Boosting gut health with short-chain fatty acids

By Pooja Toshniwal PahariaReviewed by Benedette Cuffari, M.Sc.May 9 2023

In a recent review published in the journal Nutrients, researchers review existing data on short-chain fatty acids (SCFAs), such as 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

Introduction

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 numerous 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 present review, researchers presented an overview 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 effects of SCFA on the intestines.

SCFAs increase the permeability and integrity of the intestinal barrier. Butyrate, for example, increases the concentrations of tight junction proteins such as 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 prevent cancer.

SCFAs can also regulate intestinal gluconeogenesis induced by the brain. In particular, propionate activates free fatty acid receptors-3 (FFAR-3) located on the outermost layer of afferent-type periportal neuronal cells.

SCFAs have also been shown to inhibit histone deacetylase (HDAC) activity and, as a result, may influence the pathophysiology of neuropsychiatric disorders such as Alzheimer’s disease, schizophrenia, and depression.

Moreover, SCFAs regulate neuro- and systemic inflammation by modulating microglia cell structure and function, as well as emotion and cognitive functions. SCFAs may also influence brain barrier integrity by inducing tryptophan 5-hydroxylase 1 enzymatic production, thereby increasing serotonin synthesis.

SCFAs such as acetate lower appetite by moderating dietary intake and increasing the levels of satiety hormones such as 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 in 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, in addition to preventing thrombosis by lowering plasminogen activator inhibitor-1 (PAI-1) expression.

Furthermore, SCFAs lower myeloperoxidase (MPO) levels and decrease 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 relates to human diseases

Gut microbes, particularly Firmicutes species including Lactobacillaceae, Ruminococcaceae, and Lachnospiraceae produce SCFA from complex polysaccharides through hydrolysis. In addition, 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 associated with disorders such as inflammatory bowel disease (IBD).

IBD patients often present with a lowered abundance of butyrate-producing microbes such as Roseburia species and Faecalibacterium prausnitzii, thereby resulting in 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 such as 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 associated with intestinal microbial dysbiosis and an altered Firmicutes/Bacteroidetes ratio. Furthermore, type 2 diabetes is associated with 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.

Conclusions

SCFAs are essential components of the gut microbiota that preserve cardiometabolic health. Microbiota-dependent SCFA production can be enhanced by consuming high-fiber diets such as the Mediterranean, vegan, or vegetarian diet. The consumption of prebiotics such as arabinoxylan oligosaccharides (AXOS), as well as probiotics like Lactobacillus plantarum, Lactobacillus paracasei, and Lactobacillus rhamnosus can also promote health and well-being.