Butyrate: A Double-Edged Sword for Health?

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.

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 ∼10¹⁰–10¹¹ CFUs/g wet weight or 10¹³ 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).

FIGURE 1.

Butyrate biosynthesis and absorption in the large intestine and subsequent metabolism. Two pathways of endogenous butyrate production from butyryl-CoA in bacteria have been reported. The letter “A” indicates that butyryl-CoA is phosphorylated to butyryl-phosphate and converted to butyrate via butyrate kinase. The letter “B” shows that the CoA moiety of butyryl-CoA is transferred to external acetate via butyryl-CoA:acetate CoA transferase, leading to the formation of butyrate and acetyl-CoA. Several receptors for butyrate have been identified, including GPR41, GPR43, and GPR109A. GPR41 is found in adipose tissues and immune cells. The highest expression of GPR43 has been found in immune cells, whereas GPR109A is essential for butyrate-mediated induction of IL-18 in colonic epithelium. A small portion of butyrate is transported to the liver and metabolized to produce ATP. GPR, orphan G protein–coupled receptor.

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 2003, 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.

Ligand preference, expression pattern, and functions of 3 major receptors for SCFAs¹

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., 2014 (36); Nøhr et al., 2013 (42); Trompette et al., 2014 (38); Kimura et al., 2011 (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., 2013 (40); Voltolini et al., 2012 (41); Nøhr et al., 2013 (42); Smith et al., 2013 (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., 2012 (44); Macia et al., 2015 (45); Singh et al., 2014 (46); Bermudez et al., 2011 (47)

¹FFAR, free fatty acid receptor; GLP-1, glucagon-like peptide 1; GPCR, G protein–coupled receptor; GPR, orphan G protein–coupled receptor; HCA2, hydroxycarboxylic acid 2; PYY, peptide YY; Treg, regulatory T cell.

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.

Paradoxical effect of butyrate on obesity¹

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., 2016 (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., 2013 (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., 2017 (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., 2014 (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., 2015 (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., 2017 (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., 2016 (89)

¹GH, growth hormone; GHRH, growth hormone–releasing hormone; GLP-1, glucagon-like peptide 1; GPR, orphan G protein–coupled receptor; Lep^ob/^ob, leptin-deficient; Lox/Lox, lipoxygenase/lipoxygenase; PYY, peptide YY; TLR, Toll-like receptor; wt, wild-type.

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).

FIGURE 2.

Schematic overview of the mechanisms by which butyrate affects glucose and lipid metabolism. MCTs are involved in butyrate transport in colonic luminal membrane. For glucose metabolism, butyrate increases PYY and GLP-1 expression in the colon via GPR41 and GPR43. GLP-1 increases insulin and decreases glucagon production in the pancreas, and PYY increases glucose uptake in the muscle and adipose tissue. Meanwhile, butyrate decreases hepatic gluconeogenesis. For lipid metabolism, butyrate increases FA oxidation in the muscle and decreases lipolysis via the GPR43 pathway in white adipose tissue. In addition, butyrate is converted to FAs, cholesterol, and ketone bodies in the liver. GLP-1, glucagon-like peptide 1; GPR, orphan G protein–coupled receptor; MCT, monocarboxylate transporter; PYY, peptide YY.

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.

Supported by the National Key R&D Program of China (2017YFD0500501), the National Basic Research Program of China (973 Program, 2013CB117301), the National Natural Science Foundation of China (31722054, 31472101, and 31528018), the 111 Project (B16044), and the National Department Public Benefit Research Foundation (201403047).

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