The consumption of prebiotics reminiscent of arabinoxylan oligosaccharides (AXOS), in addition to probiotics like Lactobacillus plantarum, Lactobacillus paracasei, and Lactobacillus rhamnosus can even promote health and well-being.
- Fusco, W., Lorenzo, M. B., Cintoni, M., et al. (2023). Short-Chain Fatty-Acid-Producing Bacteria: Key Components of the Human Gut Microbiota. Nutrients. doi:10.3390/nu15092211