Butyrate: A Double-Edged Sword for Health? - PMC

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Abstract

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

Introduction

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.

Endogenous Butyrate Producers and Production Pathways

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).

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Absorption of Butyrate

SCFAs 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).

Cellular Signaling Pathways of Butyrate

Butyrate functions as signaling molecules of GPCRs

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).

TABLE 1

GPCRsLigandsExpression sitesFunctionsStudy, year (reference)GPR41/FFAR3Acetate, propionate, butyrate, and pentanoateAdipocytes, bone marrow, colon, spleen, various immune cells, and enteroendocrine L cellsIncreased leptin expression, sympathetic activation increased PYY production; increased Tregs and dendritic cell precursors, hematopoiesis of dendritic cells from bone marrowDe Vadder et al., (36); Nøhr et al., (42); Trompette et al., (38); Kimura et al., (39)GPR43/FFAR2Formate, acetate, propionate, butyrate, and pentanoateAdipocytes, skeletal muscle, heart, spleen, fetal membrane, various immune cells, enteroendocrine L cells, and gut epitheliumAnorexigenic effects via secretion of PYY and GLP-1, increased insulin sensitivity and energy expenditure; anti-inflammatory, anti-tumorigenic; expansion and differentiation of Tregs, resolution of arthritis and asthmaKimura et al., (40); Voltolini et al., (41); Nøhr et al., (42); Smith et al., (43)GPR109A/HCA2Nicotinate and butyrateAdipocytes, various immune cells, intestinal epithelial cells, epidermis in squamous carcinoma, and retinal pigment epitheliumHDL metabolism, cAMP reduction in adipocytes, improved epithelial barrier function, dendritic cell trafficking, anti-inflammatory, increase in Treg generation, IL-10&#;producing T cells, and antitumorigenicIngersoll et al., (44); Macia et al., (45); Singh et al., (46); Bermudez et al., (47)Open in a separate window

Butyrate functions as an HDAC inhibitor

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.

Butyrate and Host Gastrointestinal Health

Anti-inflammation

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).

Butyrate and the intestinal barrier

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).

Butyrate and intestinal mucosal immunity

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.

Butyrate and Obesity: Inhibition or Promotion?

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) ( ).

TABLE 2

ViewpointsModelsDesignConclusionsStudy, year (reference)InhibitionSpecific pathogen&#;free, male C57BL/6J miceHigh fat diet&#;induced obese mice were gavaged with sodium butyrate, whereas the control group received vehicleShort-term oral administration of sodium butyrate alleviates diet-induced obesity and insulin resistance through activation of adiponectin-mediated pathway and stimulation of mitochondrial function in the skeletal muscleHong et al., (13)Male C57J/B6 mice and male Lepob/ob miceTwo groups were fed a low-fat diet with or without VSL#3 (Tau Sigma, Gaithersburg, MD), and 2 groups were continued on a high-fat diet with or without VSL#3Butyrate stimulates the release of GLP-1 from intestinal L cells, thereby providing a plausible mechanism for VSL#3 actionYadav et al., (85)Human L cells (NCI-h716 cell line)Stimulation with specific TLR-agonists and butyrateButyrate increases PYY expression through stimulating TLR expressionLarraufie et al., (86)Rat pituitary cell lineRat pituitary cell lines were transiently transfected with wt-GH and treated with 10 nM GHRH, 5 mM butyrate, or bothButyrate stimulates GH secretion from rat anterior pituitary cells via GPR41 and GPR43Miletta et al., (87)C57Bl/6J mice; PPAR-γ Lox/Lox miceThe experimental groups were fed a semisynthetic high-fat diet incorporated with SCFAs at 5%, whereas the control groups were fed a normal-fat dietSCFAs protect against high fat diet&#;induced obesity via a PPAR-γ&#;dependent switch from lipogenesis to fat oxidationden Besten et al., (88)PromotionFemale Sprague-Dawley ratsPregnant rats were randomly assigned to either a control or butyrate dietMaternal butyrate supplementation induces insulin resistance associated with enhanced intramuscular fat deposition in the offspringHuang et al., (14)Shrimp&#;Dietary supplementation with propionate and butyrate in different dietary concentrations modify the intestinal microbiota and improve the growth of Litopenaeus vannameida Silva et al., (89)Open in a separate window

Alleviating obesity

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).

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Similarly, 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.

Inducing obesity

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).

Butyrate Maintains Homeostasis through the Gut-Brain Axis

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.

Conclusions

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.

Acknowledgments

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.

Notes

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.

Abbreviations

FFAR

free fatty acid receptor

GH

growth hormone

GLP-1

glucagon-like peptide 1

GPCR

G protein&#;coupled receptor

GPR

orphan G protein&#;coupled receptor

HDAC

histone deacetylase

MCT

monocarboxylate transporter

PYY

peptide YY

SLC

solute carrier

SMCT

sodium-coupled monocarboxylate transporter

Used in food, cosmetics and even agriculture. Butyric acid is not only versatile, but also has a range of health benefits.

Also known as butanoic acid, it is a fascinating ingredient that can be just as versatile in your body. It is believed to counteract inflammation or regulate insulin metabolism, for example. What's more, your body produces it on its own, helped by probiotic bacteria.

From this article you will learn:

• What is butyric acid and how it differs from sodium butyrate.
• How it works.
• How butyric acid works and how it is synthesised in the body.
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• What ailments can butyric acid help with.
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• How to ensure the right concentration of butyric acid in the body.
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• Whether butyric acid can cause harm.
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See also:

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What is butyric acid?

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Butyric acid, also known as butanoic acid, is a short chain fatty acid ( short chain fatty acids - SCFA) that plays a key role in gut health. It is produced by the bacteria that live in your digestive system.

Wondering how it works? When you eat fibre that is indigestible to your body, it passes into the large intestine. There, probiotic bacteria residing in the colon convert this fibre into butyric acid. This is a perfect example of symbiosis, where both parties benefit - the bacteria have nourishment and you get an essential substance for your health .

Butyric acid is extremely important for your gut. It acts as a kind of fuel for the epithelial cells lining the colon, helping them to maintain a healthy intestinal barrier. This is important because this barrier prevents harmful substances from entering your body .

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As early as the s, studies were conducted that conclusively established butyric acid as a major source of energy for colonocytes, offering hope for its use in the prevention and treatment of gastrointestinal diseases.

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Katarzyna Grajpermagister of pharmacy

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What's more, butyric acid has anti-inflammatory properties, which may help to relieve inflammation in the gut. Some studies also suggest that it may help regulate blood sugar levels and improve metabolism. However, these are preliminary and inconclusive conclusions, so should be approached with caution .

So it is worth paying attention to your diet and making sure you are providing your body with enough fibre. By doing so, the probiotic bacteria will be able to produce butyric acid, which will contribute to your gut health.

Butyric acid versus sodium butyrate

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Sodium butyrate is the sodium salt of butyric acid, or a derivative of it. The molecules of butyric acid and butyrate are chemically different . However, the properties of the two substances are so similar that their names are often used interchangeably.

In practice, the sodium atom in butyrate makes this butyric acid derivative more stable. It is for this reason that you will most often encounter sodium butyrate in dietary supplements.

Sodium butyrate is the most common name.

Properties of butyric acid

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Butyric acid is a key ingredient for the proper functioning of the epithelial cells of the colon, called colonocytes. It provides up to 70% of the energy these cells need to function . 

This, however, is not the only function that butyric acid has in our bodies. It is currently the subject of scientific research to understand its potential effects on the immune system and its ability to reduce inflammation. In addition, its properties affecting insulin regulation are also being studied.

Although the exact mechanism of action of butyric acid at the biochemical level is not yet fully understood, there is some evidence to suggest that it may affect various aspects of bodily function. This may include :

• impact on the immune response, 
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• cell differentiation,
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• natural process of elimination of defective and damaged cells,
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Butyric acid may also help to strengthen the protective barrier in the intestines by participating in the production of the mucus that lining them .

Applications of butyric acid

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Butyric acid is a well-known ally in the fight against various digestive problems. First and foremost, this metabolite plays a key role in protecting and regenerating the end sections of the digestive system .

It is also an effective solution if you are struggling with problems such as bloating or constipation. Butyric acid aids intestinal peristalsis, which in practice means that it facilitates the bowel movement process. 

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The usefulness of butyric acid in infectious diarrhoea has also been clinically confirmed. This is related, among other things, to the mechanism of regulation of water and electrolyte absorption in the cell membrane of colonocytes.

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Katarzyna Grajpermagister of pharmacy

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What's more, butyric acid helps to control gas accumulation in the intestines. As a result, you are able to reduce the unpleasant bloating that can cause discomfort .

It is also worth adding that some studies suggest additional benefits for your body. Some scientific work has shown that butyric acid may contribute to maintaining a healthy body weight, by regulating metabolic processes related to insulin and lipid production . 

Do not, however, consider butyric acid (or its derivative, sodium butyrate) as a weight-loss agent. There is still a dispute among scientists about how butyric acid affects our metabolism. 

Most studies are in vitro experiments or those involving animals. There are also researchers who point in their work to links between high concentrations of butyrate or butyric acid and metabolic disorders and cardiovascular disease - as you can see, in this case, what's too much is unhealthy .

Butyric acid for the gut

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

Butyric acid has many important functions in your intestines. Not only is it a source of energy for the cells of the colon, but it also supports their regeneration. In addition, it supports the production of mucus, which is an important part of the protective intestinal barrier .

Thanks to this, butyric acid helps to protect your body from harmful substances and pathogens that could enter the bloodstream through this route.

Animal studies suggest that butyric acid may provide relief from irritable bowel syndrome (IBS) symptoms, such as abdominal pain or irregular bowel movements . 

A study review indicates that butyric acid derivatives may be helpful in the treatment of colorectal cancer. The results suggest that the ingredient may induce cancer cell death, improve the efficacy of radiotherapy and protect mucosa from degradation that can occur during chemotherapy .

Butyric acid provides energy to healthy cells and at the same time may inhibit the growth of cancerous ones, a phenomenon known as the Warburg effect. Therefore, there is a hypothesis that certain strains probiotics may exhibit anti-cancer effects .

Butyric acid is also used by intestinal cells to produce energy, which increases oxygen consumption by the epithelium. As a result, the presence of butyric acid-producing bacteria helps to maintain an anaerobic environment in the intestines, which further protects against the colonisation of aerobic pathogens such as Salmonella or bacteria E. coli.

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What is butyric acid found in?

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Butyric acid is not only found in your intestines. Some foods - especially milk and milk products (dairy products), for example butter, cream, yoghurt or hard yellow cheeses - also contain small amounts of it. Support for butyric acid synthesis can also be provided by products rich in probiotics and prebiotics.

By increasing the amount of probiotics in your gut, you increase the amount producers of butyric acid. And by eating prebiotic foods, you provide them with the necessary materials for this production.

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Products rich in probiotics

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Products rich in prebiotics (GOS and FOS fibre)*

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• yoghurt,
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• kefir,
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• buttermilk,
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• sugared milk,
• sugared milk,
• flax,
• flax,
• buttermilk,
• sugared milk,
• flax.
• miso,
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• tempeh,
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• sauerkraut,
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• pickled cucumbers,
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• cold boiled potatoes,
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• artichokes,
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• asparagus,
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• broccoli,
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• carrots,
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• garlic,
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• soy,
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• legumes,
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• peas,
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• apple,
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• currants,
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• morels,
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• bananas,
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• kiwi,
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• raspberries,
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• oranges,
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* GOS and FOS fibre are oligosaccharides, or complex carbohydrates (fructooligosaccharides and galactooligosaccharides), which do not digest in the stomach but are only fermented in the large intestine - providing food for probiotic bacteria and contributing to butyric acid production.

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Best results will be achieved by using different fibre fractions from three different groups including cereals, vegetables and fruit. Also ensure adequate hydration.

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Katarzyna Grajpermagister of pharmacy

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Butyric acid sweetness

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Butyric acid is considered safe, but there are situations in which its use must be abandoned.

Do not take butyric acid or its derivatives (butyrate) if :

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• you are allergic to butyric acid or any other ingredient in the supplement,
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• you have kidney problems, as butyric acid is removed from the body specifically by the kidneys,
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• you suffer from heart disease, as butyric acid can affect sodium levels in the body, which can be dangerous,
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• you should limit fibre in your diet because of certain digestive ailments,
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• you are pregnant or breastfeeding - the safety of using butyric acid during these periods is not well studied,
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• you are taking any medication - in which case consult your doctor before starting supplementation, as butyric acid may interact with some substances.

Despite its benefits, butyric acid can cause some side effects, although this is rather rare. The most common are gastrointestinal problems such as increased bowel function, nausea, abdominal pain and diarrhoea, and changes in appetite . 

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Often these symptoms disappear after a few days, but if they are bothersome or worsen, you should stop supplementation and consult your doctor.

The effects of allergic reactions are a different matter. Their symptoms are :

• rash, 
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• catarrh, 
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• swelling,
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• difficulty breathing, 
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If this occurs, discontinue use of the butyric acid preparation immediately and contact your doctor.

See also:

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Summary

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• Butyric acid is a metabolite of the fermentation of fibre by probiotic bacteria that inhabit the large intestine.
• Butyric acid is the main source of energy for colon epithelial cells. It also has protective and regenerative functions.
• Butyric acid can promote intestinal peristalsis and support the production of mucus, which is part of the natural intestinal barrier.
• The effects of butyric acid and its derivative, butyrate, in the context of influencing insulin and lipid metabolism and combating inflammation in the body are currently being investigated.
• Butyrate is an important component of the intestinal barrier.
• The appropriate concentration of butyric acid in the body is best ensured by consuming foods rich in GOS and FOS fibre, as well as probiotics.
• Butyric acid can also be taken in dietary supplements. It is most commonly found in these in the form of sodium butyrate.
• Butyrate supplements are also a good way to take it.
• Supplements with butyrate or butyric acid should be avoided by people with heart disease and ailments that require restricted fibre intake.

FAQ

.. How to make butyric acid at home .

Note: butyric acid is a really smelly thing. Think twice about whether you want to make it at home (if you live in a block of flats, think about your neighbours too). Another important thing: Do not eat butyric acid obtained this way! 

To make butyric acid, all you need to do is leave the butter out of the fridge - until it goes rancid. But to be able to isolate it, you can use this recipe:

1. Melt 500ml of butter in a pot over a low heat; 
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2. Add 500 ml distilled water, stir to combine. 
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3. Pour the mixture into a jar and add 2 tablespoons of natural yogurt as a starter. 
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4. Cover the jar and keep in a warm place for 2-3 days. 
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5. After this time, strain the liquid through a thick sieve, separating the solids. 
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6. Heat the remaining liquid to 100°C until the water evaporates. 
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7. The residue that remains is butyric acid.
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. Where does butyric acid occur? .

Butyric acid occurs naturally in many products, especially butter. You will also find it in other dairy products such as cheese, cream and yoghurt. Furthermore, it is also contained in ghee, a type of clarified butter. 

Butyric acid is also produced in the human body - in the gut, as a result of the fermentation of fibre by bacteria. For this reason, eat fibre-rich foods such as fruit, vegetables, nuts, seeds and whole-grain cereal products. This is important because butyric acid has many health benefits. It has anti-inflammatory effects and supports gut health.

. What are the side effects of taking butyric acid? .

Taking butyric acid can lead to several side effects. The most common are abdominal pain, bloating, diarrhoea and nausea. For these symptoms, reduce the dose of butyric acid or divide it into several smaller portions throughout the day. This may help to minimise discomfort. Sometimes an allergic reaction may also occur.

. What is the smell of butyric acid? .

Butyric acid has an intense, unpleasant odour that is often compared to the smell of... vomit. This is due to the specific chemical structure of this acid, which contains four carbon atoms in its chain. However, in small quantities, it can contribute to the characteristic taste of some foods (especially cheese).

. What is the formula of butyric acid? .

The chemical formula of butyric acid is C4H8O2. It is a carboxylic acid that consists of four carbon atoms (C), eight hydrogen atoms (H) and two oxygen atoms (O). Carbon (C) comes first, followed by hydrogen (H) and finally oxygen (O). 

This order is important because it indicates the structure of the molecule. Other chemical formulas of butyric acid that you may encounter are C3H7COOH and CH3(CH2)2COOH.

. How much does butyric acid cost? .

Dietary supplements containing butyric acid, or more commonly its derivative - sodium butyrate - cost from around £30 to £150. Differences in price may be due to the quality of the raw material itself, the size of the packaging and the additional active ingredients used in the formulation.

. Is butyric acid in medicinal form? .

Butyric acid (also in the form of sodium butyrate) is only available in Poland as a dietary supplement. You can find it in health food shops or pharmacies. Only buy products from trusted manufacturers to ensure the best quality and safety. 

Butyric acid is important for intestinal health, as it is the main source of energy for intestinal epithelial cells. An example of a product containing butyric acid in the form of sodium butyrate is Panaseus Formula for the Gut.

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Resources

.. See all .

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Amiri, P., Hosseini, S. A., Roshanravan, N., Saghafi-Asl, M., & Tootoonchian, M. (). The effects of sodium butyrate supplementation on the expression levels of PGC-1α, PPARα, and UCP-1 genes, serum level of GLP-1, metabolic parameters, and anthropometric indices in obese individuals on weight loss diets: A study protocol for a triple-blind, randomized, placebo-controlled clinical trial. Trials, 24(1), 489. https://doi.org/10./s-022--9

Banasiewicz, T., Domagalska, D., Borycka-Kiciak, K., & Rydzewska, G. (). Determination of butyric acid dosage based on clinical and experimental studies - a literature review. Gastroenterology Review/Review of Gastroenterology, 15(2), 119-125. https://doi.org/10./pg..

Birt, D. F., Boylston, T., Hendrich, S., Jane, J.-L., Hollis, J., Li, L., McClelland, J., Moore, S., Phillips, G. J., Rowling, M., Schalinske, K., Scott, M. P., & Whitley, E. M. (). Resistant Starch: Promise for Improving Human Health. Advances in Nutrition, 4(6), 587-601. https://doi.org/10./an.113.

Borycka-Kiciak, K., Banasiewicz, T., & Rydzewska, G. (). Butyric acid - a well-known molecule revisited. Gastroenterology Review/Review of Gastroenterology, 12(2), 83-89. https://doi.org/10./pg..

Butyric Acid-An overview | ScienceDirect Topics. (n.d.). Retrieved November 10, , from https://www.sciencedirect.com/topics/medicine-and-dentistry/butyric-acid

Candido, E. P. M., Reeves, R., & Davie, J. R. (). Sodium butyrate inhibits histone deacetylation in cultured cells. Cell, 14(1), 105-113. https://doi.org/10./-(78)-7

De la Cuesta-Zuluaga, J., Mueller, N. T., Álvarez-Quintero, R., Velásquez-Mejía, E. P., Sierra, J. A., Corrales-Agudelo, V., Carmona, J. A., Abad, J. M., & Escobar, J. S. (). Higher Fecal Short-Chain Fatty Acid Levels Are Associated with Gut Microbiome Dysbiosis, Obesity, Hypertension and Cardiometabolic Disease Risk Factors. Nutrients, 11(1), Article 1. https://doi.org/10./nu

Effects of oral butyrate supplementation on inflammatory potential of circulating peripheral blood mononuclear cells in healthy and obese males | Scientific Reports. (n.d.). Retrieved November 3, , from https://www.nature.com/articles/s-018--7

Frontiers | Protective role of butyrate in obesity and diabetes: New insights. (n.d.). Retrieved November 5, , from https://www.frontiersin.org/articles/10./fnut../full

Kaźmierczak-Siedlecka, K., Marano, L., Merola, E., Roviello, F., & Połom, K. (). Sodium butyrate in both prevention and supportive treatment of colorectal cancer. Frontiers in Cellular and Infection Microbiology, 12. https://www.frontiersin.org/articles/10./fcimb..

Lewandowski, K., Kaniewska, M., Karlowicz, K., Rosolowski, M., & Rydzewska, G. (). The effectiveness of microencapsulated sodium butyrate at reducing symptoms in patients with irritable bowel syndrome. Gastroenterology Review/Review of Gastroenterology, 17(1), 28-34. https://doi.org/10./pg..

Liu, H., Wang, J., He, T., Becker, S., Zhang, G., Li, D., & Ma, X. (). Butyrate: A Double-Edged Sword for Health? Advances in Nutrition, 9(1), 21-29. https://doi.org/10./advances/nmx009

Sodium butyrate in the treatment of functional and inflammatory bowel disease | Practical Gastroenterology-Practitioner's Journal. (n.d.). Retrieved November 3, , from https://gastroenterologia-praktyczna.pl/a/Maslan-sodu-w-leczeniu-chorob-czynnosciowych-i-zapalnych-jelit.html/

Miller, A. A., Kurschel, E., Osieka, R., & Schmidt, C. G. (). Clinical pharmacology of sodium butyrate in patients with acute leukemia. European Journal of Cancer and Clinical Oncology, 23(9), -. https://doi.org/10./-(87)-X

Pietrzak, A., Banasiuk, M., Szczepanik, M., Borys-Iwanicka, A., Pytrus, T., Walkowiak, J., & Banaszkiewicz, A. (). Sodium Butyrate Effectiveness in Children and Adolescents with Newly Diagnosed Inflammatory Bowel Diseases-Randomized Placebo-Controlled Multicenter Trial. Nutrients, 14(16), Article 16. https://doi.org/10./nu

Säemann, M. D., Böhmig, G. A., Österreicher, C. H., Burtscher, H., Parolini, O., Diakos, C., Stöckl, J., Hörl, W. H., & Zlabinger, G. J. (). Anti-inflammatory effects of sodium butyrate on human monocytes: Potent inhibition of IL-12 and up-regulation of IL-10 production. The FASEB Journal, 14(15), -. https://doi.org/10./fj.00-fje

Segain, J.-P., Blétière, D. R. de la, Bourreille, A., Leray, V., Gervois, N., Rosales, C., Ferrier, L., Bonnet, C., Blottière, H. M., & Galmiche, J.-P. (). Butyrate inhibits inflammatory responses through NFκB inhibition: Implications for Crohn's disease. Gut, 47(3), 397-403. https://doi.org/10./gut.47.3.397

Sodium butyrate. (n.d.). American Chemical Society. Retrieved November 3, , from https://www.acs.org/molecule-of-the-week/archive/s/sodium-butyrate.html

Spina, L., Cavallaro, F., Fardowza, N. I., Lagoussis, P., Bona, D., Ciscato, C., Rigante, A., & Vecchi, M. (). Butyric acid: Pharmacological aspects and routes of administration. Digestive and Liver Disease Supplements, 1(1), 7-11. https://doi.org/10./S-(08)-2

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Summer, A., Formaggioni, P., Franceschi, P., Di Frangia, F., Righi, F., & Malacarne, M. (). Cheese as Functional Food: The Example of Parmigiano Reggiano and Grana Padano. Food Technology and Biotechnology, 55(3), 277-289. https://doi.org/10./ftb.55.03.17.

Xu, Y.-H., Gao, C.-L., Guo, H.-L., Zhang, W.-Q., Huang, W., Tang, S.-S., Gan, W.-J., Xu, Y., Zhou, H., & Zhu, Q. (). Sodium butyrate supplementation ameliorates diabetic inflammation in db/db mice. Journal of Endocrinology, 238(3), 231-244. https://doi.org/10./JOE-18-

Zou, X., Ji, J., Qu, H., Wang, J., Shu, D. M., Wang, Y., Liu, T. F., Li, Y., & Luo, C. L. (). Effects of sodium butyrate on intestinal health and gut microbiota composition during intestinal inflammation progression in broilers. Poultry Science, 98(10), -. https://doi.org/10./ps/pez279

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