Comprehensive Guide to Butyrate: What it is, Benefits, Side Effects, & More

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Key Takeaways:

• Butyrate is a short-chain fatty acid that is a necessary component to a balanced microbiome and works as an inflammation guard.*

• Our body can&#;t make enough butyrate because we eat too few resistant starches.

• One of several, short-chain fatty acids created from fermented resistant starches, low butyrate levels have been associated with serious health concerns.

• Butyrate not only nourishes the gut but also promotes cell differentiation, helps to regulate blood sugar, and promotes healthy DNA.*

• You can increase butyrate levels by eating foods with butyrate or taking supplements that can come in various forms.

Our gut is where the immune system gets its oomph, where the final products of digestion sit, and where water is absorbed into the body. About 400 different kinds of bacteria live there, most of them good, some not so much. Maintaining the balance of these bacteria is critical to staving off one or another pathology, including IBS/IBD, diverticular issues, and even polyposis. The bottom line is that no one should suffer colon disease, and fewer have to if healthy and appropriate bacteria levels are maintained.

The cells that line the colon walls are called colonocytes. These endothelial beauties are flat and constitute a layer that is only a single cell thick. They live shorter than a week and then are replaced by new ones. Because of this high turnover rate, there&#;s no need to do harsh cleanses, our bodies do the work for us!

All cells need a source of energy to do their work. Evidence is strong that the epithelial lining of the gut relies more on luminal energy supply than on vascular, meaning that energy comes from outside, not from the bloodstream, as most cells require. So, then, what is this energy supply? Short-chain fatty acids (SCFA&#;s) derived from the bacterial fermentation of resistant starch are the luminal substrates for colonocytes.

What are short-chain fatty acids?

Short-chain fatty acids, or SCFAs, are metabolites created by the microorganisms in our gut. There are several kinds of these SCFAs, including acetate, butyrate, and propionate. They all serve an important purpose in the gut, but we&#;ll be focusing on butyrate today.

Quickly find what you&#;re looking for:

What is Butyrate?

Butyrate is a short-chain fatty acid produced by bacteria in the colon that&#;s essential for a healthy microbiome. In fact, appropriate levels of butyrate are key, not only to digestion, but to cellular and DNA health as well.*

How does butyrate support the immune system & digestive system?

Butyrate is a key SCFA that supports the colon and the gut lining. Butyrate in particular has been found to be a key factor in supporting a healthy inflammation response in the colon.[4]* On its own, it provides up to 90% of the energy required by the colonocytes, the cells of the colon!* It&#;s no wonder a deficiency can lead to degradation of the gut lining and subsequent illness. When we have enough butyrate, we have a stronger gut, stronger gut-associated lymphoid tissue (GALT), and a stronger immune response.* Butyrate also supports the mucosa that hydrates the gut lining, promotes cell differentiation, and inhibits enzymes that can interfere with DNA replication.*[5]

Butyrate vs. butyric acid

Butyric acid and butyrate can often be confused but are simply different forms of the same molecule. Butyric acid is the form that you&#;ll find in food and many supplements and is also called butanoic acid. It&#;s an SCFA with four carbon atoms at its heart and is found in butter (hence its name) and other dairy products. When butter goes rancid, (i.e. when your Romano cheese sits on the kitchen table for a few hours at ninety degrees), you can experience the unfortunate aroma of butyric acid &#; a sharp, fermented, rather unpleasant smell. 

Butyric acid has a pH low enough to cause an upset stomach, but when compounded with an alkali, it becomes more than just an agreeable friend. When an acid is mixed with a base, the combination forms a salt plus water. At this stage, we no longer have butyric acid, but butyrate, a buffered form of butyric acid. The terms might be used interchangeably because they have some commonality, but they are not the same.

What Causes Low Butyrate?

At this point, you may be wondering if you have low levels of butyrate, or how you would know if you did. We took this question to our resident expert, Dr. Tom, who let us know that the only way to truly know is by taking a stool test. But, he also mentioned that if you&#;re not getting adequate fiber from starchy foods in your diet, chances are good you could use some extra butyrate. As we know, the SAD (Standard American Diet) is full of processed foods that are devoid of fiber, and the 25-28 grams we need per day are generally lacking in many diets. In fact, 97% of Americans do not eat enough fiber!

Butyrate levels in the gut can be negatively affected by high-protein, high-fat, low-carb diets. Keto and Paleo diets that restrict carbohydrates and fiber lack the starch needed to make your own butyrate. Carnivore diets can skew SCFA production away from producing butyrate and see higher levels of propionate and acetate.

Butyrate deficiency symptoms

Another way to determine if you might be deficient in butyrate is to consider common symptoms of those who are. These symptoms take time to develop and can include:

• Leaky gut

• Gas and bloating

• Chronic diarrhea

• Eventual IBS/IBD

• Crohn's disease 

• Behavioral irregularities

• Obesity

• Aberrant fatty acid metabolism

• Frequent illness from impaired immune function

• Foggy thinking from faulty protein metabolism and consequent ammonia accumulation

• Upset microbiome balance (may look like candida overgrowth or other bacterial imbalance)

• Increases in inflammation markers

• Reduced insulin sensitivity

• Missteps in DNA replication

Who would benefit from having more butyrate in their gut?

Anyone who is experiencing digestive symptoms such as gas, bloating, constipation, diarrhea, and abdominal pain and discomfort may benefit from having more butyrate in their gut. However, every microbiome and body is unique, so you should consult with a trusted practitioner to determine what is right for you.

Butyrate Benefits

So now that we know the symptoms of low butyrate levels, what benefits does this nutrient actually provide? While there are many (including simply reducing the symptoms we mentioned above), there are three primary advantages that butyrate gives us.

Colon Support*

Of the short-chain fatty acids and those having fewer than six carbon atoms, butyrate is the one that nourishes the gut and promotes cell differentiation, a process that helps to prevent serious colonic diseases.* Because of its protective nature, butyrate is a highly-desirable molecule and should be cultivated as a friend, or at least introduced as a partner.

Healthy Inflammation Response*

The fiery process of inflammation is linked to most chronic disorders, from heart attack to stroke to type 2 diabetes. Inflammation fuels a cytokine known as interleukin-6 (IL-6), which remains elevated in chronic sickness. Butyrate is a rescue molecule in inflammatory diseases, wherein it impairs the oxidative processes that initiate their genesis.* By supporting a healthy inflammation response, butyrate may be helpful for many other autoimmune and inflammatory conditions.*

Multi-purpose Repair from Gut to Brain*

Butyrate inhibits enzymes that harm and unwind DNA, just like the kinked-up Slinky we ruined as kids. Butyrate sequesters harmful ammonia that forms from faulty protein metabolism and/or from inborn metabolic errors. In clearing mental fog, it increases brain-derived neurotrophic factors.* Depending on its concentration, butyrate decreases intestinal permeability, closing tight junctions and preventing leaky gut.* SCFAs in general, including butyrate, have also been shown to affect cholesterol metabolism and increase mineral absorption, which is highly beneficial for heart health and circulation health.*

Learn more about the benefits of butyrate here. 

Butyrate Side Effects

The good news is there appear to be very few side effects associated with supplementing butyrate. Our on-staff expert RD, Dr. Tom, says &#;All reports in the medical papers admit there are no known ill effects from butyrate taken at "normal" doses, which I have extrapolated to be less than 8.0 grams a day for several months. One study does state that more than 20.0 grams a day will waken latent herpes simplex (fever blisters). But that high a dose is not recommended.&#;

Dr. Tom also notes that, &#;colonocytes absorb butyrate supplements immediately and rapidly, with more than 95% precision and completeness. The remaining 5% goes to the toilet.&#; The FDA cites butyrate as Generally Recognized As Safe (GRAS).

How to Increase Butyrate in the Colon

Knowing that there are serious benefits to increasing your butyrate levels and not many negative side effects, how can you incorporate it into your everyday life? The two main ways to achieve this are by eating food with butyrate, or taking specialized butyrate supplements.

Eat foods containing butyrate

As we mentioned earlier, butyrate and SCFA production only come from the food we ingest and the microbial balance in the gut available to break down that food into SCFAs. Most of the foods that allow our microbiome to produce SCFAs are resistant starches, and some of them aren&#;t the most appetizing. But, when you&#;re dealing with severe digestive issues or autoimmune diseases, you may find them worth adding to your diet.

It is possible to get butyrate from the foods you consume, but in looking at the average diet, there are generally not enough slowly-digesting fibers to produce the necessary levels with food alone. That&#;s because a lot of the foods highest in resistant starch are not particularly appetizing, think cold mashed potatoes and white rice.

Foods that do help boost butyrate include:

• High-quality dairy (but the high serving sizes needed may not be recommended for all)

• Cold rolled oats (try soaking oats in non-dairy milk overnight)

• Legumes (when cooled after cooking)

• Cooled potatoes

• Cooled white rice

• Unripe bananas and plantain flour

• Whole grains

• Fibrous vegetables like asparagus and broccoli stems

• Some fruit peels like apples

For more information, check out our blog: What Foods Can Help Increase Your Butyrate Levels?

While many foods contain small amounts of butyrate-producing resistant starch, it&#;s still quite hard to reach the adequate amount. For this reason, ample supplementation with a butyrate supplement is vital to overall well-being.

Butyrate supplements

Want more information on butyric acid benefits? Feel free to contact us.

In addition to adding butyrate-producing foods, you may also consider butyrate supplementation. Supplementing butyrate is a great way to keep your gut happy and healthy, but as always, quality matters! BodyBio Butyrate is formulated without extra additives or fillers to deliver the beneficial butyrate your gut craves without any junk. Because it&#;s fermented, butyrate is well known for its smell, but this is a natural byproduct of the fermentation process &#; don&#;t worry! This is exactly how it&#;s supposed to be.

Butyric acid on its own is quite acidic, so we pair it with different minerals to raise the pH and stabilize it for delivery to the gut. We have created Calcium Magnesium, Sodium, and Sodium Potassium Butyrate varieties depending on your needs. Due to widespread calcium and magnesium deficiency, we recommend most people start with our Calcium Magnesium Butyrate. Dozens of folks have reviewed our butyrate saying that it helped ease their digestive problems and get back to a healthy, balanced gut.

Interested in trying butyrate? Learn more here.

Types of Butyrate Supplements

Sticking to a diet with high levels of butyrate can be difficult, so if you&#;re thinking that supplements are the better option for you, there are three general categories that products fall under. Below we discuss each in more depth, and help you make an informed decision on which is right for you.

Butyrate salts

BodyBio&#;s butyrates (we have three kinds!) are simply butyrate, a thirteen-atom complex joined to an alkali. Butyric acid, butyrate, and tributyrin are ingredients you may see in this category of supplements. While their names vary slightly, they all have the same purpose with different characteristics.

At BodyBio, the butyrate powder we use is covered with MCT from palm kernel oil. This is how it gets to the colon somewhat intact. If at least a little butyrate didn't get partially digested and enter the bloodstream through the walls of the small intestine, it wouldn't be able to act as an ammonia sequestrant, an HDAC inhibitor, a glucose modulator/appetite suppressant and support normal inflammation levels.*

Glycerol-bound butyrate (tributyrin)

Glycerol-bound butyrate is called tributyrin &#; 3 butyrates attached to a glycerol. Now, before we explain tributyrin any further, it helps to understand the concept of a prodrug. In this case, &#;pro&#; has nothing to do with for or against, but with precursor. 

The term describes compounds that must undergo chemical changes within the body prior to exerting their pharmacological or therapeutic actions. One example is aspirin, which is the prodrug for salicylic acid. Aspirin, you see, is less corrosive to the pathways of the GI system. We may want the benefits of salicylic acid, but in order to get them internally, we take aspirin so that the body can convert it to salicylic acid without having to actually ingest such an acidic substance.

There are times, too, when prodrugs can sneak past pharmaceutical barriers by adjusting the delivery form. This is how tributyrin works as a stable and rapidly-absorbed prodrug of butyric acid, just like sodium butyrate, calcium-magnesium butyrate, or another form of the salt. The active portion of butyrate and tributyrin is butyric acid, which we can get by ingesting either form. 

And yet &#; If tributyrin is butyric acid joined to a glycerol to make a compound of more than forty atoms, why not use the alkalized butyrate with a compound of fewer than twenty? This compound is much easier for the body to process and extract the benefit we want &#; the butyric acid.

Liquid butyrate

A final option, liquid butyrate, is typically butyric acid bound to a fat like MCT oil. There are often many additives, flavorings, and sweeteners to hide the notably pungent smell of effective butyrate supplements. If you are going to go with a liquid butyrate supplement, we recommend checking your labels first.

Choosing the Right Butyrate Supplement

We created BodyBio Butyrate supplements in three different types: Calcium Magnesium, Sodium, and Sodium Potassium. For most people, the Calcium Magnesium form will do just fine, but athletes or those who have low sodium levels may benefit more from the Sodium or Sodium Potassium forms. Whichever one you decide to try, you&#;ll get at least a 1,000 mg dose of butyric acid per two capsules.

You may have read that taking a butyrate supplement won&#;t increase your butyrate levels because the supplement will not reach the large intestine. Fortunately, for the last 20 years, we have been making butyrate, we have worked with countless physicians across the globe who tell us their patient's butyrate levels have increased with BodyBio Butyrate. If you can&#;t add high-quality fibers to your current diet, supplementation may be a great option for you!

Learn more with our Butyrate/Gut+ Get Started Guide!

References

Scheppach W. Effects of short chain fatty acids on gut morphology and function.  Gut. Jan;35(1 Suppl):S35-8.

Mortensen PB, Clausen MR.  Short-chain fatty acids in the human colon: relation to gastrointestinal health and disease.   Scand J Gastroenterol Suppl. ;216:132-48.

HM Hamer, D Jonkers, K Venema, S Vanhoutvin, FJ Troost, RJ  Brummer. Review article: the role of butyrate on colonic function.  Alimentary Pharmacology and Therapeutics. , 27(104-119).

Roberto Berni Canani, Margherita Di Costanzo and Ludovica Leone.  The epigenetic effects of butyrate: potential therapeutic implications for clinical practice.  Clinical Epigenetics , 4:4. http://www.clinicalepigeneticsjournal.com/content/4/1/4

Nagendra Singh, Muthusamy Thangaraju, Puttur D. Prasad, Pamela M. Martin, Nevin A. Lambert, Thomas Boettger, Stefan Offermanns_, and Vadivel Ganapathy.  Blockade of Dendritic Cell Development by Bacterial Fermentation Products Butyrate and Propionate through a Transporter (Slc5a8)-dependent Inhibition of Histone Deacetylases.  The Journal of Biological Chemistry. Sept . 285: 36 (-). http://www.jbc.org/content/285/36/.full.pdf

Ohira H, Fujioka Y, Katagiri C, Mamoto R, Aoyama-Ishikawa M, Amako K, Izumi Y, Nishiumi S, Yoshida M, Usami M, Ikeda M. Butyrate attenuates inflammation and lipolysis generated by the interaction of adipocytes and macrophages.

J Atheroscler Thromb. ;20(5):425-42. 

Abstract

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.

Keywords: butyrate, irritable bowel syndrome, dosage, short-chain fatty acids

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:

1. Enhanced metabolism of intestinal epithelial cells in conditions with damage/inflammation of these cells.

2. Increased energy expenditure of the organism in pathological conditions.

3. Stimulation of intestine growth in &#;stress&#; situations

4. Conditions with accelerated intestinal passage and increased secretion into the lumen of the intestine (diarrhoea).

5. Decreased production of endogenous butyric acid due to changes in bacterial flora in different pathological conditions.

6. Other conditions associated with increased demand for butyric acid in the digestive tract.

1. 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.

2. 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).

3. 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.

4. 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.

5. 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.

6. 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:

1. 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.

2. The trend observed in developed countries toward a decline in the production of endogenous SCFA, which may not even cover physiological needs.

3. 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.

4. 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&#;.

5. Clinical and experimental observations confirming good effects of the use of high doses of butyrate in different pathological conditions.

6. Safety of high doses and no side effects or adverse reactions.

Conflict of interest

The authors whose names are listed immediately below certify that they have no affiliations with or involvement in any organization or entity with any financial interest, or non-financial interest in the subject matter or materials discussed in this manuscript.

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