What Is Butyric Acid? Benefits, Dosage and Side Effects

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You may not have realized it, but chances are you&#;ve consumed something called butyric acid before, and believe it or not, your body produces it as well. It&#;s true &#; butyric acid, also known as butanoic acid or BTA, is a saturated short-chain fatty acid found in butter, ghee, raw milk, animal fats and plant oils.

It&#;s also formed in and therefore found in our colons through the bacterial fermentation of carbohydrates like dietary fiber. Butyric acid supports the health and healing of cells in the small and large intestine. It&#;s also the favored source of fuel for the cells lining the interior of the large intestine or colon. (1)

The BTA content in ghee is one of the main components that provides all those wonderful ghee benefits. Consuming butyric acid in foods like ghee or in supplement form has been shown to aid digestion, calm inflammation and improve overall gastrointestinal health.

People who suffer from irritable bowl syndrome and Crohn&#;s disease have been shown to benefit from butyric acid, and studies show promise when it comes to diabetes and insulin resistance too. BTA is also known as a potential anticancer fatty acid, especially when it comes to colon cancer. (2)

I&#;m excited to tell you more about this extremely interesting fatty acid and how it can improve your overall health &#; and how it already is without you even knowing it!

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What Is Butyric Acid?

Butyric acid is a colorless liquid that is soluble in water. Scientifically speaking, its structure is four carbon fatty acids with the molecular formula C4H8O2 or CH3CH2CH2COOH. Butyric acid has other chemical names, including butanoic acid, n-butyric acid, n-butanoic acid and propylformic acid. (3) Along with acetic and propionic acids, it account for approximately 83 percent of the short chain fatty acids in the human colon.

On its own, BTA has an unpleasant smell and bitter, pungent taste, with a somewhat sweet aftertaste. It occurs as esters in animal fats and plant oils. What&#;s an ester? An ester is an organic compound that reacts with water to produce alcohols and organic or inorganic acids. Esters derived from carboxylic acids like butyric acid are the most common type of esters.

BTA is generated in the large intestine together with other short chain fatty acids from the fermentation of dietary carbohydrates, specifically prebiotics like resistant starches, fructooligosaccharides and other dietary fiber. (4)

The names &#;butyric acid&#; and &#;butyrate&#; are commonly used interchangeably even in scientific articles and studies. Technically, they have slightly different structures, but they&#;re still very similar. Butyrate or butanoate is the traditional name for the conjugate base of butyric acid. Put simply, butyrate is almost identical to butyric acid, but it just has one less proton. Judging by scientific studies, they appear to be pretty much identical in their health benefits.

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Health Benefits

1. Weight Loss

Butyric has gained popularity for its ability to possibly help people shed unwanted pounds. Scientific evidence has shown that people who are obese (as well as people who have type II diabetes) have a different composition of gut bacteria. Short chain fatty acids are believed to play a positive role along with probiotics in preventing metabolic syndrome, which almost always includes abdominal obesity. (5)

Short chain fatty acids like butyric acid help regulate the balance between fatty acid synthesis and the breakdown of fats. In a  animal study, after five weeks of treatment with BTA, obese mice lost 10.2 percent of their original body weight, and body fat was reduced by 10 percent. Butyric acid was also shown to improve insulin sensitivity, which helps guard against weight gain. (6)

Most of the evidence for linking BTA supplementation specifically to weight loss is based on animal research so far, but it does show positive effects in treating obesity naturally.

2. Potential Colorectal Cancer Treatment

Multiple studies have shown butyric acid&#;s potential ability to fight cancer, especially cancer in the colon. It&#;s actually shown an ability to &#;modify nuclear architecture&#; and induce the death of colon cancer cells. This is likely a huge reason why increased fiber intake has been linked with less colon cancer since higher fiber intake can typically equate to more butyric acid present in the colon. (7)

According to research published in the International Journal of Cancer, &#;the role of short chain fatty acids, particularly butyrate, in colon cancer therapy has been extensively studied, and its tumor suppressive functions are believed to be due to their intracellular actions.&#; This laboratory study further shows that butyrate treatment led to an increase in the programmed cell death of colon cancer cells. (8)

According to a scientific article, it looks like &#;a high-fiber diet protects against colorectal tumors in a microbiota- and butyrate-dependent manner.&#; (9) What does that mean? It means that most likely getting plenty of fiber isn&#;t what fends off cancer on its own. It&#;s eating a diet rich in healthy fiber AND having enough good gut flora AND enough BTA present in the body that can provides cancer defense in the colon.

3. Irritable Bowel Syndrome (IBS) Relief

In general, butyric acid can have a very positive impact on gut health, which greatly affects the health of your entire body. Short chain fatty acids like butyric acid can help keep the gut ling healthy and sealed, which prevents leaky gut syndrome and all kinds of issues linked to a leaky gut like IBS symptoms. This is a type of digestive disorder that&#;s characterized by a group of common symptoms, including changes in bowel movements and abdominal pain.

A scientific article published in the Gastroenterology Review looked at butyric acid&#;s potential as an IBS diet therapy based on numerous studies conducted to date. Researchers conclude that &#;butyrate supplementation seems to be a promising therapy for IBS.&#; (10)

Some notable  research included in the article was a double-blind, randomized, placebo-controlled study involving 66 adult patients with IBS who were given microencapsulated butyric acid at a dose of 300 milligrams per day or a placebo in addition to receiving standard therapy.

After four weeks, researchers found that subjects who took the butyric acid had a statistically significant decrease in the frequency of abdominal pain during bowel movements. After 12 weeks, subjects in the BTA group experienced decreases in the frequency of spontaneous abdominal pain, postprandial abdominal pain, abdominal pain during defecation and urge after defecation. (11)

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4. Crohn&#;s Disease Treatment

Crohn&#;s disease is a type of inflammatory bowel disease (IBD) characterized by inflammation of the lining of the GI tract, abdominal pain, severe diarrhea, fatigue, weight loss and malnutrition. Again, this is a disease related to a leaky gut. A study published in the journal Alimentary Pharmacology & Therapeutics was small, but it found that &#;oral butyrate is safe and well tolerated, and may be effective in inducing clinical improvement/remission in Crohn&#;s disease.&#; (12)

Another study showed that butyric acid can reduce pain during bowel movements and inflammation in the gut, both of which are extremely helpful to Crohn&#;s disease and other inflammatory bowel diseases. (13)

Short chain fatty acids like BTA truly play a crucial role in the maintenance of gut barrier integrity, which can help ward off a leaky gut and avoid an IBDs like Crohn&#;s.

5. Combats Insulin Resistance

A study published by the American Diabetes Foundation looked at butyric acid&#;s effect on the regulation of insulin sensitivity in mice consuming a diet high in fat. The study concluded that &#;dietary supplementation of butyrate can prevent and treat diet-induced insulin resistance in mouse.&#; Researchers also found that the mice treated with butyrate did not have any increase in body fat and the butyrate supplement actually appeared to prevent obesity. (14)

Researchers agree that more studies need to be conducted to further explore how butyrate affects insulin levels in humans, but it looks promising so far, which could have profound effects on treating diabetes.

6. General Anti-inflammatory Effects

Studies have shown the broad anti-inflammatory powers of butyric acid. It&#;s believed that not only can BTA help inflammatory conditions, but it might also have a helpful ability to manage immune responses. (15)

As we&#;ve said before, inflammation is the root of most diseases, which is why having more butyric acid in your body could likely benefit many people with various health problems with inflammatory roots.

How to Use

An increased intake of highly processed, low-fiber, high-sugar foods has been shown to decrease levels of butyrate production in the large intestine. Supplementing with butyric acid might be a good idea if you&#;re unable to obtain enough of it from your diet.

A butyric acid supplement is typically available at health stores or online. It&#;s most commonly found in capsule or tablet form. Dosage recommendations vary by product. Some recommend one to six capsules/tablets after meals while others suggest taking one capsule three times daily with meals, a few hours before or after taking other medications. It&#;s best to read product labels carefully and consult your doctor if you feel unsure.

If you prefer to get your butyric acid from foods, then the following are good choices: butter, ghee, raw milk and parmesan cheese. When looking for a high-quality butter, raw and cultured is best. This might be hard to find, however. Organic butter from grass-fed cows is your next best option. Some properly made kombucha (a fermented tea drink) can also contain butyric acid.

To naturally increase the butyric acid production in your body, you can up your intake of healthy prebiotics like raw Jerusalem artichokes, raw dandelion greens, raw jicama and under-ripe bananas.

Scientific research has found that fecal butyrate levels can vary greatly among individuals, but eating a diet high in resistance starches (like an under-ripe banana) typically increases butyric acid levels and may help maintain colorectal health. (16)

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Butyric Acid Interesting Facts

Butyric acid gets its name from the Greek word βούτ&#;ρον, which means butter. Butyric acid makes up about 3 percent to 4 percent of butter. Ever smell rancid butter? That unpleasant odor is the result of the chemical breakdown of the BTA glyceride. While on the topic of gross odors, butyric acid is actually responsible for human vomit&#;s distinctive scent too.

During his extremely long life (102 years plus), a French organic chemist named Michel Eugène Chevreul is said to have first observed butyric acid in its impure form in . It was by the acidification of animal fat soaps that he was able to identify butyric acid along with several other fatty acids for the first time, including oleic acid, capric acid (naturally occurs in coconut oil) and valeric acid. (17)

Risks and Side Effects

It&#;s hard to find any documented negative side effects of butyric acid supplements. If you take a butyric acid and experience any negative side effects, you may need to cut back on your dosage. Of course, if you have any serious side effects then you should discontinue use and seek immediate medical attention.

If you&#;re pregnant or nursing, speak to your doctor before taking a butyric acid supplement. Also talk to your doctor if you have any ongoing medical conditions or if you already take any other medications before taking a BTA supplement.

Final Thoughts

To increase the production of butyric acid in your body naturally, focus on getting more foods that contain butyric acid like ghee and high-quality butter on a regular basis. Also increase your daily intake of fiber-rich foods like vegetables, fruits, legumes and whole grains.

If you can increase your intake of these prebiotics, then you can help increase the probiotics and short chain fatty acids in your body. This is a healthy and easy way to increase your butyric acid levels, not to mention your overall health.

Having the right balance of all prebiotics, probiotics and short chain fatty acids appears to not only improve minor as well as chronic gastrointestinal issues, but many studies show how butyric acid may have some serious cancer-fighting power, especially colon cancer.

What about a supplement? A butyric acid supplement might be helpful, especially if you suffer from an inflammatory bowel disease or are trying to prevent colon cancer. When it comes to weight loss, most of the evidence linking butyric acid to weight loss is based on animal and test-tube studies. A butyric acid supplement should definitely not be thought of as a magic weight loss supplement but might be helpful along with an overall healthy lifestyle.

Abstract

The properties of butyric acid, and the role it plays in the gastrointestinal tract, have been known for many years. However, the newest research shows that butyric acid still remains a molecule with a potential that has not as yet been fully exploited. The article provides an outline of relevant up-to-date knowledge about butyric acid, and presents the expert position on the clinical benefits of using butyric acid products in the therapy of gastrointestinal diseases.

Keywords: butyric acid, irritable bowel syndrome, inflammatory bowel disease, constipation, diarrhea

Introduction

The properties of butyric acid, and the role it plays in the gastrointestinal tract, have been known for a long time now. However, butyric acid is still subject to intensive research which shows that it is a factor in the pathogenesis of gastrointestinal diseases, and has a range of previously unknown properties and potential therapeutic applications. Butyric acid remains a molecule with a potential that has not as yet been fully elucidated and realized.

The article provides an outline of relevant up-to-date knowledge about butyric acid, and presents the position of gastroenterology and surgery experts on the clinical benefits of using butyric acid products in the therapy of patients with gastrointestinal diseases. Since the article is a follow-up to the study published in [1], a number of issues already addressed in detail in the previous publication are left out, including the formation and roles of butyric acid in the gastrointestinal tract, problems associated with its deficiency, clinical indications and basic use recommendations.

Immunomodulatory activity of butyric acid in the gastrointestinal tract

Research conducted in recent years provides evidence for the long postulated mechanism of action of butyric acid, i.e. its effect on the gastrointestinal immune system. In studies on mice, Furusawa et al. [2] showed that the concentration of butyric acid on the colonic wall stimulates the differentiation of Treg lymphocytes, reducing the severity of inflammation induced by the transfer of TCD4+ CD45RBhi lymphocytes into Rag1&#;/&#; mice. Furthermore, in an in vitro study on undifferentiated T cells incubated with butyric acid, the authors demonstrated an increased acetylation of histone H3, which points to a possible mechanism by which butyric acid (produced by bacteria residing in the gastrointestinal tract) affects the differentiation and specialization of Treg lymphocytes. These very interesting studies have shed new light on the relationship between the host and the gut microflora, and its impact on immune homeostasis in the gut.

Gut-associated lymphoid tissue (GALT) and enterocytes (intestinal epithelial cells &#; IECs) act as the first barrier of defence against bacterial invasion through the secretion of mucins and/or defensins (antibacterial peptides) or the detection of pathogens by Toll-like receptors (TLRs). In addition, specialized IECs are capable of transporting bacterial antigens and presenting them to the immune cells in the lamina propria of the gut wall. The system becomes disturbed, for example, in the elderly, as the relationships and proportions between bacterial groups forming the microbiome are thrown off balance [3]. Similar unfavourable alterations in the microbiome composition are observed in inflammatory bowel diseases (IBD) or in irritable bowel syndrome (IBS), which is described in subsequent sections below. For many years butyric acid has been postulated to play a role of a primary messenger between commensal bacteria and the human immune system. In this understanding, the presence of butyric acid at an appropriate physiological concentration in the colonic lumen is interpreted by the body as information that the bacterial equilibrium is not disturbed, which reduces immune response and tolerance to thousands of antigens representing commensal bacteria and, hence, prevents the initiation of the inflammatory process [4].

Role of butyric acid in irritable bowel syndrome

Symptoms associated with gastrointestinal dysfunction, such as IBS, are estimated to occur in 10&#;30% of the population. The main signs of the disorder include abdominal pain, diarrhoea and altered conditions in the colon. Patients are typically advised to adopt dietary and lifestyle modifications, and are referred for psychotherapy. Pharmacological management includes antibiotics which act topically in the gastrointestinal lumen (rifaxamin) and, additionally, probiotics and in some cases antidepressants.

In one study, the microbiomes of 113 patients with IBS and 66 control subjects were analyzed. A statistically significant decrease in the amount of butyric acid-producing bacteria was found in the group of patients with IBS, particularly with IBS-D and IBS-M (p = 0.002). Also, there was a statistically significant reduction in the level of methane-producing bacteria (Methanobacteria) (p = 0.005), which increases local oxygen reservoirs and probably contributes to an increased incidence of flatulence in this patient group [5].

Considering the above, a compound which offers a high chance for success in the therapy of dysfunctional bowel disorders is sodium butyrate. In Tarnowski et al. [6] assessed the effect of sodium butyrate on selected clinical parameters in patients with irritable bowel syndrome during a 6-week follow-up. The patients were divided into two groups: control group (29 patients) receiving standard treatment with trimebutine and mebeverine (depending on the characteristics of the disease) throughout the entire follow-up period, and study group receiving sodium butyrate at 300 mg daily as an add-on to standard therapy. At baseline and 6 weeks into the study, a questionnaire was completed to assess the symptoms of the disease (on a scale from 0 to 5) and the quality of life IBS-QoL (on a scale from 0 to 100). At the time of inclusion in the study, there were no differences between the patient groups in the severity of discomfort and pain, bowel movement disorders, severity of flatulence and other gastrointestinal and IBS-associated symptoms. After 6 weeks, a statistically significant improvement was observed in the study group for the symptoms listed above. What is more, a significant improvement was achieved in the subjective assessment of the quality of life in all patients receiving sodium butyrate.

In Banasiewicz et al. [7] conducted a randomized clinical trial in a group of 66 patients with a long history of IBS diagnosed on the basis of the ROME II Diagnostic Criteria. The patients were divided into the control group (n = 32) and the study group receiving sodium butyrate (n = 34) at 300 mg/day (2 × 150 mg). The follow-up was 4, and then 12 weeks, with data collected using the Visual Analogue Scale for IBS (VAS-IBS). The following symptoms were assessed: pain in the epigastric region, incidence of flatulence, bowel movement disorders, mucus in stool and the quality of life (based on the IBS-QoL questionnaire). Four weeks after the start of the study, a significant decrease in the incidence of epigastric pain and a reduction in the severity of pain after meals were noted in the group receiving sodium butyrate. After 12 weeks, there was a statistically significant decrease in the incidence of all the symptoms studied, accompanied by an improvement in the patients&#; QoL. In subsequently published results [8], based on the closed question (yes or no) &#;Did you achieve good relief from abdominal discomfort or pain associated with IBS during the last week preceding the follow-up visit?&#;, &#;Yes&#; answers were achieved respectively in 32 and 6.25% of the patients (p < 0.01) in the study and control groups at week 4 of the study, and in 53 and 15.6% of the patients (p < 0.01), respectively, at week 12 of the study. Importantly, patients in both groups continued previously prescribed therapy (e.g. drotaverine, trimebutine) throughout the whole duration of the study, and received standard treatment for at least 3 months before the inclusion in the study. The authors concluded that butyric acid used as adjunct therapy in the treatment of IBS reduced the incidence of selected clinical symptoms, however without any effect on their severity.

Abdominal pain in patients with IBS is typically a result of disorders related to digestion and fermentation, and the build-up of gases in the gut lumen. The underlying causes of functional diseases have not been fully investigated and require further study, however existing hypotheses suggest that pain is a consequence of transmission abnormalities in the gut-brain axis. In patients with intestinal dysfunctions (IBS) sodium butyrate is one of the key factors contributing to gut homeostasis, enhancing natural processes of healing and regeneration in the intestinal epithelium. A decreased incidence of pain characteristic of IBS may be attributable to a diminished receptor sensitivity in the gut [9]. Based on an animal model butyric acid was shown to have an ability to increase the neuronal concentration in the Enteric Nervous System via phenotypic changes in the enteric neurons [10], which in turn has a favourable effect on colonic transit [11].

Another study assessed the efficacy of butyric acid in IBS. Fifty patients with IBS were divided into two subgroups &#; IBS with constipation (IBS-C) and IBS with diarrhoea (IBS-D) &#; and treated with butyric acid in the form of enteric-coated tablets at a dose of 1 g/day. The IBS form and the severity of symptoms were recorded at baseline and at the end of the study. Butyric acid treatment resulted in a reduction or normalization of symptoms in 71% of patients with IBS-D and in 16% of patients with IBS-C (p < 0.005) [12].

As of today, more than 1,000 bacteria residing in the human gastrointestinal tract have been detected. A vast majority of them belong to about a dozen genera. In adults, Firmicutes and Bacteroidetes are the most abundant phyla, and the Firmicutes to Bacteroidetes ratio appears to determine the bacterial balance in the gastrointestinal tract (in healthy adults Firmicutes is the dominant phylum, however the proportion evolves with age and changes as a result of specific pathological processes) [13]. Pozuelo et al. [5] studied the microbiome in 113 patients with IBS and 66 healthy individuals. Stool samples were collected from the study&#;s subjects twice, at a monthly interval. Bacterial diversity in patients with IBS was found to be reduced in a statistically significant manner, which resulted from a considerably lower abundance of butyrogenic bacteria (p = 0.002, q < 0.06), particularly in patients with IBS-D and mixed IBS. The findings of the study are important for considering the benefits of using probiotics in patients with IBS. The most popular probiotic products contain lactic acid bacteria. Assuming colonic colonization with these strains, an increase in local lactate production can be achieved. Tsukahara et al. identified among the commensal bacteria residing in the human gastrointestinal tract a group of Megasphaera elsdenii bacteria belonging to Firmicutes which have an ability to convert lactates into butyrate [14]. Perhaps the same mechanism is responsible for the observed efficacy of lactic acid bacteria in IBS.

Functional constipation

The composition of bacterial flora is determined by two main classes of bacteria: Firmicutes (a phylum of common Gram-positive bacteria comprising, among others, Clostridium, lactic bacteria and butyric-acid producing bacteria) and Bacteroidetes (Gram-negative rods classified as obligate anaerobes), making up 90&#;99% of the total microbiome; Firmicutes is the dominant phylum (50&#;80% of the microbiome) [15].

A study conducted in a group of 161 individuals aged 65&#;96 years showed that their stool microbiota composition (assessed by molecular biology methods), compared to that determined in nine young volunteers (28&#;46 years old), shifted significantly toward Bacteroidetes [16].

Basic research in an animal model demonstrated that butyric acid increased the effectiveness of peristalsis by improving colonic smooth muscle contractility and regulating neurotransmission, particularly in cases of impaired peristalsis accompanying functional constipation in the elderly [17].

A double-blind, randomized, placebo-controlled study conducted in a group of 11 healthy volunteers involved self-administration of enemas by the study&#;s subjects according to the following regimen: enema with 100 mmol/l of butyric acid in week 1; 50 mmol/l of butyric acid in week 2; and placebo (saline solution) in week 3 of the study. At the start and end of each test period, a rectal barostat measurement was performed to determine the severity of pain, discomfort, and the urge to pass gas or stool. Butyric acid administered at 50 mmol/l resulted in a decrease in pain score by 23.9%, at 100 mmol/l &#; by 42.1%; and a decrease in discomfort score by 44.2% and 69.0%, respectively, at a pressure of 4 mm Hg. The authors concluded that rectal administration of butyric acid led to a dose-dependent decrease in visceral sensitivity which plays a key role in disorders of intestinal motility (including functional constipation), abdominal pain or discomfort [18].

A beneficial effect of butyric acid as one constituent of a multifaceted mechanism modulating gastrointestinal function has also been stressed in patients with stoma and coexisting constipation. Butyric acid supplementation combined with the use of probiotics should be adopted as one of the basic therapeutic strategies in this patient group, preceding treatment with laxatives [19].

Sodium butyrate has also been introduced into the algorithm of dietary treatment in patients with stoma [20].

Diarrhoea

Sodium butyrate may also prevent diarrhoea through an increased passive absorption of water in the colon and its effects on the gut microflora [21].

Butyrate is easy to administer and counteracts acute dehydration; it may be used in long-term treatment and prevention of traveller&#;s diarrhoea affecting individuals moving from countries with higher hygienic standards to destinations with a lower hygienic status. Even though antibacterial substances bring rapid and tangible therapeutic benefits in the treatment of traveller&#;s diarrhoea, there is no possibility to prevent the illness. In addition to standard recommendations such as additional caution about hygiene and food, travellers are advised to eat warm foods, drink bottled water, and eat only fruit and vegetables with intact skin. Pharmacological recommendations include rifaxamin, fluoroquinolone and Lactobacillus bacteria. Krokowicz et al. [22] made an attempt to demonstrate the preventive activity of a mixture of organic acids in a lipid matrix (250 mg of sodium butyrate; 100 mg of fumaric acid; 60 mg of citric acid; 50 mg of sorbic acid; 40 mg of malic acid) in traveller&#;s diarrhoea. A total of 42 patients completed the study, including 20 in the placebo group and 22 individuals taking the acid mixture 3 days before the journey. The incidence of traveller&#;s diarrhoea was 4.5% in the treatment group, and 40% in the placebo group. In addition, a statistically significant improvement was noted in the study group in terms of reduction in the number of bowel movements a day and relief of gastric symptoms (abdominal pain, nausea). Similar beneficial effects are observed after using a mixture of sodium butyrate and silicon dioxide (A300) [23].

Persistent and difficult-to-treat diarrhoea is one of the more common side effects of chemo- and radiotherapy in cancer treatment [24]. Karakulska-Prystupiuk [25] described the case of a patient with diarrhoea which developed during the period of myelosuppression in chemotherapy administered for anaplastic lymphoma. The differential diagnosis included recurrence of the primary disease and gastrointestinal tract infection. Subsequent microbiological tests excluded bacterial and fungal diarrhoea, and cytomegalovirus infection. Diarrhoea caused a considerable weight loss: 12 kg over 2 months. Dietary supplementation with butyric acid at 300 mg daily was initiated. After just several days the patient reported a substantial relief of symptoms and elimination of diarrhoea. In addition, the patient reported an elevated appetite and an increased frequency of meals. During successive follow-up examinations the patient was found to gradually return to his normal body weight.

Non-specific inflammatory bowel diseases

Butyric acid shows a protective effect in inflammatory response secondary to inflammatory bowel diseases. Recent research indicates that chronic stimulation by interferon γ (IFN-γ) plays an important role in the formation of inflammation-associated colon cancer, and the development of colitis ulcerosa is linked to the gene encoding IFN-γ. An in vitro study conducted on human intestinal epithelial cells sampled from the colon of patients with colitis ulcerosa showed an increased infiltration with unspecified T cells in the mechanism of activation of the signal transducer and activator of transcription 1 (STAT1). Butyric acid was also demonstrated to effectively inhibit STAT1 activation by reducing IFN-γ production, which results in the apoptosis of T cells of unspecified type and the suppression of the inflammation [26].

Molecular biological methods offer a possibility to gradually identify the relationship between the microbiome, diet, immune response and, consequently, the development of inflammatory bowel diseases. Experience shows that bowel inflammation may be induced by fat-rich diet. In one study, the composition of the microbiota in intestinal biopsies and stool samples was assessed using gene sequencing methods in a group of 231 subjects. One of the findings was a decrease in the amount of Anaerostipes bacteria belonging to Furmicutes in IBD patients who are active smokers or have a history of smoking. Similarly to Megasphaera elsdenii discussed above, Anaerostipes are bacteria responsible for the conversion of lactate to butyrate. In addition, the study revealed that patients with IBD had a reduced amount of Roseburia and Phascolarctobacterium bacteria which produce butyric and propionic acids in the colon [27]. The described ability of some bacteria to convert lactates to butyric acid may also be effectively induced by the commercially available mixture of eight lactic acid-producing probiotic bacteria &#; VSL#3 (Lactobacillus plantarum, Lactobacillus delbrueckii subsp. Bulgaricus, Lactobacillus paracasei, Lactobacillus acidophilus, Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis and Streptococcus salivarius). Studies in humans who used VSL#3 orally showed the preparation to reduce the clinical symptoms and severity of the inflammatory process in patients with pouchitis (after pancolectomy due to colitis ulcerosa) [28], and mild and moderate colitis ulcerosa [29].

A beneficial effect of sodium butyrate in post-proctocolectomy patients has also been demonstrated in research undertaken by the authors of the present publication. In a group of patients with pouchitis, sodium butyrate was found to be a beneficial element of combined therapy, accelerating the remission of symptoms &#; primarily diarrhoea and pain. However, the main effect linked to sodium butyrate was a reduction in the incidence and severity of inflammation in patients taking microencapsulated sodium butyrate at 2 × 200 mg [30].

A high concentration of IgA-coated bacteria plays a role in inducing inflammatory bowel diseases, mainly Crohn&#;s disease. A group of researchers [31] assessed the effect of sodium butyrate on the composition of the microbiota in IBD-prone IL-10&#;/&#; mice. At 8 weeks old, the mice were divided into three groups (four pergroup): normal (C57BL/6 &#; negative control), IL-10&#;/&#; (positive control) and IL-10&#;/&#; treated with sodium butyrate administered in drinking water (study group). The severity of colitis symptoms, and the concentrations of proinflammatory cytokines and short-chain fatty acids were assessed in the proximal section of the colon, whereas the percentage of IgA-coated bacteria and the microbiota composition in stool samples were evaluated by 16S ribosomal RNA analysis 4 weeks after the initiation of treatment. The study found that sodium butyrate reduced the histologically observed severity of colitis and decreased the level of tumor necrosis factor α (TNF-α) and IL-6 in IL-10&#;/&#; mice treated with sodium butyrate compared with the positive control. At the level of microbiota composition, a reduction in IgA-coated and Bacteroidetes bacteria, and an increase in the group of Firmicutes, were noted in IL-10&#;/&#; mice treated with sodium butyrate. The authors concluded that sodium butyrate lowered the risk of colitis, possibly by modifying the composition of the microbiota, i.e. enriching its biodiversity and reducing the amount of colitogenic IgA-coated bacteria.

Effect in cancer prevention and treatment

A study by Zhang et al. [32] analyzing human colorectal cancer cell lines (HCT-116 and HT-29) treated with sodium butyrate at concentrations ranging from 0.5&#;5 mM found that sodium butyrate inhibited the growth of the studied cancer cells, stimulated autophagy and induced apoptotic cell death, thus revealing a new possible mechanism underlying the anticancer activity of butyric acid.

Mouse studies revealed a 75% reduction in the risk of colon cancer in animals fed fibre-rich diets in a mechanism with butyric acid-producing colonic bacteria acting as intermediaries &#; compared to bacteria-free mice. It is concluded that the presence of bacteria producing butyric acid is a prerequisite for a fibre-rich diet to exert its beneficial effect which has been extensively described in the literature [33].

Another interesting role of sodium butyrate was described by Bueno-Carrazco et al. [34]. The authors found that oral administration of sodium butyrate supports the anti-cancer efficacy of photodynamic therapy in astrocytoma cells, most likely in a mechanism based on the modulation of gene expression and differentiation of cancer cells.

The synergistic cytotoxic effect on cancer cells was also demonstrated in a study conducted by Encarnacao et al. [35]. The authors showed that butyric acid increased the sensitivity of resistant cancer cells to irinotecan, a second-line drug used in the treatment of colon cancer. The finding may put a new perspective on the application of irinotecan which is regarded by clinicians who balance benefit against risk in the choice of therapy as a drug associated with uncertainty and interindividual variability of response. In vitro observations of colon cancer cell lines conducted over a period of up to 96 h showed a significant inhibition of cancer cell proliferation in the group where the cells were simultaneously exposed to irinotecan and butyric acid, compared to the group where only irinotecan was used.

The same group of researchers performed an in vitro assessment of the effect of butyric acid on the uptake of the 18F-labelled glucose analogue (18F-FDG) and the increase in glycolysis in a colon cancer cell line [35, 36]. The results show that the addition of butyric acid reduces the uptake of 18F-FDG and may affect the Warburg effect which is correlated with tumour aggressiveness. The greatest differences were observed at the lowest labelled glucose concentrations which, in turn, most accurately reflects the clinical situation. Furthermore, the results of the study suggest that butyric acid may play a role in cancer cells at an advanced stage of development.

Other applications of butyric acid

In a randomized prospective clinical trial patients with clinically diagnosed diverticulosis (n = 73) were assigned to the control and study groups. The study group received sodium butyrate at 300 mg/day (2 × 150 mg) with a follow-up examination after 12 months. The study was completed by 30 patients receiving sodium butyrate and 22 control group patients receiving placebo. Patients in the study group declared a decrease in the frequency of clinical symptoms of diverticulosis and a significant reduction in the sensation of abdominal discomfort and pain compared to the placebo group [37].

Sodium butyrate in the form of enemas (combined in a mixture with A-300 silicon dioxide) may be a successful method of therapeutic management in patients with radiation proctitis. Sodium butyrate was shown to have an ability to reduce inflammation, as confirmed by clinical and endoscopic assessment. A key aspect related to sodium butyrate which appears to be of great relevance for this challenging and treatment-resistant form of proctitis is a multifaceted mechanism of action of butyrate which prevents inflammation, stimulates proliferation and normalizes the profile of secreted mucus [38].

Conclusions

The body of knowledge about the roles and importance of butyric acid has been expanding steadily, and the mechanisms by which butyric acid affects the relationship between the microbiome and the host are becoming increasingly elucidated. It is currently believed that the clinical aspects of using butyric acid described above arise from the effect of the compound on the local immune system, the mechanisms regulating the gut peristalsis, the severity of inflammatory processes and the regulatory mechanisms of the gut-brain axis [39]. The complex mechanism of action of butyric acid seems to play a vital role in maintaining symbiosis and homeostasis in the human body.

The scope of the present article is limited to oral butyric acid preparations used at doses which provide no possibility for significant quantities of butyric acid to pass into the systemic circulation. Consequently, it excludes studies focused on the role of butyric acid in reducing peripheral insulin resistance in diabetes mellitus type 2 [40] or preventing body weight gain [41], which represent important future challenges for pharmaceutical companies. The coming years are bound to bring new discoveries and fascinating reports on other areas of activity of butyric acid, and therefore new therapeutic opportunities associated with its use.

Conflict of interest

The authors declare no conflict of interest.

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