All About Butyrate

Butyrate is one of the best kept secrets as a dietary supplement. With more and more people struggling with chronic inflammation, our gut flora is often to blame. However, as outlined in a previous article, studies have shown many problems with prebiotic and probiotic supplements, so that they may be neither safe nor effective. In this article, we will cover everything you need to know about butyrate and how to harness its powerful health benefits.

What is Butyrate?

Butyrate is derived from the Greek word for butter because the molecule is responsible for the characteristic smell of rancid butter and cheeses. It is one of the short-chain fatty acids that is produced by our friendly gut bacteria from fermenting prebiotic fibers, such as resistant starches and soluble fibers.  

Among all the beneficial bacterial metabolites produced, butyrate is the most potent, and thus the most beneficial1. Therefore, butyrate is the most promising molecule for replicating the benefits of probiotics.

How does butyrate work?

1) As an epigenetic modifier – by turning genes on

Butyrate is the strongest epigenetic modifier among all short-chain fatty acids produced by beneficial gut bacteria1. Acetyl groups on chromosomes are epigenetic marks that keep chromosomes open, allowing genes to be easily read2. Butyrate can keep certain genes on by inhibiting the removal of acetyl groups from our chromosomes.

2) Fueling the gut cells and supporting the mitochondria

Butyrate is the fuel that your gut cells prefer4,5. Butyrate also stimulates mitochondrial energy production, including when there is oxidative stress5,6.

3) By affecting cellular activities through cell-surface receptors

Many of our tissues outside the gut and liver have receptors to sense butyrate directly. These tissues include fat cells, immune cells, and neurons3.

Health Benefits of Butyrate

1) Promoting a balanced immune response

A healthy immune system needs not only to fight off infections, but also needs to know when to shut off and ignore its own healthy cells and harmless molecules. The failure of the immune response to shut off or ignore accordingly may result in chronic inflammation, allergies, and autoimmunity. The immune cells that orchestrate this shut-off or ignorance are called regulatory T cells, which work in opposition to the autoimmunity and allergy-promoting Th17 cells. 

Butyrate might be the key molecule that explains why butyrate-producing bacteria helps balance the immune response. Newly diagnosed type 1 diabetic children have significantly less butyrate production by their microbiome than otherwise similar nondiabetic children (control group)7. Several rodent studies have shown that butyrate promotes healthy levels and functions of regulatory T cells in the gut and other mucosal barriers in the mouth, eyes, lungs, and vagina8,9,10.

Butyrate might be the key molecule that explains why butyrate-producing bacteria helps balance the immune response. Newly diagnosed type 1 diabetic children have significantly less butyrate production by their microbiome than otherwise similar nondiabetic children (control group)7. Several rodent studies have shown that butyrate promotes healthy levels and functions of regulatory T cells in the gut and other mucosal barriers in the mouth, eyes, lungs, and vagina8-10. 

Butyrate may also reduce inflammation by stimulating the vagus nerve11.

Taken together, the evidence suggests that butyrate may help with autoimmunity, allergies, and chronic inflammation.

2) Repairing leaky gut and protecting the gut barrier

Butyrate promotes the health of the mucosal barrier. It is a preferred energy source of the gut lining. At low concentration, it repairs and enhances the gut mucosal barrier function, improves tight junctions, and increases mucus levels12. However, at excessive concentrations, it may trigger cellular suicide (apoptosis)13.

Contrary to popular belief, although some probiotics may prevent antibiotic-associated diarrhea, probiotic supplementation after a course of antibiotics may slow down the recovery of the gut flora14. Probutyrin, with or without probiotics, supports gut barrier repair after antibiotics15.

Probutyrin also protects the gut barrier in the presence of chemical insults or infections. For example, alcohol is known to cause leaky gut. In mice, probutyrin protects the gut barrier from alcohol-induced injuries16.

3) Supporting healthy metabolic health

A high-fiber diet may help reduce cholesterol by increasing short-chain fatty acids. In a test tube study, butyrate reduces lipoprotein production in gut cells17. A meta-analysis found that resistant starch lowers total serum cholesterol and low-density lipoprotein18. In mice, a high-fat diet often triggers both dysbiosis (imbalanced gut microbiome) and metabolic disorder, such as insulin resistance, diabetes, and high cholesterol, which could be reversed by butyrate19. Short-chain fatty acids may also reduce appetite20.

The relationships between obesity and fecal short-chain fatty acids appear to be more complex. Some studies have found that obese people have more butyrate in their stools than nonobese ones, while others found the opposite21,22. 

In newborn pigs, butyrate stimulates the activity of satellite cells (muscle stem cells)23, suggesting that butyrate may also stimulate muscle growth and repair, which is beneficial for long-term metabolic health. 

Overall, dietary fiber and resistant starch consumption can unequivocally help with several aspects of metabolic health by normalizing the microbiome and increasing short-chain fatty acids like butyrate. However, the effects are best when combined with a healthy diet and exercise.

4) Supporting brain and cognitive health

Butyrate is a nootropic. Butyrate can cross the blood-brain barrier and also keep the barrier healthy, preventing outside toxins or inflammation from entering the brain24,25. It improves mitochondrial function, which is a hallmark of many cognitive enhancers6. The epigenetic effects of butyrate help with neuroplasticity and memory26,27. Butyrate also supports healthy levels of brain-derived neurotrophic factors, which promote healthy mood, learning, and neuronal repairs28.

It also protects neurons and reduces cognitive impairments. In a mouse model of multiple sclerosis, short-chain fatty acids slow down the destruction of myelin (the fat layers that help neurons work efficiently) and support the re-creation of myelin29. Several preclinical studies suggest that butyrate may be a promising treatment or adjunctive treatment for addictions, depression, autism spectrum disorders, and neurodegenerative diseases3.

5) Improving sleep

Our gut flora controls how we sleep with its metabolites, and human sleep disruption can lead to dysbiosis30. Not surprisingly, sleep disruption correlates with many diseases that are often found with dysbiosis30. Deep sleep is the most restorative sleep, and thus a major determinant of sleep quality31.

Butyrate and probutyrin ingestion in rats resulting in 50% – 70% increase in total sleep for up to 6 hours afterward. In addition, deep sleep (slow-wave brain activity) increased during the first six hours32.

6) Prevent abnormal cell growth

Inhibiting the removal of acetyl groups tends to stop multiplying cells (stem cells) from multiplying and trigger them to differentiate into its eventual specialized form (such as colonocytes) instead. For example, cells on the top of the villi that line the gut differentiate into its final function because it’s exposed to butyrate, whereas cells deep inside the villi maintain their ability to multiply as they are kept away from the butyrate. This property of butyrate, which is similar to how several tumor-suppressor genes work, is one of the reasons it can stop cancer cell growth1. 

Butyrate is, therefore, one of the most promising natural treatments for cancers. However, the problem is how to deliver enough butyrate into the cancer cells to produce the desired clinical results. In fact, numerous inventors have attempted to engineer drug discovery systems to deliver it into cancer cells in the past few decades33.

Antineoplaston, a promising candidate for cancer treatment in clinical trials, may work similarly to butyrate34. 

Pharmacokinetics of butyrate: a major challenge

Butyrate holds great promise for many modern lifestyle diseases, for which we currently do not have safe and effective drugs. However, the key challenge is how to bring enough butyrate to the target cells because gut lining cells will rapidly consume free butyrate, making it unavailable to the large intestine or to be absorbed into the bloodstream. 

Therefore, several forms of butyrate have been tested for both efficacies and effectiveness. Sodium and calcium/magnesium butyrate products provide bioavailable butyrate but the butyrate will not reach the large intestine or other target organs. Therefore, very large doses (10 – 20 capsules) will be necessary to achieve any benefits beyond the small intestine. These doses, resulting in an excessive concentration of butyrate in the gut, may trigger apoptosis in the gut lining13, which may result in leaky gut. 

Some calcium/magnesium butyrate products on the market may contain a trace of heavy metals, which can be harmful to sensitive people or healthy people who take large doses for long periods of time35.

Tributyrin is a prodrug triglyceride form of butyrate with more favorable pharmacokinetics36. It has three molecules of butyrate attached to a molecule of glycerol. It is a slow-release form of butyrate because a lipase (fat-digesting enzyme) is needed to cleave it into three molecules of butyrate and one of glycerol. 

Tributyrin can also be absorbed whole into the bloodstream and directly into target cells, where lipase inside these cells release butyrate over time37. Tributyrin “DR”™ capsules result in therapeutic levels of butyrate both in the cell and the blood. It is also well tolerated38.

If tributyrin is present in the small intestine, the intestinal lipase will cleave it, making the free butyrate available to the gut cells, which will rapidly metabolite the butyrate for energy. Healus Complete Biotic is an innovative product that circumvents this problem with a patented delivery technology. Complete Biotic will release butyrate right inside your large intestine, where it will help promote a healthy microbiome. It is more likely to get absorbed whole to release butyrate throughout the body.