. Feb 9;9(1):21&#;29. doi: 10./advances/nmx009

Butyrate: A Double-Edged Sword for Health?

Hu Liu

Hu Liu

1State Key Laboratory of Animal Nutrition, China Agricultural University, Beijing, China Find articles by Hu Liu 1, Ji Wang

Ji Wang

1State Key Laboratory of Animal Nutrition, China Agricultural University, Beijing, China Find articles by Ji Wang 1, Ting He

Ting He

1State Key Laboratory of Animal Nutrition, China Agricultural University, Beijing, China Find articles by Ting He 1, Sage Becker

Sage Becker

2Department of Animal Science, Oklahoma State University, Stillwater, OK; Departments of Internal Medicine and Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX Find articles by Sage Becker 2, Guolong Zhang

Guolong Zhang

2Department of Animal Science, Oklahoma State University, Stillwater, OK; Departments of Internal Medicine and Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX Find articles by Guolong Zhang 2, Defa Li

Defa Li

1State Key Laboratory of Animal Nutrition, China Agricultural University, Beijing, China Find articles by Defa Li 1, Xi Ma

Xi Ma

1State Key Laboratory of Animal Nutrition, China Agricultural University, Beijing, China 3Internal Medicine and Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 4Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX Find articles by Xi Ma 1,3,4,&#;

1State Key Laboratory of Animal Nutrition, China Agricultural University, Beijing, China 2Department of Animal Science, Oklahoma State University, Stillwater, OK; Departments of Internal Medicine and Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 3Internal Medicine and Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 4Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX

Received Jul 1; Revised Aug 9; Accepted Nov 11; Issue date Jan.

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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 (Figure 1). 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).

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) (Table 1). 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) (Figure 1). 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) (Table 1). 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.

GPCRs Ligands Expression sites Functions Study, year (reference) GPR41/FFAR3 Acetate, propionate, butyrate, and pentanoate Adipocytes, bone marrow, colon, spleen, various immune cells, and enteroendocrine L cells Increased leptin expression, sympathetic activation increased PYY production; increased Tregs and dendritic cell precursors, hematopoiesis of dendritic cells from bone marrow De Vadder et al., (36); Nøhr et al., (42); Trompette et al., (38); Kimura et al., (39) GPR43/FFAR2 Formate, acetate, propionate, butyrate, and pentanoate Adipocytes, skeletal muscle, heart, spleen, fetal membrane, various immune cells, enteroendocrine L cells, and gut epithelium Anorexigenic 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 asthma Kimura et al., (40); Voltolini et al., (41); Nøhr et al., (42); Smith et al., (43) GPR109A/HCA2 Nicotinate and butyrate Adipocytes, various immune cells, intestinal epithelial cells, epidermis in squamous carcinoma, and retinal pigment epithelium HDL metabolism, cAMP reduction in adipocytes, improved epithelial barrier function, dendritic cell trafficking, anti-inflammatory, increase in Treg generation, IL-10&#;producing T cells, and antitumorigenic Ingersoll et al., (44); Macia et al., (45); Singh et al., (46); Bermudez et al., (47)

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).

TABLE 2.

Viewpoints Models Design Conclusions Study, year (reference) Inhibition Specific pathogen&#;free, male C57BL/6J mice High fat diet&#;induced obese mice were gavaged with sodium butyrate, whereas the control group received vehicle Short-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 muscle Hong et al., (13) Male C57J/B6 mice and male Lepob/ob mice Two 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#3 Butyrate stimulates the release of GLP-1 from intestinal L cells, thereby providing a plausible mechanism for VSL#3 action Yadav et al., (85) Human L cells (NCI-h716 cell line) Stimulation with specific TLR-agonists and butyrate Butyrate increases PYY expression through stimulating TLR expression Larraufie et al., (86) Rat pituitary cell line Rat pituitary cell lines were transiently transfected with wt-GH and treated with 10 nM GHRH, 5 mM butyrate, or both Butyrate stimulates GH secretion from rat anterior pituitary cells via GPR41 and GPR43 Miletta et al., (87) C57Bl/6J mice; PPAR-γ Lox/Lox mice The experimental groups were fed a semisynthetic high-fat diet incorporated with SCFAs at 5%, whereas the control groups were fed a normal-fat diet SCFAs protect against high fat diet&#;induced obesity via a PPAR-γ&#;dependent switch from lipogenesis to fat oxidation den Besten et al., (88) Promotion Female Sprague-Dawley rats Pregnant rats were randomly assigned to either a control or butyrate diet Maternal butyrate supplementation induces insulin resistance associated with enhanced intramuscular fat deposition in the offspring Huang et al., (14) Shrimp &#; Dietary supplementation with propionate and butyrate in different dietary concentrations modify the intestinal microbiota and improve the growth of Litopenaeus vannamei da Silva et al., (89)

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) (Figure 2). 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).

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.

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Articles from Advances in Nutrition are provided here courtesy of American Society for Nutrition

In the early s Michel-Eugène Chevreul, a French organic chemist, first discovered butyric acid in its impure form while acidifying animal fat soaps. (Source)

Butyric acid, also known as butanoic acid, is a four-carbon short-chain fatty acid that is found in a number of foods and is also produced in our bodies. Its name comes from the ancient Greek word for butter.

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Known as the &#;stinky fat,&#; butyric acid boasts an aromatic odor (to put it kindly) that has been described as both rancid butter and stale cheddar. It&#;s also responsible for the familiar lactic acid flavor that we often associate with fresh, homemade bread, butter, and yogurt.

Although butyric acid is naturally occurring in different types of dairy products, it's found in even greater amounts in the digestive tracts of humans and other mammals. The organic compound is produced when complex sugars are broken down during the process of fermentation. Its main function is to provide energy to cells of the colon, but it also supports the immune system with its powerful anti-inflammatory and antimicrobial properties.

In today's edition, we're exploring butyric acid, AKA the pungent, rancid odor that you might recognize from that time your butter went bad &#; and also a powerful healing nutrient in our bodies.

What Is Butyric Acid and Why Should I Care?

Butyric acid is an important short-chain fatty acid produced in the gut 

Butyric acid, also known as butanoic acid, is a short-chain, saturated fatty acid (SCFA) that is found in plant oils and animal fats, especially products such as butter, ghee, and raw milk. It&#;s also produced when carbohydrates like fiber are fermented by bacteria in the colon.

Butyric acid is the preferred fuel of your enterocytes, the cells that line the intestines. In other words, it's what your gut cells prefer to burn for energy. Estimates suggest that the compound provides your colon cells with about 70% of their energy needs. (Source)

Note: Although the terms &#;butyric acid&#; and &#;butyrate&#; are commonly used interchangeably even in the literature, scientifically speaking, the two compounds have slightly different structures (butyrate has one less proton than butyric acid). However, research appears to show that they have identical health benefits. 

Butyric acid is a powerful healing nutrient

Butyric acid can also help support your immune function and keep your gut barrier healthy. It's known to have anti-inflammatory and anti-carcinogenic properties and to play a role in gut barrier function, immune system regulation, and metabolic regulation. (Source) That's why the compound has gained attention for its potential role in treating inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), and colorectal cancer. On the flip side, decreased butyrate concentrations and numbers of butyrate-producing bacteria have been linked with disorders, ranging from dysbiosis to strokes and even metabolic conditions. (Source, Source, Source, Source)

It may explain the tremendous health benefits of high-fiber diets 

A diet high in fiber has long been considered a cornerstone of gut health, and now science is backing that up. Fiber promotes healthy intestinal flora and helps maintain healthy gut barrier function. It can also help reduce inflammation and insulin resistance, and may help reduce your risk of developing certain diseases, such as diabetes and heart disease. 

As dietary fiber is fermented by bacteria in the gut, butyric acid is formed. Research suggests butyric acid in the gut helps kill colon cancer cells, making a high-fiber diet an important cancer prevention tool. (Source) Beyond that, butyrate can affect our brains by acting via the gut&#;brain axis. Through its ability to cross the blood&#;brain barrier, butyrate can activate the vagus nerve and hypothalamus, indirectly affecting appetite. (Source)

What Does the Research Show About Butyric Acid?

Butyric acid has powerful effects on the immune system 

Thanks to its anti-inflammatory properties, butyrate can help control inflammation and modulate the immune response. In addition, butyric acid helps regulate the production and development of regulatory T cells in the colon, which are responsible for helping your body distinguish between itself and foreign invaders. Without the ability to tell self from nonself, the immune system may begin to attack your own tissues and organs, resulting in an autoimmune condition. (Source)

Butyric acid helps promote gut barrier integrity 

Related to immune function, butyrate also helps maintain healthy gut barrier function and prevent the incidence of leaky gut. (Source) Emerging evidence suggests there may be a link between butyrate and autoimmunity in humans as well. For example, people with type 1 diabetes &#; an autoimmune condition that affects the ability of the pancreas to produce insulin &#; have been found to have lower levels of butyrate-producing bacteria in their gut than those without diabetes. (Source)

Butyric acid may improve your brain function 

Studies have revealed that butyric acid has a profound effect on the brain, ranging from memory and cognition issues to neurodegenerative diseases. In rat studies, butyrate stimulated the release of brain-derived neurotrophic factor (BDNF), a molecule that supports the growth and differentiation of healthy neurons in the brain. (Source) And in studies looking at animal models of Huntington&#;s disease and Parkinson&#;s disease, butyric acid has been shown to protect brain neurons from cell death and to extend the lifespan of mice with Huntington&#;s. (Source, Source)

Butyric acid may help treat IBD

Numerous studies have reported that butyrate metabolism is impaired in patients with IBD. (Source) Butyric acid has been shown to decrease colitis-associated intestinal inflammation and colon cancer in both animal and human models. In a small study looking at the effects of butyrate on Crohn&#;s disease, 69% of patients saw clinical improvements after treatment, with 53% of participants achieving remission. (Source)

Butyric acid is a promising therapy for IBS

Emerging evidence suggests that butyric acid may be a potential treatment option for IBS as well. (Source)

In one double-blind, randomized, placebo-controlled study, 66 adult patients with IBS took either a placebo or 300 milligrams of sodium butyrate (the sodium salt of butyric acid) per day, in addition to receiving standard therapy. Just four weeks into the 3-month study, researchers found that subjects who took the butyric acid had a statistically significant decrease in the frequency of abdominal pain during bowel movements. (Source)

Butyric acid may improve insulin sensitivity

One of the more controversial potential applications of butyric acid is its ability to impact insulin sensitivity and obesity. In many studies, butyrate has been shown to significantly improve insulin sensitivity and reduce insulin resistance in people with metabolic syndrome. (Source) Researchers believe that this may be a result of the compound's ability to increase GLP-1 (glucagon-like peptide-1) and PYY (peptide YY), hormones that help your body to control food intake and increase fat burning (Source, Source, Source). 

However, although a large body of evidence has suggested that butyrate may attenuate obesity and insulin resistance, a few studies have shown the opposite effect. Therefore, more research is needed to understand the effects of butyrate on obesity.

How Does Butyrate Work?

Studies have shown that butyrate has multiple modes of action:

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Butyrate is a &#;histone deacetylase inhibitor&#;

Butyrate is known to increase the expression of genes that promote the growth of gut cells and suppress genes that cause inflammation. It appears to do this by inhibiting histone deacetylase (HDAC), an enzyme that regulates gene expression. This protects the DNA wrapped around proteins called histones, which has led researchers to believe that butyrate has anti-inflammatory and anticancer effects in the gut. In other words, it prevents genes from getting damaged, rather helping them to survive and adapt. (Source)

Butyrate is capable of increasing mitochondrial activity

As mentioned, butyric acid plays a key role in metabolism and mitochondrial activity. Not only does it serve as the primary source of fuel for colon cells, studies have also shown its ability to support energy homeostasis and promote mitochondrial activity in animal models. (Source) Researchers have also postulated that reduced glucose availability in the brain may contribute to mitochondrial dysfunction in acute and chronic neurological diseases, which could theoretically be supported via butyrate because of its effects on energy metabolism. (Source)

Butyrate promotes microbiome homeostasis

Research has shown that butyrate is a key regulator of microbiome health and helps to strengthen the gut barrier. As a major energy source for the cells that line the colon, butyrate is preferentially absorbed to repair damaged cells and support the growth of new ones. In effect, it also keeps harmful bacteria and endotoxins from passing through the intestinal wall into the bloodstream, which can help reduce inflammation and the risk for chronic disease. (Source)

Butyrate targets key receptors on cell membranes 

G-protein-coupled receptors (GPCRs) are members of a large protein family that are activated by a variety of neurotransmitters, hormones, and drugs. GPCRs are involved in many important physiological functions, such as the regulation of cell growth and proliferation, hormone secretion, and neurotransmitter release. 

They are a common target in medications, but interestingly butyrate has been found to signal through a GPCR receptor called GPR109a. Scientists believe that butyrate's triggering of GPR109a may be responsible for the compound&#;s anti-inflammatory and anti-carcinogenic effects. (Source)

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What Should I Do About Butyric Acid?

Incorporate butyrate-rich dietary sources 

Some of the food sources with the most naturally-occurring butyric acid include butter, ghee, parmesan cheese, and raw milk. (Source) Butter contains 3% to 4% butyric acid, making it the richest dietary source of butyrate. (Source) Some types of kombucha can also contain butyric acid as well. However, even the richest food sources contain relatively little of this fatty acid compared to the amount that can be created in the large intestine, so your best bet is to feed fiber to the microbes that generate butyrate in your gut.

Try fructo-oligosaccharides

Fructo-oligosaccharides (FOS) are a type of prebiotic, substances that promote the growth of beneficial bacteria in the colon, such as butyric acid. Other prebiotic superstars to consider incorporating into your diet include garlic, bananas, onions, leeks, and asparagus. One study in rats showed a high-FOS diet increased levels of butyrate in the large intestine while maintaining the levels of anaerobic bacteria. (Source)

Increase your resistant starch intake 

Resistant starches are gut-friendly carbohydrates that feed the beneficial bacteria in your gut and help them thrive. As a bonus, they also increase butyrate production in the large intestine as they are fermented by other bacteria in the gut. The best way to get more butyrate is to eat prebiotic foods that are rich in resistant starch, such as artichokes, plantains, and cooked potatoes. (Source)

Supplement with butyrate 

Although diet is typically the best way to increase butyrate production in the gut, if resistant starch isn't a staple in your diet you can also supplement with butyrate directly. It&#;s commonly found in fiber supplements and often sold as sodium butyrate. However, you may want to hold off if you&#;re pregnant or breastfeeding &#; one animal study found that giving pregnant and breastfeeding rats sodium butyrate led to insulin resistance and increased fat storage in their offspring. (Source)

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