Butyrate is crucial for gut and brain health and may prevent autoimmunity and obesity. Read on to learn about the benefits of butyrate, possible side effects, and sources.
What is Butyrate?
Butyrate is a short-chain fatty acid (SCFA). Fatty acids are the building blocks of fats that our cells need to function. Butyrate is made when the bacteria living in our guts ferment otherwise indigestible fibers from grains, beans, onions, bananas, and other foods rich in complex carbs [1, 2, 3].
Butyrate is the preferred energy source for the cells in your colon wall. It is essential for maintaining a healthy barrier between the colon and bloodstream and it prevents inflammation in the gut [4].
Butyrate production depends largely on the pH of the large intestine. Bacteria that produce butyrate thrive in a more acidic environment (lower pH), whereas bacteria that produce other SCFAs such as acetate and propionate prefer a more alkaline environment (higher pH) [3].
Snapshot
Proponents:
- Is a major energy source for colon cells
- Believed to help prevent colon cancer
- Increases mitochondrial activity
- Prevents toxins from crossing the gut barrier
- Improves insulin sensitivity
- Promotes healthy weight
- Fight inflammation
- Prevents the growth of pathogenic bacteria
- Protects the brain
Skeptics:
- Strong odor
- Lack of high-quality human research
- Difficult to separate butyrate from other short-chain fatty acids
How Does Butyrate Work?
Butyrate inhibits histone deacetylase (HDAC), an enzyme that packs up DNA into tight, compact structures and prevents it from being expressed; in other words, butyrate loosens up the DNA structure and increases gene expression [5, 6].
Drugs that inhibit HDAC are currently used to manage bipolar disorder and prevent epileptic seizures. Early research suggests that they may also be effective antidepressants [7, 8].
The relationship between butyrate and HDAC helps explain why our gut flora have such a large influence on our mental health. Sure enough, people with major depressive disorder have fewer butyrate-producing bacteria in their intestines [9].
Functions & Benefits of Butyrate
Because butyrate is present in essentially everyone’s colon and produced by almost everyone’s gut flora, this section will describe the physiological function of butyrate and the potential benefits of supplementation.
Butyrate supplements have not been approved by the FDA for medical use and generally lack solid clinical research. Regulations set manufacturing standards for them but don’t guarantee that they’re safe or effective. Speak with your doctor before supplementing.
Important Functions
1) Gut Health
Butyrate is essential for maintaining a healthy environment in the gut. In the human colon, anaerobic bacteria such as Clostridium butyricum, Roseburia intestinalis, and Faecalibacterium prausnitzii ferment carbohydrates and produce short-chain fatty acids (SCFAs): acetate, propionate, and butyrate [3, 10, 11].
Colon Cell Energy Source
Butyrate nourishes the colon wall, maintains a healthy lining and barrier function of the colon, and prevents intestinal inflammation [4].
In the mitochondria of colon cells, 70-90% of butyrate is oxidized into acetyl-CoA, which is then used to generate large quantities of ATP, the primary form of cellular energy [12].
If you don’t have enough butyrate-producing bacteria in your gut, you may be more likely to develop diarrhea, inflammatory bowel disease (IBD), and even colon cancer [13, 14, 15, 16, 17].
Inflammatory Bowel Disease
Short-chain fatty acids, especially butyrate, can reduce the symptoms of inflammatory bowel disease (IBD). In one study of 13 people with Crohn’s disease, a type of IBD, butyrate supplements improved 69% of cases, with symptoms completely disappearing in 54% (seven participants) [18, 19, 20, 21].
There are a variety of approaches for using butyrate to manage IBD and colitis. The treatment strategies range from a high-fiber diet to butyrate-producing probiotics, coated butyrate tablets, and rectal enemas [22, 23].
Diarrhea & Gut Inflammation
Resistant starch is a type of soluble fiber that your gut bacteria can ferment into butyrate. A diet containing lots of resistant starch improved diarrhea in a trial of 57 baby boys [24].
Butyrate can also prevent inflammation and stomach ulcers caused by alcohol. Mice given butyrate before alcohol had less inflammation and damage to the lining of their stomachs [25].
Sodium butyrate in combination with other SCFAs and silicon dioxide was also shown to benefit traveler’s diarrhea, a condition common among those who travel to exotic countries [26].
2) Inflammation
Butyrate suppresses the activity of cells and proteins that drive inflammation [27].
In one study on human cells, butyrate drastically reduced the activity of interleukin-12 (IL-12), an inflammatory cytokine, while increasing interleukin-10 (IL-10), which is generally anti-inflammatory [28].
In mice, butyrate-producing dietary fibers counteracted inflammation and illness caused by bacterial toxins. The inflammatory cytokines inhibited by butyrate included interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-alpha), and interferon gamma (INF-y) [29].
Immune Response
Butyrate may reduce inflammation by increasing the activity of immune cells called regulatory T cells or Tregs. These specialized cells stop other immune cells – Th1, Th2, and Th17 – in their tracks, before they lose control. In turn, Tregs prevent the lining of the gut from overreacting to harmless food proteins [30].
Gut Barrier
Butyrate also strengthens the barrier formed by cells in the colon wall, thus preventing microbes and bacterial toxins from invading the bloodstream [31].
Inflammation Due to Aging
As we grow older, inflammation increases throughout our bodies. In aging mice, a diet high in fiber that produces butyrate counteracted age-related increases in inflammation, suggesting that butyrate may be especially helpful to the elderly. Human studies will be required to confirm this benefit, however [32].
3) Fine-Tuning the Immune System
As an HDAC inhibitor, butyrate adjusts the immune system in a number of ways.
HDAC inhibitors improve the tumor-targeting abilities of immune cells like T cells and natural killer cells; they are currently under investigation as potential cancer drugs. This class of compounds also reduces many inflammatory signals and increases Tregs, a type of white blood cell that prevents allergies and autoimmunity [33, 34, 35].
Butyrate more specifically protects the gut barrier and prevents pathogens and other harmful agents from crossing into the bloodstream [36].
4) Brain and Nerve Cells
The gut and the microbiome strongly affect the brain. Your gut bacteria “talk” to your cells by releasing butyrate, which (as an HDAC inhibitor) turns on certain genes [37].
Cognition
Butyrate may improve learning and long-term memory. Similar to exercise, sodium butyrate increased brain-derived neurotrophic factor (BDNF) in mice. Simply put, butyrate supplies “brain food” (neuro = brain, trophic = food) to the hippocampus, the brain’s hub for memory and emotions. This gives birth to new neurons, called neurogenesis, a process that can reshape the brain [38].
The effect of butyrate supplements or intestinal butyrate concentration on cognition has not been tested in humans. However, this effect has been repeated multiple times in animals, and probiotics containing butyrate-producing bacteria have been associated with reduced stress in humans. Human trials on butyrate and cognition are likely to be next [39, 40, 32, 41].
Brain Injury
There’s a huge overlap between cognitive enhancement and recovery from brain damage. Both rely on neurogenesis, a process that replenishes and reshapes the brain.
In a mouse study, sodium butyrate given after a stroke supported the development of new nerve cells in the damaged areas. It also strengthened the blood-brain barrier in mice with brain trauma, which helped them recover. Butyrate-producing bacteria also strengthened this barrier in mice [42, 43, 44].
Clostridium butyricum, a butyrate-producing species of bacteria, may help manage vascular dementia, a disease whereby blood vessel blockages prevent brain cells from getting enough oxygen. In a mouse study, animals with C. butyricum in the gut experienced less cell death in their brains [45].
These effects have not yet been investigated in human trials.
Nerve Damage
Butyrate may also help manage other types of nerve damage. In guinea pigs, sodium butyrate protected nerve cells in the ear after treatment with antibiotics, thus preventing hearing loss [46].
Mice with brain damage due to lack of oxygen fared better when they were given the butyrate-producing bacteria Clostridium butyricum before the injury [47].
Sodium butyrate also prevented the death of nerve cells in the spine of mice with spinal muscular atrophy [48].
5) Social Life
Butyrate may impact your social life. Along with other fatty acids produced by your gut bacteria, butyrate is a “social odor.” According to one study, it may even influence whether people will find you attractive [37].
Humans can detect even the tiniest amount of butyrate by smell; in fact, our noses are better at picking out butyrate than almost any other chemical on Earth. At high concentrations, it triggers a disgust response because it may indicate that something is rotting or diseased. At low concentrations, however, it can tell us about the immune status of other humans [37].
Some researchers have suggested that a light smell of butyrate in another person’s body odor may indicate that they are healthy, strong, and a good person to socialize with [37].
Insufficient Evidence For
The following purported benefits are only supported by limited, low-quality clinical studies. There is insufficient evidence to support the use of butyrate for any of the below-listed uses. Remember to speak with a doctor before taking butyrate supplements, and never use them in place of something a doctor recommends or prescribes.
6) Weight Regulation
Firmicutes and Bacteroidetes are two major groups of microbes that live in the human gut. A higher ratio of Firmicutes to Bacteroidetes has been associated with weight gain and obesity. Interestingly, supplementation of SCFAs (including butyrate) has been shown to promote Bacteroidetes, leading to weight loss in mice [49, 50].
In a trial of 118 overweight people, butyrate-producing fiber supplements also led to reduced body weight and BMI [51].
In a trial of 12 men, SCFAs delivered directly into the colon increased the amount of fat being burned and energy being spent [52].
In mice, the SCFAs butyrate and propionate (but not acetate) prevented obesity and insulin resistance caused by diet [53, 50].
In another mouse study, butyrate caused obese mice to lose 10% of their body weight, while their body fat was reduced by 10%. In combination with calorie restriction and exercise, butyrate may promote weight loss in obesity [54].
SCFAs may prevent weight gain and obesity through several mechanisms, including [50]:
- Revving up fat burning (enhancing triglyceride breakdown and fatty acid oxidation)
- Transforming fat cells into brown fats, which are more easily burned for energy [55]
- Promoting the generation of new mitochondria
- Inhibiting chronic inflammation
7) Blood Sugar Regulation
People with diabetes often have gut flora imbalances; less butyrate tends to be produced in their guts. A review study found that butyrate helped control blood sugar in both animals and humans with type 2 diabetes [11].
Human studies have also reported associations between fermentable dietary fiber and improved blood sugar control [56, 57].
In mice, butyrate supplementation increases insulin sensitivity. Meanwhile, in diabetic rats, sodium butyrate protected insulin-producing cells and reduced blood sugar [54, 58].
Additionally, in diabetic mice, butyrate decreased blood hemoglobin A1c (HbA1c, a measure of long-term blood sugar), inflammatory cytokines, and lipopolysaccharides (LPS). It also strengthened the gut barrier [59].
Animal & Cell Research (Lacking Evidence)
No clinical evidence supports the use of butyrate supplements for any of the conditions listed in this section. Below is a summary of the existing animal and cell-based research, which should guide further investigational efforts. However, the studies listed below should not be interpreted as supportive of any health benefit.
8) Mood
Butyrate increases the enzyme that produces dopamine (tyrosine hydroxylase) [60].
Through its action on dopamine, butyrate may also stabilize mood; in rodents, it prevents both depression and mania. In mice kept under chronic stress, it acted as an antidepressant; it also stabilized rats with mania. Sodium butyrate also relieved depression and improved cognitive function in mice [61, 62, 39].
Butyrate increases neuronal growth in the hippocampus, a part of the brain that usually shrinks in people with depression. In rats, sodium butyrate increased proteins that help regrow the brain, including brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF) and glial cell-derived neurotrophic factor (GDNF). This may explain butyrate’s mood-stabilizing benefits [63].
Sodium phenylbutyrate, a butyrate-containing drug used to treat urea cycle disorders, also lessened anxiety and depression in mice [64].
9) Addiction and Relapse
Because of its action as a histone deacetylase (HDAC) inhibitor, some researchers have suggested that butyrate could potentially prevent or even help reverse drug addiction. Sodium butyrate reduced the quantity of alcohol addicted rats chose to drink [65].
Phenylbutyrate also reduced the desire for cocaine in rats with cocaine addiction [66].
However, there is evidence that very high doses of butyrate can act in concert with drugs of abuse and help to promote addiction, while lower doses of butyrate could prevent dependence [67].
One review study found that butyrate’s effect on addiction also depends on timing: small doses of butyrate given at the same time as cocaine most effectively prevented drug-seeking behavior and accelerated recovery time in animals [68].
10) Allergies
Sodium butyrate improved symptoms and biological markers of allergy in mice with allergic rhinitis (hay fever) [69].
In human cells and mice, SCFAs including butyrate inhibited the increase in white blood cells called eosinophils in response to allergens. During an allergic reaction, eosinophils are highly activated and produce harmful inflammation; butyrate helps deactivate these cells and resolve the inflammatory response [70].
This potential benefit has not yet been tested in human studies.
11) Symptoms of Autism
Sodium butyrate reduced autistic behavior in mice. Another study showed sodium butyrate helped autistic mice to recognize objects better [71, 72].
Notably, propionic acid, another SCFA, is used to simulate autism-like behavior in mice and rats. The contrasting effects of propionate and butyrate demonstrate just how important it is to fine-tune the gut flora and their products; not all SCFAs are created equal [73].
12) Neurodegenerative Diseases
According to animal studies, butyrate may potentially protect nerves and brain cells from degenerative disease. In mice, butyrate promoted the survival of nerve cells in mice with amyotrophic lateral sclerosis (ALS), a disease which makes the nerves responsible for movement die off [74].
In a mouse model of Alzheimer’s disease, the most common neurodegenerative condition, sodium butyrate improved memory function through inhibition of histone deacetylase (HDAC). In mice, phenylbutyrate also prevented the accumulation of beta-amyloid proteins in the brain. When these proteins build up into plaques, the cognitive symptoms of Alzheimer’s progress [75, 76].
Huntington’s disease is a condition in which brain cells die out, causing muscle problems and disordered movement. In mice with this condition, phenylbutyrate improved movement, body weight, and the ability to recognize objects [77].
The same beneficial effect was demonstrated in human cell cultures. In neurons with a buildup of the mutated protein huntingtin, the marker of Huntington’s disease, sodium butyrate allowed the cells to live longer [78].
13) Damage from Radiation
One cell study suggests butyrate may protect mitochondria – the energy factories inside cellS – against radiation. Butyrate may also protect the mitochondria from other forms of oxidative stress, but its potential against radiation poisoning is especially encouraging [79].
14) Liver & Pancreas Health
Sodium butyrate prevented mice from developing non-alcoholic steatohepatitis (NASH), an inflammatory disease caused by fat building up in the liver [80].
Sodium butyrate also blocked inflammation and protected the pancreas from inflammation in mice [81].
15) Heart Health
In a combined mouse and cell study, sodium butyrate prevented hardening of the arteries (atherosclerosis) by inhibiting inflammation [82].
What’s more, a cell study revealed that butyrate can decrease the expression of genes that make cholesterol, possibly reducing cholesterol production [83].
If these results can be reproduced in humans, butyrate may decrease the risk of cardiovascular disease.
16) Anemia
Butyrate can switch on a hemoglobin gene that generates red blood cells. Thus, butyrate may prevent or manage some forms of anemia, especially during pregnancy [84].
17) Antibacterial Activity
Butyrate is toxic to certain harmful species of bacteria. Cell studies revealed that butyric acid can directly kill or inhibit the common foodborne pathogen Salmonella and Clostridium perfringens, which causes gangrene [85].
Moreover, butyrate can influence gene activity in Salmonella, reducing the bacteria’s ability to invade tissues and possibly cause disease [86].
Recently, researchers discovered butyrate can destroy the cell wall in H. pylori, a bacterium that causes gastritis and ulcers [87].
A trial of butyrate against shigellosis in rabbits demonstrated that it is anti-inflammatory during infection. As many symptoms of infection stem from inflammation, this result suggests that butyrate may lessen the severity of bacterial disease [88].
Butyrate can also kill bacteria indirectly by increasing the host’s production of antimicrobial proteins that destroy bacteria. This is also true for phenylbutyrate [89, 90].
Cancer Research
Butyrate has shown anticancer effects in cell studies; it inhibited tumor growth by promoting programmed cell death (apoptosis) of cancer cells [91, 92, 93, 94].
However, butyrate is not effective enough on its own because it is eliminated too quickly. For this reason, a prodrug of butyrate—that is, another chemical which the body metabolizes into butyrate—has been proposed for use instead [95].
Tributyrin is a novel prodrug of butyrate that is found in milk fat and honey Tributyrin was able to destroy cancer cells in patients with advanced solid tumors [96, 97].
At least two more butyrate-containing preparations with anti-cancer activity have been or are currently being tested:
- Pivanex (pivaloyloxymethyl butyrate), which prevented metastases and blood vessel growth in tumors [98]
- Butyroyloxyethyl esters, which transform into formaldehyde, which in turn kills cancer cells [99]
Another possible approach is to inject butyrate-producing bacteria into the tumors to destroy them from within. This strategy has not yet been tested [100].
Synergies
Sodium butyrate can also be combined with other cancer-killing substances. For example, its combination with nicotinamide and calcium glucarate prevented the formation of skin tumors in mice [101].
In leukemia cells, a combination of sodium butyrate and artemisinin, a plant-derived compound, was very effective at killing cancer cells, even at low doses [102].
Some have proposed to combine interleukin-2 (IL-2), a cytokine that activates killer cells, with butyrate. According to rat trials, this combination helps the immune system target the cancer cells [103].
Against Colon Cancer
In multiple cell studies, butyrate prevented the growth of tumor cells and encouraged cancer cell destruction in the colon [104, 105, 106, 107].
Several review studies show a link between high-fiber diets, which feed butyrate-producing bacteria, and a reduced risk of colon cancer in humans [108, 109, 110].
Mice on a high-fiber diet who had butyrate-producing bacteria in their guts got 75% fewer colon tumors than mice without the bacteria. Mice were only protected from colon cancer if they had the appropriate bacteria; the high-fiber diet alone was not protective [111].
Butyrate Side Effects & Safety
Butyrate is considered safe and beneficial in the quantities normally produced by a healthy gut flora. Eating dietary fiber instead of supplements to increase butyrate likely prevents any risk of overdose.
In a rat study, supplementation of butyrate during pregnancy and breastfeeding led to insulin resistance and fat accumulation in the offspring. If you are pregnant or nursing, it is best to avoid butyrate supplements until we know more [112].
Butyrate Supplements & Foods
Sodium Butyrate vs. Cal Mag Butyrate
Butyrate supplements come in a few different forms, the most common among them being sodium butyrate and “cal mag” butyrate. These supplements, as their names suggest, deliver butyrate bound to either sodium or calcium and magnesium.
You may also be able to find coated butyrate tablets, in which butyrate “beads” are protected by a layer of fatty acids. In theory, the fatty coating should prevent the release of butyrate before it reaches the intestine.
Unfortunately, we didn’t find any studies comparing and contrasting the different forms of butyrate supplements; we currently don’t know which supplement form might be more or less bioavailable or effective [113, 114].
Food Sources
You get can butyrate from food. For example, butyric acid abounds dairy products, especially butter. Butter, which gave butyrate its name, contains about 3 to 4% of butyrate in the form of tributyrin. Plant oils also contain butyrate to some extent [115, 116, 117].
Eating more fiber increases butyrate production by some bacteria in your gut. There is generally an association between a higher intake of plant foods and increased levels of short-chain fatty acids (SCFAs), including butyrate, in stools. However, not all plant-based foods yield butyrate; for example, diets rich in fruit or starch are associated with high butyrate levels in the gut, but starch-free wheat bran is not [118, 119, 120, 121].
Depending on the composition of your gut flora, the following fibers may encourage them to produce SFCAs, including butyrate [122, 123, 124]:
- Inulin: artichokes, garlic, leeks, onions, and asparagus
- Fructooligosaccharides (FOS): fruits and vegetables, including bananas, onions, garlic, and asparagus
- Resistant starch: cooked and cooled rice, potatoes and green bananas
- Pectin: apples, apricots, carrots, oranges, and others
- Oat bran
- Arabinoxylan
- Guar gum
- Arabinogalactan
- Hi-Maize, potato or plantain starch flours
Takeaway
Among the short chain fatty acids, butyrate may be the most beneficial for health. Butyrate, produced by healthy gut bacteria, reduces inflammation, protects the brain and may help prevent obesity and cancer.
While supplementation with butyrate directly is possible, it is likely safer and more efficient to use dietary fiber to boost butyrate production by the gut flora. The best fibers for this purpose include inulin (as in artichokes and garlic), resistant starches (rice, potatoes, and green bananas), pectin (many fruits), and oat bran.
