Exploring the immunomodulatory and anti-inflammatory properties of butyrate

By Dr. Chinta SidharthanFeb 24 2023Reviewed by Aimee Molineux

In a recent study published in the journal Fermentation, researchers reviewed studies examining the role of butyrate in inflammatory responses, immunological properties, and diseases related to the immune system such as atopic dermatitis, systemic lupus erythematosus, human immunodeficiency virus (HIV), psoriasis, and cancer.

Background

The short-chain fatty acid butyrate is created when undigested resistant starch and fermentable dietary fibers, and small amounts of endogenous and dietary proteins are fermented by bacteria in the lumen of the intestine. Butyrate is thought to play an important role in systemic and local immunity by modulating the gut microbiome. It is also thought to be essential in the management of immunological and inflammatory responses.

Bacteroides and Firmicutes are the two predominant phyla that produce butyrate in the human colon. Butyrate production is prevalent in anaerobic Gram-positive bacteria, and Eubacterium rectale and Roseburia species belonging to Clostridium coccoides cluster and Faecalibacterium prausnitzii belonging to the Clostridium leptum cluster are the two most significant butyrate-producing groups.

Properties of butyrate

Butyrate is known to play various important roles in the immune system and in maintaining intestinal homeostasis. It modulates the expression of tight junction proteins and promotes the secretion of intestinal mucus, maintaining the integrity of the epithelial barrier in the intestine.  Furthermore, butyrate is thought to be essential in cellular energy metabolism and the digestive system, providing energy to the mucosal layer in the colon and regulating inflammation, gene expression, cell differentiation, and cell death.

Within the intestine, butyrate improves the diversity of the gut microbiota, regulates the intake of electrolytes and fluids, and reduces oxidative stress. Systemically, butyrate increases insulin sensitivity, decreases ischemic and atherosclerotic lesions, scavenges ammonia, stimulates peroxisome proliferation, and plays a role in neurogenesis and apoptosis of tumor cells.

Within the immune system, butyrate is an agonist for various G protein-coupled receptors, stimulates anti-inflammatory cells such as macrophages and T-regulatory cells, reduces the activation of nuclear factor kappa B (NF-κB) and secretion of tumor necrosis factor-alpha (TNF-α), and is involved in the inhibition of proinflammatory cytokines.

Butyrate is produced by the direct conversion of carbohydrates to butyrate by the enzyme butyrate kinase, indirect conversion of lactate, succinate, or acetate, or through amino acid fermentation of lysine and glutamate. Apart from E. rectale and F. prausnitzii, Butyricicoccus pullicaecorum, Anaerotruncus colihominis, Papillibacter cinnamivorans, Subdoligranulum variabile, Butyrivibrio species, Anaerostipes species, Ruminococcus species, and Clostridium species are also known to produce butyrate. Additionally, Bacteroidetes, Actinomycetes, Spirochetes, and Proteobacteria are also thought to be butyrate-producing.

Preventative and therapeutic uses of butyrate

Based on its anti-inflammatory, immunomodulatory, and anti-atherogenic properties and its role in cholesterol biosynthesis and insulin sensitivity, butyrate is an important therapeutic agent. Its role in the management of inflammatory bowel disease, diabetic kidney disease, obesity, and colon cancer has been extensively studied. Butyrate also has potential benefits in cardiovascular and renal health.

Studies have also explored the application of butyrate in treating diseases related to an overactive immune system, such as systemic lupus erythematosus, where dysregulation of immune responses results in dysbiosis of the gut microbiota. With gut microbial diversity regulating properties, butyrate has shown promising results in increasing the diversity and restoring the gut microbiome balance in lupus patients.

Butyrate has also been used in treating chronic inflammatory conditions of the skin, such as atopic dermatitis and psoriasis. Butyrate can modulate pH and restrict microbial growth, reduce the permeability of the epidermis, and suppress cutaneous inflammation. Treatment with single-chain fatty acids, especially butyrate, was seen to improve the barrier functions of the skin in animal atopic dermatitis models by modifying the metabolism of the mitochondria in epidermal keratinocytes. Furthermore, the T-regulatory cell-modulating properties of butyrate could also make it a potential treatment option for psoriasis, where the activity and number of T-regulatory cells are reduced.

The review also discussed studies that examined the effect of butyrate supplementation in HIV patients and reported that butyrate supplementation alone was seen to be insufficient in increasing the epithelial integrity or immunological reconstitution of HIV macaque models being treated with antiretroviral therapy. Various studies have also investigated the use of butyrate supplements in cancer therapy, especially for restoring gut microbial diversity. The findings indicate that while butyrate alone cannot inhibit the growth of the tumor, it has significant anti-cancer effects when it is combined with chemotherapy. Butyrate has also been seen to play a significant role in modulating circadian rhythms and regulating the levels of sleep hormones.

Conclusions

Overall, the findings suggested that butyrate has substantial immunomodulatory and anti-inflammatory properties and plays an important role in maintaining a healthy balance in the gut microbiome. The evidence from various studies indicated that butyrate can potentially be used as a therapeutic or prophylactic agent in various immune-related diseases in combination with other therapies.