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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&#;.
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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.
Butyrate, a four-carbon short-chain fatty acid, is produced through microbial fermentation of dietary fibers in the lower intestinal tract. Endogenous butyrate production, delivery, and absorption by colonocytes have been well documented. Butyrate exerts its functions by acting as a histone deacetylase (HDAC) inhibitor or signaling through several G protein&#;coupled receptors (GPCRs). Recently, butyrate has received particular attention for its beneficial effects on intestinal homeostasis and energy metabolism. With anti-inflammatory properties, butyrate enhances intestinal barrier function and mucosal immunity. However, the role of butyrate in obesity remains controversial. Growing evidence has highlighted the impact of butyrate on the gut-brain axis. In this review, we summarize the present knowledge on the properties of butyrate, especially its potential effects and mechanisms involved in intestinal health and obesity.
Keywords:
butyrate, G protein&#;coupled receptors, gut-brain axis, histone deacetylase, inflammation, intestinal barrier, intestinal microbiota, obesity
SCFAs, primarily acetate, propionate, and butyrate, are organic acids produced in the intestinal lumen by bacterial fermentation of mainly undigested dietary carbohydrates, specifically resistant starch and dietary fiber and, to a lesser extent, dietary and endogenous proteins (1, 2). Most micro-organisms prefer to ferment carbohydrates over proteins, so the concentrations of SCFAs are highest in the proximal colon, where most substrates for fermentation are available, and decline towards the distal colon (3). It has been estimated that SCFAs contribute to &#;60&#;70% of the energy requirements of colonic epithelial cells and 5&#;15% of the total caloric requirements of humans (4).
Among SCFAs, butyrate has received particular attention for its beneficial effects on both cellular energy metabolism and intestinal homeostasis (5). Although it is the least abundant SCFA produced (&#;60% acetate, 25% propionate, and 15% butyrate in humans) (6, 7), butyrate is the major energy source for colonocytes (8, 9). Butyrate modulates biological responses of host gastrointestinal health by acting as a histone deacetylase (HDAC) inhibitor and binding to several specific G protein&#;coupled receptors (GPCRs) (10). Numerous in vitro and in vivo studies have shown that butyrate plays an important role in modulating immune and inflammatory responses and intestinal barrier function (11, 12). However, the effect of butyrate on obesity remains controversial, with opposite results also reported (13, 14). Although butyrate is well known to exert a plethora of beneficial effects on the intestinal tract, growing evidence points to the impact of butyrate on the brain via the gut-brain axis. For example, changes in butyrate-producing bacteria can modulate the peripheral and central nervous systems and brain functions, reinforcing the notion for the existence of the microbiota-gut-brain axis (15). Herein, we summarize current knowledge on butyrate, especially its potential effects and possible mechanisms of action in relation to host gastroenteric health and obesity.
A large number of bacteria are present in the human cecum and colon, accounting for &#;&#; CFUs/g wet weight or CFUs in total of the hindgut (16). Similar estimates have been reported in other omnivores such as pigs (17). More than 50 genera and 400 species of bacteria have been found in human feces (18). The dominant bacteria are anaerobes, including Bacteroides, Bifidobacteria, Eubacteria, Streptococci, and Lactobacilli. Other anaerobes, including Enterobacteria, are usually found in smaller quantities (19).
Among gram-positive anaerobic bacteria, butyrate-producing bacteria are widely distributed. Two of the most important groups are Faecalibacterium prausnitzii in the Clostridium leptum cluster (or Clostridial cluster IV) and Eubacterium rectale/Roseburia spp. in the Clostridium coccoides (or Clostridial cluster XIVa) cluster of Firmicutes (20). Each of these groups typically accounts for &#;5&#;10% of the total bacteria detectable in fecal samples of healthy adult humans. In addition to these groups, butyrate-producing bacteria are widely distributed across several clusters including clusters IX, XV, XVI, and XVII (21).
Butyrate is produced from dietary fibers through bacterial fermentation via 2 metabolic pathways ( ). In the first pathway, butyryl-CoA is phosphorylated to form butyryl-phosphate and transformed to butyrate via butyrate kinase (22). In the second pathway, the CoA moiety of butyryl-CoA is transferred to acetate via butyryl-CoA:acetate CoA-transferase, leading to the formation of butyrate and acetyl-CoA (23). Analysis of the metagenome data also suggested that butyrate can be synthesized from proteins via the lysine pathway (24).
Open in a separate windowSCFAs are absorbed in both the small and large intestine by similar mechanisms (25, 26). Different mechanisms of absorbing SCFAs across the apical membrane of the colonocytes are reported, including diffusion of the undissociated form and active transport of the dissociated form by SCFA transporters (27). Two SCFA transporters exist, including monocarboxylate transporter (MCT) isoform 1 (MCT1), which is coupled to a transmembrane H+-gradient (28), and solute carrier (SLC) family 5 member 8 (SLC5A8), which is also known as sodium-coupled monocarboxylate transporter (SMCT) 1 (SMCT1) and is a Na+-coupled co-transporter (11).
A carrier-mediated, HCO3&#; gradient-dependent anion-butyrate exchange system is present on the basolateral membrane (5). In humans, MCT3 is expressed in low concentrations in the ileum, whereas MCT4 and MCT5 are expressed abundantly in the distal colon (29).
MCTs are also involved in butyrate transport on the apical membrane of colonocytes (30). Butyrate transportation with MCTs is saturated, coupled with H+, and inhibited by several monocarboxylates such as acetate, propionate, pyruvate, lactate, and α-ketobutyrate. The pH for the optimal activity of the colonic butyrate transporters appears to be &#;5.5. In addition, a second class of MCTs, called SMCTs, was identified (31), such as SLC5A8 (SMCT1) and SLC5A12 (SMCT2) (32). Different from MCTs, SMCT transport involves Na+ uptake by the transport cycle and also uses nicotinate and ketone bodies as substrates (33).
GPCRs are the largest and most diverse family of transmembrane proteins (34). In , orphan G protein&#;coupled receptor 41 (GPR41) and GPR43 were identified as receptors for SCFAs and thus renamed FFA receptors (FFARs) 3 and 2, respectively (35). However, these receptors show specificities for different SCFAs (36&#;47) ( ). For example, butyrate preferentially binds to GPR41 over GPR43, which has higher affinities for acetate and propionate (30). GPR43 is expressed in a variety of tissues, with the highest expression in immune cells. This includes polymorphonuclear neutrophils, indicating that SCFAs could be involved in the activation of leucocytes (48, 49) ( ). GPR41 is even more widely expressed than GPR43, having been detected in adipose tissues, the pancreas, spleen, lymph nodes, bone marrow, and peripheral blood mononuclear cells (26). Butyrate directly regulates GPR41-mediated sympathetic nervous system activity to control body energy expenditure and maintain metabolic homeostasis (39). Another major GPCR activated by butyrate is GPR109A (50) ( ). GPR109A signaling activates the inflammasome pathway in colonic macrophages and dendritic cells, resulting in the differentiation of regulatory T cells and IL-10&#;producing T cells (46). The secretion of IL-18 is also increased in intestinal epithelial cells via butyrate-stimulated signaling of GPR109A (45). On the other hand, the anti-inflammatory properties of butyrate are also achieved through inhibition of the production of proinflammatory enzymes and cytokines (51).
HDACs are a class of enzymes that remove acetyl groups from ε-N-acetyl lysine on histones, allowing the histones to wrap the DNA more tightly (52). Among the SCFAs, butyrate is the most potent in inhibiting HDAC activities both in vitro and in vivo (53, 54). The mechanism by which butyrate inhibits HDAC activities remains obscure. A model was proposed that butyrate inhibits the recruitment of HDACs to the promoter by transcription factors, specificity protein 1/specificity protein 3 (Sp1/Sp3), leading to histone hyperacetylation (55). Many of the anticancer activities of butyrate have been found to be mediated through HDAC inhibition, which includes inhibition of cell proliferation, induction of cell differentiation or apoptosis, and induction or repression of gene expression (56, 57). In addition to acting as an antitumor agent, butyrate achieves the anti-inflammatory effects partly through HDAC inhibition as well (58, 59). For example, butyrate plays a key role in the downregulation of proinflammatory effectors in lamina propria macrophages (30) as well as regulating cytokine expression in T cells (60). Thus, butyrate-mediated HDAC inhibition and concomitant beneficial health outcomes depend not only on its production amounts but also on which tissue or cell type that it targets.
Intestinal epithelium maintains a low grade of inflammation in order to prepare for constant immunological challenges on the mucosal surface (48, 61). If the immunological control is disrupted, the enterocytes might suffer from inflammatory and oxidative damages and even cause cancer (62, 63). Many studies have shown that butyrate can act as an anti-inflammatory agent. Several human and animal studies reported that the proinflammatory cytokines IFN-γ, TNF-α, IL-1β, IL-6, and IL-8 are inhibited, whereas IL-10 and TGF-β are upregulated in response to butyrate (25). The mechanism underlying the anti-inflammatory effect of butyrate is at least in part due to inhibition of the activation of a transcription factor known as NF-κB (64). NF-κB is a transcription factor that regulates the expression of a variety of genes involved in inflammation and immunity, such as proinflammatory cytokines and enzymes, adhesion molecules, growth factors, acute-phase proteins, and immune receptors (48, 65). Several studies suggested that butyrate suppresses the NF-κB signaling pathways by rescuing the redox machinery and controlling reactive oxygen species, which mediates NF-κB activation (66). Further studies also showed that butyrate is capable of activating PPAR-γ (67), which is a member of the nuclear hormone receptor family and highly expressed in colonic epithelial cells, and its activation is thought to exert anti-inflammatory effects (68). Apart from the inhibition of NF-κB activation and upregulation of PPAR-γ, butyrate may also exert its anti-inflammatory activities through inhibition of IFN-γ signaling (69).
The barrier function of intestinal epithelial cells is an important first line of defense and ensures appropriate permeability characteristics of the epithelial layer (3, 70). Butyrate is known to repair and enhance barrier function of intestinal epithelial cells (71, 72). A current study by Elamin et al. (73) showed that butyrate exerts a protective effect on intestinal barrier function in Caco-2 cell monolayers. For example, butyrate is capable of upregulating the expression of mucin 2 (MUC2) (74), which is the most prominent mucin on the intestinal mucosal surface and can reinforce the mucous layer, leading to the enhanced protection against luminal pathogens (1, 74). In addition, the expression of trefoil factors (TFFs), which are mucin-associated peptides that contribute to the maintenance and repair of the intestinal mucosa (12), can be increased by butyrate (75). Furthermore, butyrate modulates the expression of tight junction proteins to minimize paracellular permeability (62, 76). One of several mechanisms in which butyrate enhances barrier function is through activation of AMP-activated protein kinase in monolayers (77). Butyrate can also stimulate the production of antimicrobial peptides, such as LL-37 in humans (78). However, on the basis of in vitro models, Huang et al. (79) showed that the effect of butyrate on the intestinal barrier function may be concentration-dependent. Butyrate promotes intestinal barrier function at low concentrations (&#;2 mM) (77) but may disrupt intestinal barrier function by inducing apoptosis at high concentrations (5 or 8 mM) (79). On the basis of the physiologic concentration in mammalian gastrointestinal tract, the recommended concentration of butyrate used in in vitro models is currently 0&#;8 mM (80). However, considering that the majority of butyrate is metabolized as energy substrate by the colonic epithelium (12), the dosages used for treatment may be quite different between in vivo and in vitro models (4). For example, a dose of 100 mM butyrate by rectal administration was commonly used in clinical practice, which is comparable with physiologic concentrations in the colon of humans after the consumption of a high-fiber diet (81).
In addition to anti-inflammatory properties, SCFAs, especially butyrate, can act as modulators of chemotaxis and adhesion of immune cells (61). Butyrate can modulate intestinal epithelial cell&#;mediated migration of neutrophils to inflammatory sites, and such an effect is concentration-dependent (82, 83). In addition, butyrate plays a role in cell proliferation and apoptosis. Butyrate stimulates cell growth and DNA synthesis and induces growth arrest in the G1 phase of the cell cycle (5, 61). Although low concentrations of butyrate enhance cell proliferation (5), high concentrations of butyrate induce apoptosis (57). Overall, butyrate can influence the immune response by affecting immune cell migration, adhesion, and cellular functions such as proliferation and apoptosis.
The abnormalities in glycolipid metabolism are a main reason for obesity, diabetes, and other metabolic syndromes (84). So far, the effect of butyrate on glycolipid metabolism remains controversial. We summarized the experimental studies that evaluated the potential relation between butyrate and obesity (85&#;89) ( ).
The involvement of butyrate in diet-induced obesity and insulin resistance has been studied (90). Butyrate has been reported to improve glucose homeostasis in rodents (36). A recent study by Hong et al. (13) showed that butyrate alleviates diet-induced obesity and insulin resistance in mice. Another study in mice also showed that dietary butyrate supplementation prevented and reversed high-fat-diet&#;induced obesity by downregulating the expression and activity of PPAR-γ, promoting a change from lipogenesis to lipid oxidation (88). Consequently, the expression of mitochondrial uncoupling protein 2 and the AMP-to-ATP ratio were increased, thereby stimulating the oxidative metabolism in the liver and adipose tissue (88, 91).
Nevertheless, different mechanisms have been proposed to explain the effects of butyrate on alleviating obesity. The stimulation of gut hormones and inhibition of food intake by butyrate may represent a novel mechanism by which the gut microbiota regulates host metabolism (92). In vitro and in vivo studies have shown that butyrate enhances the secretion of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) (85, 93) ( ). GLP-1 is a gastrointestinal hormone that is secreted mainly by enteroendocrine L cells in the distal gut (94). It exerts multiple biological effects, including a glucose-dependent insulinotropic effect on pancreatic B cells, reduction in appetite, and inhibition of gastric emptying (95). These properties can be extended to patients with obesity. By using a cell culture system, Yadav et al. (85) showed that butyrate stimulated the release of GLP-1 from intestinal L cells. However, several studies in FFAR3-deficient mice showed that FFAR3 plays a minor role in butyrate stimulation of GLP-1 (92). Thus, these effects indicated the involvement of additional mechanisms in butyrate-mediated stimulation of GLP-1 (92).
Open in a separate windowSimilarly, PYY is also synthesized and released from endocrine L cells throughout the intestinal tract (96, 97) and is implicated in the regulation of food intake, gut motility, and insulin secretion (98, 99). As a gut hormone, PYY can also contribute to alleviating obesity in obese people (100). Numerous studies have shown the close relation between butyrate and PYY expression (86, 101). In in vitro models, Larraufie et al. (86) showed that butyrate can increase PYY expression through upregulation of Toll-like receptor&#;dependent microbial sensing. In addition to gastrointestinal hormones, butyrate also has positive effects on the secretion and metabolic actions of growth hormone (GH) (102), which is a type of somatotropin hormone secreted from the pituitary gland in a pulsatile manner (87). GH plays a potent role in controlling energy homeostasis by stimulating lipolysis and protein retention (103, 104). By using a rat pituitary tumor cell line, Miletta et al. (87) reported that butyrate can stimulate GH synthesis and promote basal and GH-releasing hormone-induced GH secretion, indicating an improved lipolysis and oxidative metabolism.
The findings that the total amount of SCFAs is higher in obese humans than in lean individuals (105) and that treated obese individuals showed reduced fecal SCFAs (106) suggest that SCFAs are rapidly assimilated into host carbohydrates and lipids and could contribute to the obese phenotype by providing &#;10% of our daily energy requirements (107, 108). Several in vitro studies have shown that intestinal epithelial cells, especially colonocytes, have adapted to the use of butyrate as their primary source of energy, accounting for &#;70% of ATP produced (109, 110). Through FA oxidation, colonic cells exhibit a great capacity to rapidly oxidize butyrate into carbon dioxide (111). Furthermore, butyrate is able to increase lipid synthesis from acetyl-CoA or ketone bodies via the β-hydroxy-β-methylglutaryl-CoA pathway, which potentially contributes to obesity (112).
A small fraction of butyrate could be transported via the portal vein and reach the liver, where it is involved in lipid biosynthesis and influences glycolipid metabolism (109). First, butyrate metabolism yields acetyl-CoA in the liver, similar to colonocytes that enter into the citric acid cycle (113). Second, butyrate is shown to be metabolized to produce FAs, cholesterol, and ketone bodies via acetyl-CoA, thereby providing specific substrates for lipid biosynthesis (5). Butyrate plays a role in obesity not only through providing the substrate for energy expenditure but also by engaging in signaling pathways involved in glycolipid metabolism. Consistently, maternal butyrate supplementation induces mRNA and protein expression of lipogenic genes and decreases the amount of lipolytic enzymes in the offspring, indicating insulin resistance and impaired glucose tolerance (14).
In conclusion, although a large body of evidence has suggested the effect of butyrate on alleviating high fat diet&#;induced obesity and insulin resistance, a few studies showed an opposite effect. Therefore, additional investigations are warranted to understand the apparently paradoxical effects of butyrate on obesity (34, 114).
A growing body of evidence indicates extensive communications between the brain and the gut via the gut-brain axis (115, 116). The gut-brain axis is composed of the central nervous system, enteric nervous system, and different types of afferent and efferent neurons that are involved in signal transduction between the brain and gut (15, 117). The bidirectional communication between the gut and the brain occurs through various pathways, including the vagus nerve, neuroimmune pathways, and neuroendocrine pathways (118, 119). As a microbial metabolite, butyrate is capable of exerting its effects on host metabolism indirectly by acting through the gut-brain axis (114, 120). For instance, butyrate can enhance the proportion of cholinergic enteric neurons via epigenetic mechanisms (121). Moreover, with an ability to cross the blood-brain barrier, butyrate activates the vagus nerve and hypothalamus, thus indirectly affecting host appetite and eating behavior (122, 123). Some of the beneficial metabolic effects of butyrate are mediated through gluconeogenesis from the gut epithelium and through a gut-brain neural circuit to increase insulin sensitivity and glucose tolerance (124, 125). For example, butyrate binds to its receptor in the intestinal cells and signals to the brain through the cAMP signaling pathway (126, 127). More studies are needed to explore the impact of butyrate on glycolipid metabolism abnormalities and disease via the gut-brain axis.
Microbe-derived butyrate plays an important role in both gut health and obesity of the host. New mechanisms are being revealed. The reason behind the paradoxical effect of butyrate on glucose and lipid metabolism, especially with regard to its role in obesity, remains elusive. The effect of endogenous butyrate on the gut-brain axis warrants further investigations. A better understanding of the mechanism of action of butyrate in intestinal physiology and lipid metabolism will facilitate the application of butyrate and HDAC inhibitors in gut health improvement and control and the prevention of metabolic diseases.
The authors&#; responsibilities were as follows&#;XM: conceived and designed the review; HL and JW: collected and analyzed the literature and drafted the manuscript; TH, XM, SB, and GZ: edited the manuscript; DL: provided advice and consultation; and all authors: read and approved the final manuscript.
Supported by the National Key R&D Program of China (YFD), the National Basic Research Program of China (973 Program, CB), the National Natural Science Foundation of China (, , and ), the 111 Project (B), and the National Department Public Benefit Research Foundation ().
Author disclosures: HL, JW, TH, SB, GZ, DL, and XM, no conflicts of interest.
HL and JW contributed equally to this work.
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