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Short-chain fatty acids produced by bacteria living in the large intestine are the main energy substrate for the colonocytes. Butyric acid is used for the treatment and prevention of exacerbations of various gastrointestinal diseases: diarrhoea, intestinal inflammations, functional disorders, dysbiosis, and post-surgery or post-chemotherapy conditions. The current standard doses of butyric acid (150&#;300 mg) range between 1.5&#;3% and 15&#;30% of the reported daily demand. Increased metabolism of the colonocytes in conditions involving intestine damage or inflammation, increased energy expenditure during a disease, stimulation of intestine growth in &#;stress&#; conditions with accelerated intestinal passage and increased intestinal excretion, and decreased production of endogenous butyrate due to changes in bacterial flora in different pathological conditions require a significant increase of the supply of this acid. Physiological high demand for butyrate and known mechanisms of pathological conditions indicate that current supplementation doses do not cover the demand and their increase should be considered.
Short-chain fatty acids (SCFA) are produced by bacteria dwelling in the large intestine. They are a product of the metabolism of polysaccharides that are not digested by the digestive system enzymes. At the same time, they are the main energy substrate for the epithelial cells of the intestinal mucosa. More and more scientific reports focus on the significance of SCFA and in particular that of butyric acid [1].
Butyric acid present in the lumen of the gastrointestinal tract is indispensable for maintenance of normal homoeostasis of the mucosa cells. It conditions their normal metabolism (as the basic source of energy) and proliferation, and it is responsible for regeneration and repair processes. It stimulates local cellular response, maintains intestinal barrier integrity, and inhibits tumour cell differentiation [2, 3]. It also has a favourable effect on the intestinal microbiome [1] by stimulation of the growth of the saprophytic flora and by an inhibitory effect on the development of other pathogens, such as Escherichia coli, Campylobacter, or Salmonella [4].
Butyric acid is increasingly used as a supportive agent in the treatment and prevention of exacerbations of various diseases and disorders of the digestive tract, such as diarrhoea (specific and non-specific), inflammatory conditions (non-specific bowel inflammation, diverticulitis, diversion colitis, radiation-induced bowel inflammation), functional disturbances (irritable bowel syndrome), dysbiosis, and post-surgery (resections, short bowel syndrome) or post-chemotherapy conditions. Recently, it has been stressed that SCFA affect not only processes occurring in the lumen of the gastrointestinal tract but also other systems and organs, such as circulatory or nervous systems, through mechanisms associated with the intestinal barrier, carbohydrate metabolism, immunomodulation, and appetite control, and with an effect on obesity [5].
150&#;300 mg/day is the most common dosage recommendation for currently available butyric acid products. It is not easy to determine the optimal dose of butyric acid supplementation, and the results of the studies conducted to date are often highly inconclusive. High viscosity of the intestinal contents, the presence of bacterial biofilm and mucus layer on the mucosa surface, and rapid absorption of SCFA make it difficult to determine their concentration on the mucous membrane surface itself. On the other hand, SCFA concentration in the intestinal lumen or faeces does not reflect the rate of their production [6].
Physiologically, butyric acid, like other SCFA, is a product of anaerobic bacterial fermentation of resistant starch and food fibres. The total concentration of SCFA in the intestinal lumen varies between 60 and 150 mmol/kg, and their daily production in the large intestine of a healthy individual is 300&#;400 mmol [4, 7]. This translates into 50&#;70 mmol of butyric acid or about 5.5&#;7.5 g/day. According to some studies, the physiological range of butyrate concentrations in the intestinal lumen is between 1 and 10 mmol/l of the food content [8], which, assuming a daily production of 9 l of the intestinal content, corresponds to 9&#;90 mmol/day, i.e. 1&#;10 g/day. The daily demand for butyric acid in physiological conditions falls therefore within a very wide range of mg/day to as much as 10,000 mg/day, which should be covered by fermentation processes of resistant starch and food fibres. However, in the Western population insufficient supply of these nutrients is observed, which can explain the rapidly growing incidence of all types of gastrointestinal diseases, both inflammatory, neoplastic, and functional. In studies with significantly increased supply of fibre in the diet growth of probiotic bacteria such as Bifidobacterium (BfB) and Lactobacillus (Lab), improved condition of the intestinal mucosa, and even reduced risk of cancer of the lower colon segments were observed [9]. It seems that similar effects may be obtained by increased supplementation with butyric acid products.
In the analysis of the daily demand for butyric acid it is noticeable that the currently used standard doses of 150&#;300 mg represent only 15&#;30% of the lowest daily demand reported, or they are even as low as 1.5&#;3% if the highest possible values are taken into consideration. Thus, even under physiological conditions the current supplementation doses are low or even very low, and their increase may be considered. The possibility of dose increase depends on the formulation of butyric acid because packing more than 300 mg of butyrate into a single capsule is a technical limitation here. Of course, the dose of &#;clean&#; (non-enveloped) butyrate may be increased, but this form is absorbed already in the upper gastrointestinal tract and reaches the intestine at a much lower concentration. Therefore, to achieve effective supplementation (with adequately high butyrate doses), the forms of butyrate supply should be optimised.
Animal studies showing beneficial trophic or anti-inflammatory effects are usually carried out with use of much higher doses of butyric acid. In an experiment where mice were administered 11 g of butyrate in drinking water per day (i.e. about 55 g/kg of body weight!) an improvement of the immune functions of the intestinal epithelium was shown, which, according to the authors, may be an important mechanism of prevention of several chronic diseases [10]. In another study, conducted on birds, butyrate was used at a dose of mg/kg of body weight, and a reduction of interleukin 6 (IL-6) and tumour necrosis factor α (TNF-α) levels as well as increased activity of peroxide dismutase and of catalase were observed [11]. This confirms an anti-inflammatory effect of butyrate. Of course, animal test results cannot be directly translated into human test results; however, much higher doses of butyrate are used also in clinical trials. An example is the above-mentioned publication with a dose of 4 g of butyrate per day in obese and healthy patients [12]. Efficacy of high doses was confirmed by a study in which healthy individuals received enemas containing 100 mmol of butyrate. Anti-inflammatory effect, an increase in glutathione antioxidation, and a decrease of uric acid production were achieved in this study [13]. High doses of butyrate may thus have a favourable metabolic effect as well because they may exert epigenetic action [14]. Very good clinical results of high doses of butyrate ( mg/day) were found in patients with mild to moderate Crohn&#;s disease [15]. A very good clinical effect was found in the majority of patients, as well as remission of lesions on endoscopic examination and a decrease of white blood cells (WBC) counts and nuclear factor κB (NF-κB) and IL-1β activity.
However, particular attention should be paid to conditions with an increased demand for SCFA. They will be described below, but their common features include an increased demand for butyric acid on one hand, and reduction of its endogenous production on the other (lack of appetite, dietary restrictions, limited volume of the eaten food, malabsorption, disturbances in the composition of the saprophytic intestinal flora responsible for physiological fermentation processes). Taking into consideration the increased demand with concurrent reduction of endogenous production, additional supplementation with butyric acid seems particularly important for the achievement of the expected optimal clinical outcomes.
Causes of increased demand:
Enhanced metabolism of intestinal epithelial cells in conditions with damage/inflammation of these cells.
Increased energy expenditure of the organism in pathological conditions.
Stimulation of intestine growth in &#;stress&#; situations
Conditions with accelerated intestinal passage and increased secretion into the lumen of the intestine (diarrhoea).
Decreased production of endogenous butyric acid due to changes in bacterial flora in different pathological conditions.
Other conditions associated with increased demand for butyric acid in the digestive tract.
Butyric acid is used by intestinal epithelial cells, especially in processes associated with their intensive proliferation, related to inflammation, damage, and subsequent repair processes. It is difficult to quantify the level of this increase in demand, and there are few data in the subject literature. However, some analogies may be assumed, where in tissue and wound regeneration, metabolic demand increases by a factor of 1.6&#;2.0 with respect to the basic demand. It should be borne in mind that the energy demand of the intestinal epithelial cells is mainly covered by energy substrates available in the intestinal lumen, i.e. predominantly by butyric acid. The dose of butyric acid should therefore be increased accordingly during inflammatory conditions. This finds confirmation in clinical studies. In one of the studies on the treatment of ulcerative colitis butyric acid was used in the form of enema at doses of 40 mmol/l to up to 100 mmol/l, which corresponds to 4.4&#;11 g/l. For 200 ml enemas this translates into 800&#; mg/enema. Very good clinical outcomes were observed with these doses, with no side effects [ 16 ]. Similar observations were made in patients with a related condition, who received sodium butyrate enemas at a dose of mg/l with very good effect [ 17 ]. In animal studies, significantly higher doses of butyrate are used successfully. In one of these studies, supplementation with butyrate was used in pigs with induced ulcerative colitis. With use of butyrate at a dose of mg/kg body weight, a significant preventive effect with respect to intestine damage was achieved, through inhibition of apoptosis, improvement of tight junctions between cells, which improved the integrity of the intestinal barrier and activation of the endothelial growth factor (EGF) that stimulates regeneration processes [ 18 ]. This confirms the hypothesis that inflammation and regeneration conditions in the gastrointestinal tract causing a significant increase of energy demand of mucosal cells [ 19 ] may require higher doses of butyrate.
In most diseases and pathological conditions, especially those with regeneration, healing, and proliferation processes, the demand of the entire organism is increasing. If a patient undergoes surgical treatment, this should be taken into account in the calculations, and the demand for energy should be multiplied by a factor of 1.2 for patients after medium-extent surgical procedures (laparoscopy), by a factor 1.6 for patients after more extensive procedures, and even by a factor of 1.8 in case of large wounds with exudate, inflammatory reactions, or infections [ 20 ]. The energy demand of different organs varies. The intraperitoneal organs, including intestines, pancreas, spleen, and stomach, which account for 6% of the body&#;s weight, use 20&#;35% of the body&#;s total energy demand, and the intestines themselves &#; about 12&#;20% [ 21 ]. In overweight patients, in patients with concurrent diseases, and in cachectic patients, energy demand of the visceral organs may increase at various treatment stages and may be difficult to cover [ 22 ]. A small proportion of this demand comes from blood vessels, and the vast majority of this demand is covered by SCFA. This indicates, on one hand, the importance and role of enteric nutrition, and on the other hand it justifies an increase in the dose of butyrate for all indications in patients with increased energy demand (patients after trauma or surgery, patients on rehabilitation or practising intensive exercise, cachectic patients, and cancer patients).
In the recent years, a very interesting observation emerged, that during various pathological and energy-consuming processes (surgical procedures, exposure to low temperatures, lactation, restrictions in caloric supply) the cells of the mucous membrane are stimulated to grow and proliferate. This may be a compensatory mechanism whose aim is to improve absorption and to prepare the body for better, i.e. more efficient, use of the food provided. The mechanism of this phenomenon is complex and still under investigation. One of the explanations is increased metabolism of the white fatty tissue, which induces secretion of a number of mediators (probably including leptin) that stimulate, via hypothalamus, intestine growth and cause increased supply of food (through the sensation of hunger) [ 23 ]. Experimental models have also shown that deficits in energy supply (&#;caloric restriction&#;) lead to intestine growth, both quantitative (increase in organ mass and size) and qualitative (increase in intestinal cell amount) [ 24 ]. A very interesting study was conducted in a group of overweight patients with metabolic syndrome. Within that study, both the study group and a healthy control group received mg of sodium butyrate per day. Decreased inflammatory activity of several investigated molecules and monocytes was observed in that study, which was particularly evident in the group of obese patients. This high dose of butyrate (almost eight times higher than the maximum dose currently recommended for butyric acid products available on the Polish market) showed a positive anti-inflammatory and immunomodulatory effect without side effects or adverse reactions [ 12 ].
In various pathological conditions, the demand of intestinal epithelial cells for energy can therefore increase significantly, due to intense proliferation of intestinal epithelium, i.e. increasing number of cells requiring energy substrates (butyric acid among them, to a large extent), high metabolism level, and concurrent increase in energy demand of the other organs. Because of the above, intestinal epithelial cells must cover the highest possible proportion of the increased energy demand by using substrates available in the digestive tract, i.e. mainly butyric acid, which justifies an increase in its supply.
In many situations, intestinal passage is accelerated and there is increased secretion into the intestinal lumen. This is associated, on one hand, with disturbances of the absorption ability of the intestinal epithelial cells, and on the other hand &#; with their increased energy expenditure. Another important consequence is decreased production of endogenous SCFA, because there is not enough time for natural fermentation of resistant starch and food fibre to occur. A significant reduction of SCFA production in patients with antibiotic-induced diarrhoea may be an example here. The use of antibiotics itself, without concurrent diarrhoea, also caused a decrease of SCFA levels, including the level of butyric acid, when dicloxacillin, erythromycin, and combined intravenous therapy with ampicillin and metronidazole were used [ 25 ]. The use of antibiotics, through their negative effect on the saprophytic intestinal flora, is a factor that significantly impairs the ability of intestinal epithelial cells to cover their energy demand in a physiological manner. This effect is greater during diarrhoea, which accelerates the passage time. This is confirmed by studies showing a favourable effect of supplementation with selected fatty acids in patients with travellers&#; diarrhoea, including butyric acid at a dose of mg/day in the form of sodium butyrate [ 26 ]. A very good clinical effect was found in that study, without side effects or adverse reactions.
The clinical situations described above may therefore be an indication and justification for an increase of the dose of butyric acid supplementation in this group of patients.
A normal level of endogenous butyric acid production, as well as of other SCFA, depends on the physiological intestinal flora. Various types of microbiome disturbance may lead to a significant decrease of SCFA production [ 25 ]. Adverse changes within the intestinal microbiome may occur in several other conditions, often apparently unrelated. In a model of induced stroke in monkeys, significant changes in the intestinal microbiome were found; first of all, decreased amounts of Faecalibacterium, Oscillospira and Lactobacillus. This resulted in a significant decrease of endogenous fatty acid levels [ 26 27 ]. This study shows, on one hand, how apparently unrelated conditions can negatively affect the SCFA level, and on the other hand it confirms the complexity of the intestine-brain axis mechanism. It is difficult to draw far-reaching clinical conclusions, but these are the mechanisms that can explain very frequent diagnosis of functional disorders of the gastrointestinal tract in neurological patients. Recent studies demonstrating that in patients with Alzheimer&#;s disease a significant decline in fermenting bacteria and associated endogenous SCFA levels occur [ 28 ] indicate, on one hand, how complex the mechanisms leading to the SCFA deficit may be, and, on the other hand, how important SCFA supplementation in neurological diseases can be. The decrease of endogenous SCFA levels may justify an increase of the dose of butyrate supplementation.
The above-mentioned conditions associated with increased energy demand decreased the production of endogenous SCFA or their increased loss do not, of course, cover the entire broad spectrum of clinical situations where the demand for butyric acid rises. First of all, it should be recognised that a significant proportion of SCFA, including butyric acid, is absorbed along the entire length of the digestive tract. Of course, commercially available products protect butyrate in special matrices, but always some part of it will be absorbed earlier, and most of the diseases requiring butyric acid supplementation affect the lower digestive tract, including its distal parts. Studies with administration of butyric acid to chickens showed its very high absorption already at the level of the duodenum. A favourable trophic effect, growth stimulation, and optimisation of the function of the duodenal mucosa were found. Therefore, this seems to justify an increase in butyrate supplementation dose, as, on one hand, pathological conditions may also increase absorption in the upper part of the digestive tract and, on the other hand, provision of adequately high doses to the lower gastrointestinal tract should be aimed at [ 29 ]. Publications showing a role of SCFA after surgeries of the gastrointestinal tract (resections, anastomoses) as well as of the abdominal cavity (laparotomy, peritonitis, pancreatitis) are very interesting. The decrease in SCFA (levels), including butyric acid (levels), has been shown to have a negative effect on the integrity of the intestinal barrier and the tightness (normal healing) of anastomoses [ 30 ]. The conditions that are indication for surgery (inflammatory conditions, cancers) increase the demand for butyric acid, and surgery additionally raises this demand in a specific (anastomosis healing) and non-specific (increased energy demand due to surgical trauma and healing) way. Taking the above into consideration, it should be assumed that supplementation with high doses of butyrate in this group of patients is fully justified, both in the preoperative and in the postoperative period.
Supplementation with increased butyric acid doses seems to be particularly important in patients using substances, especially in cigarette smokers and alcohol drinkers, as well as in patients with other metabolic diseases, such as diabetes.
Alcohol significantly disturbs the intestinal microbiota, the final result of which is a significant decrease in production of endogenous fatty acids. Alcohol is also a factor that increases oxidative stress and increases the production of a number of its associated cytokines, such as tetradecane [31]. Decreased production of SCFA is also noted in patients smoking cigarettes, in whom microbiome changes are observed, predominantly in the form of decreased counts of fermenting bacteria responsible for the production of endogenous SCFA [32]. Smoking is also a factor that directly damages the mucous membrane of the gastrointestinal tract [33], which activates energy-consuming regeneration and repair processes and justifies supplementation with increased doses of butyrate. Particular attention should be paid to the appropriate dose of butyrate in persons who are both alcohol consumers and smokers [33].
Metabolic diseases also affect the level of endogenous fatty acids, which may lead both to a decrease in their content in the lumen of the digestive tract and to an increase in demand. Diabetes may be one of the examples, where significant microbiome changes in microbiome and decreased production of butyric acid are observed [34]. On the other hand, it is known that the supply of endogenous butyric acid can have a positive effect on the normalisation of bacterial flora [35], as well as on the efficiency of the immune system [36].
In light of available literature and pharmacological and clinical data, it should be concluded that butyric acid is a safe drug, with a very high safe and tolerated dose. In clinical conditions, it is practically impossible to overdose butyrate in a patient, both during drug studies and when used by a patient. No clinical side effects were observed in healthy volunteers administered therapeutic doses. No toxicity or adverse effects were observed in patients in clinical trials with a mixture of SCFA in the form of enemas containing from 40 mmol/l to 100 mmol/l [16, 17]. In clinical trials with oral drug administration, the safety of the use of butyrate and the absence of side effects, as well as its fully physiological mechanism of action, are emphasised [37]. Even with doses significantly higher than the standard currently recommended doses, reaching mg/day [26] or even mg/day [15], no adverse reactions or side effects were observed, and good tolerance of oral butyrate was underlined.
It can therefore be concluded that butyric acid is a substance with physiological action, showing a high safety level, both at the current standard doses and at significantly higher doses (four or six times higher). The need to increase the dose of butyrate supplementation is supported by many of the above-mentioned reasons, and such a dose increase is safe for the patient within the range specified above.
Short-chain fatty acids, including first of all butyric acid, are essential for the proper function of the gastrointestinal tract. This demand may increase significantly across the whole range of diseases and gastrointestinal dysfunctions, which justifies supplementation at higher doses than those used at present. The most important factors supporting such action are the following:
Physiological high demand of the epithelial cells for butyric acid, which is their primary energy substrate; current supplementation doses cover only a small proportion of the demand.
The trend observed in developed countries toward a decline in the production of endogenous SCFA, which may not even cover physiological needs.
A large number of pathological conditions or clinical situations that significantly increase the demand for SCFA, notably by enhancing the metabolism of the epithelial cells and their energy demand.
Frequent coexistence of these conditions and the greater demand of intestinal epithelial cells at concurrent reduction of the production of endogenous SCFA, including butyric acid. One can say about a sort of &#;SCFA paradox&#; here: &#;the more our digestive tract needs SCFA, the more difficult it is to provide substrates and to maintain normal microbiome to assure endogenous SCFA production&#;.
Clinical and experimental observations confirming good effects of the use of high doses of butyrate in different pathological conditions.
Safety of high doses and no side effects or adverse reactions.
Prz Gastroenterol.
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1Department of General and Gastrointestinal Surgery MCPE, Orlowski Hospital, Warsaw, Poland
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2Department of General and Endocinological Surgery, and Gastrointestinal Oncology, Poznan University of Medical Sciences, Poznan, Poland
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3Department of Internal Medicine and Gastroenterology, Division of Inflammatory Bowel Diseases, Central Clinical Hospital of Ministry of Internal Affairs and Administration, Warsaw, Poland
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Author information Article notes Copyright and License information PMC Disclaimer1Department of General and Gastrointestinal Surgery MCPE, Orlowski Hospital, Warsaw, Poland
2Department of General and Endocinological Surgery, and Gastrointestinal Oncology, Poznan University of Medical Sciences, Poznan, Poland
3Department of Internal Medicine and Gastroenterology, Division of Inflammatory Bowel Diseases, Central Clinical Hospital of Ministry of Internal Affairs and Administration, Warsaw, Poland
Corresponding author.Corresponding author.
Address for correspondence: Katarzyna Borycka-Kiciak MD, PhD, Department of General and Gastrointestinal Surgery MCPE, Orlowski Hospital, 231 Czerniakowska St, 00-461 Warsaw, Poland. : +48 502 766 961. :Katarzyna Borycka-Kiciak MD, PhD, Department of General and Gastrointestinal Surgery MCPE, Orlowski Hospital, 231 Czerniakowska St, 00-461 Warsaw, Poland. : +48 502 766 961. : lp.airetni@akcyrobk
Copyright © Termedia Sp. z o. oThis is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License, allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.
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
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.
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].
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.
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].
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.
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.
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.
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].
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.
The authors declare no conflict of interest.
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