(PDF) The Role of Short-Chain Fatty Acids in Health and Disease

Evidence is accumulating that short chain fatty acids (SCFA) play an important role in the maintenance of gut and metabolic health. The SCFA acetate, propionate and butyrate are produced from the microbial fermentation of indigestible carbohydrates and appear to be key mediators of the beneficial effects elicited by the gut microbiome. Microbial SCFA production is essential for gut integrity by regulating the luminal pH, mucus production, providing fuel for epithelial cells and effects on mucosal immune function. SCFA also directly modulate host metabolic health through a range of tissue-specific mechanisms related to appetite regulation, energy expenditure, glucose homeostasis and immunomodulation. Therefore, an increased microbial SCFA production can be considered as a health benefit, but data are mainly based on animal studies, whereas well-controlled human studies are limited. In this review an expert group by ILSI Europe’s Prebiotics Task Force discussed the current scientific ...

Portal appearance of short-chain fatty acids (SCFA) produced from fermentation of three different resistant starch (RS) sources (raw potato starch, high-amylose maize starch and retrograded high-amylose maize starch) was investigated in pigs. The catheterization technique coupled with determination of portal blood flow was used to estimate SCFA uptake by the colonic mucosa. Our hypothesis was that these three RS were not equivalent butyrate providers for the colonic mucosa and that butyrate uptake would therefore be different after in vivo fermentation of each starch. The starches induced different patterns of appearance of SCFA in the portal blood; raw potato starch was the only RS source to show a significant appearance of butyrate in the portal blood. Thus, uptake of butyrate by the colonic mucosa apparently differed between starches. This finding suggests that butyrate uptake does not only depend on the flow of butyrate appearing in the lumen. Indeed, for unexplained reasons, ut...

CHAPTER THREE The Role of Short-Chain Fatty Acids in Health and Disease Jian Tan, Craig McKenzie, Maria Potamitis, Alison N. Thorburn, Charles R. Mackay1, Laurence Macia1 Department of Immunology, Monash University, Clayton, Victoria, Australia 1 Corresponding authors: e-mail address: charles.mackay@monash.edu; laurence.macia@monash.edu Contents 1. Introduction 1.1 The production of SCFAs 1.2 Transport of SCFAs 2. SCFA Sensing and Signal Transduction 2.1 HDAC inhibitors 2.2 G-protein-coupled receptors 3. Varied Functions of SCFAs 3.1 Anti-inflammatory and antitumorigenic roles 3.2 SCFAs and antimicrobial activities 3.3 SCFAs and gut integrity 4. Integrative View of the Gut Microbiota, SCFAs, and Disease 5. Perspective References 92 92 96 97 97 99 103 103 106 107 109 112 112 Abstract There is now an abundance of evidence to show that short-chain fatty acids (SCFAs) play an important role in the maintenance of health and the development of disease. SCFAs are a subset of fatty acids that are produced by the gut microbiota during the fermentation of partially and nondigestible polysaccharides. The highest levels of SCFAs are found in the proximal colon, where they are used locally by enterocytes or transported across the gut epithelium into the bloodstream. Two major SCFA signaling mechanisms have been identified, inhibition of histone deacetylases (HDACs) and activation of G-protein-coupled receptors (GPCRs). Since HDACs regulate gene expression, inhibition of HDACs has a vast array of downstream consequences. Our understanding of SCFAmediated inhibition of HDACs is still in its infancy. GPCRs, particularly GPR43, GPR41, and GPR109A, have been identified as receptors for SCFAs. Studies have implicated a major role for these GPCRs in the regulation of metabolism, inflammation, and disease. SCFAs have been shown to alter chemotaxis and phagocytosis; induce reactive oxygen species (ROS); change cell proliferation and function; have anti-inflammatory, antitumorigenic, and antimicrobial effects; and alter gut integrity. These findings highlight the role of Advances in Immunology, Volume 121 ISSN 0065-2776 http://dx.doi.org/10.1016/B978-0-12-800100-4.00003-9 # 2014 Elsevier Inc. All rights reserved. 91 92 Jian Tan et al. SCFAs as a major player in maintenance of gut and immune homeostasis. Given the vast effects of SCFAs, and that their levels are regulated by diet, they provide a new basis to explain the increased prevalence of inflammatory disease in Westernized countries, as highlighted in this chapter. 1. INTRODUCTION There is increasing evidence implicating the gut microbiota as critical contributors to host health and gut/immune homeostasis. This may be achieved, at least in part, through the release of short-chain fatty acids (SCFAs), which are the main bacterial metabolites produced following the fermentation of dietary fiber and resistant starches by specific colonic anaerobic bacteria. SCFAs are a subset of saturated fatty acids containing six or less carbon molecules that include acetate, propionate, butyrate, pentanoic (valeric) acid, and hexanoic (caproic) acid. Recent advances in the study of SCFAs, especially acetate, propionate, and butyrate, have highlighted their effects on various systems both at cellular and molecular levels. Indeed SCFAs or their deficiency may affect the pathogenesis of a diverse range of diseases, from allergies and asthma to cancers, autoimmune diseases, metabolic diseases, and neurological diseases. 1.1. The production of SCFAs SCFAs are carboxylic acids defined by the presence of an aliphatic tail of two to six carbons. Although SCFAs can be produced naturally through host metabolic pathways particularly in the liver, the major site of production is the colon which requires the presence of specific colonic bacteria explaining their absence in germ-free mice (Hoverstad & Midtvedt, 1986). Acetate (C2), propionate (C3), and butyrate (C4), being the major SCFA released through fermentation of fiber and resistant starches, are mostly released in the proximal colon in very high concentrations (70–140 mM) while their concentrations are lower in the distal colon (20–70 mM) and in the distal ileum (20–40 mM) (Wong, de Souza, Kendall, Emam, & Jenkins, 2006). The molar ratio of acetate, propionate, and butyrate production in the colon is 60:25:15, respectively (Tazoe et al., 2008), although proportions can vary depending on factors such as diet, microbiota composition, site of fermentation, and host genotype (Hamer et al., 2008). Butyrate is mostly utilized by colonocytes while acetate and propionate reach the liver through the portal vein. Propionate is subsequently metabolized by hepatocytes while acetate either remains in the liver or is released systemically The Role of Short-Chain Fatty Acids in Health and Disease 93 to the peripheral venous system (Pomare, Branch, & Cummings, 1985). Thus, only acetate is usually detectable in peripheral blood. Extensive research has highlighted the beneficial effects of SCFAs on health, detailed below in this chapter. Health authorities have thus established a recommended daily intake of fiber, which according to the World Health Organization is 20 g per 1000 kcal consumed (in adults) and this quantity is reached through the daily consumption of grains as well as 400 g per day of fresh fruits and vegetables (www.who.int). Notably, the typical consumption of fiber in most Western countries is much less than this (King, Mainous, & Lambourne, 2012) and consumption of fiber is inversely related to premature death from all causes of disease (Park, Subar, Hollenbeck, & Schatzkin, 2011) 1.1.1 Substrates for SCFA production Indigestible saccharides are the major substrates leading to SCFA production. Polysaccharides are subdivided into three categories: starch, starch-like, and nonstarch polysaccharides (NSPs). Starch, such as amylose, and starchlike polysaccharides, such as glycogen, consist of polymers of glucose linked by alpha 1–4 and alpha 1–6 glycosidic bonds. These bonds are broken down by salivary, pancreatic, and intestinal brush barrier enzymes and are thus digestible by mammals. Under healthy conditions, starch and starch-like polysaccharides are fully digested in the small intestine yielding glucose. Polysaccharides that are undigested or partially digested in the small intestine are able to undergo a process of fermentation by specific colonic anaerobic bacteria leading to the release of SCFAs in addition to gases and heat. These polysaccharides are called fermentable polysaccharides and are subclassified as NSPs, or dietary fibers, and resistant starch (RS). Depending on their degree of solubility, fibers are subclassified into insoluble or soluble fibers and in both cases are found in plant cell walls. Cellulose and lignin are examples of insoluble fibers while pectin substances or gums forming a gel in water are classified as soluble fibers. Insoluble fibers are highly fermentable and hence generate greater quantities of SCFA in the colon while soluble fibers have a rather low fermentability but increase fecal bulking and decrease colonic transit time. RS can be subdivided into four types: physically trapped starch (in coarse grains), RS granules naturally rich in amylose (i.e., raw potato flour), retrograded starch (i.e., cooked and cooled potato), and chemically modified starch (i.e., processed foods) (Englyst, Kingman, & Cummings, 1992). RS is considered as the most powerful butyrogenic substrate where fermentation of RS in vitro as well as in vivo generally results in a significant higher level of butyrate production compared to NSP 94 Jian Tan et al. (Englyst et al., 1992). Oligosaccharides, defined by a short chain of monosaccharide units, such as galactooligosaccharides, fructooligosaccharides, mannanoligosaccharides, and chitooligosaccharides are also substrates for SCFAs (Pan, Chen, Wu, Tang, & Zhao, 2009). Finally, to a lesser extent, some SCFAs such as isobutyrate and isovalerate are produced during the catabolism of branched chain amino acids valine, leucine, and isoleucine and intermediate of fermentation in the microbiota such as lactate or ethanol can also be metabolized into SCFA (Macfarlane & Macfarlane, 2003). 1.1.2 Mechanism of SCFA production The process involved in the production of SCFAs from fiber involves complex enzymatic pathways that are active in an extensive number of bacterial species. The most general pathway of SCFA production in bacteria is via the glycolytic pathway, although certain groups of bacteria such as the Bifidobacteria can utilize the pentose phosphate pathway to produce the same metabolites (Cronin, Ventura, Fitzgerald, & van Sinderen, 2011; Macfarlane & Macfarlane, 2003). Other pathways utilizing a variety of substrates are also able to produce SCFAs. Radioisotope analysis by Miller and Wolin (1996) demonstrated that a major pathway of acetate production by bacteria was via the oxygen-sensitive Wood–Ljungdahl pathway and is regarded as the most efficient pathway of acetate production (Fast & Papoutsakis, 2012). Using similar methods they show that propionate was generally generated by a carbon dioxide fixation pathway while butyrate was most commonly formed by conventional acetyl-S coenzyme A condensation (Miller & Wolin, 1996). Other pathways, such as the Bifidobacterium pathway (fructose-6-phosphate phosphoketolase pathway) found in the Bifidobacterium genus are able to utilize monosaccharides in a unique manner to ultimately generate SCFAs (Pokusaeva, Fitzgerald, & van Sinderen, 2011). These results suggest that different species possessing specific enzymes are involved in the production of the various SCFAs. Indeed, the Wood–Ljungdahl pathway is typically found in acetate-producing bacteria (known as acetogens) where the majority are of the Firmicutes phylum (Ragsdale & Pierce, 2008). On the other hand, the major groups involved in the production of butyrate are of the Cytophaga and Flavobacterium group belonging to the Bacteroidetes phylum (Guilloteau et al., 2010). Specific species of bacteria characterized by their high levels of butyrate production include Clostridium leptum, Roseburia species, Faecalibacterium prausnitzii, and Coprococcus species belonging to both the Firmicutes and Bacteroidetes phyla (Guilloteau et al., 2010). The Role of Short-Chain Fatty Acids in Health and Disease 95 The production of SCFAs is a highly complex and dynamic process. For example, butyrate and propionate may be degraded into the smaller two carbon chain acetate by sulfate- or nitrate-reducing acetogenic bacteria such as Acetobacterium, Acetogenium, Eubacterium, and Clostridium species (Westermann, Ahring, & Mah, 1989). However, increased proportion of butyrateproducing or -consuming species such as F. prausnitzii and Roseburia species can reverse this process (Duncan et al., 2004). Such interactions can involve the mutualistic production of SCFAs as demonstrated by the cocolonization of Bacteroides thetaiotaomicron and Eubacterium rectale where acetate produced by B. thetaiotaomicron acted as a substrate for butyrate generation by E. rectale (Mahowald et al., 2009). In addition to enzymatic requirements, expression of protein transporters is also imperative for SCFA production. For example, the presence of ATPbinding cassette (ABC) transporters in Bifidobacterium longum is crucial for the uptake and transport of substrates, such as fructose, required for acetate production (Davidson & Chen, 2004; Fukuda et al., 2011). Another transporter, the PEP translocation group or the phosphotransferase system (PTS) is able to transport carbohydrates which can be subsequently metabolized to produce SCFAs (Postma, Lengeler, & Jacobson, 1993; Zoetendal et al., 2012). Genomic analysis revealed that Bacteroidetes possesses more polysaccharide-degrading enzymes but less ABC transporters and fewer PTS than the Firmicutes (Mahowald et al., 2009) suggesting that despite having the machinery to produce SCFAs they might not efficiently uptake the substrate necessary for their production. However, Firmicutes may be excellent scavenger of acetate through their ABC transporters and can uptake acetate to produce butyrate and propionate as fermentative by-products. It has therefore been hypothesized that the two predominant phyla could exist in a balance whereby acetate from Bacteroidetes is used to produce butyrate and propionate by Firmicutes (Mahowald et al., 2009). Therefore, the complex and delicate interaction within the microbiota may also control the proportion and levels of SCFAs in the gut lumen. Accordingly, prebiotics (agents favoring the growth of beneficial bacteria) or probiotic (introduction of beneficial bacteria) agents altering such balance may modulate the production of SCFAs. 1.1.3 Manipulation of SCFA production via modulation of microbiota Dietary changes can alter the composition of the gut microbiota in as little as a day (Wanders, Graff, & Judd, 2012) and even minute alteration of dietary factors such as fiber content could shape microbial communities (Donohoe 96 Jian Tan et al. et al., 2011). The biggest issue presented by a Western diet typically high in fat and digestible saccharides is that nutrients are mostly absorbed in the duodenum leaving very few substrates for the colonic bacteria. Consequently, this results in dysbiosis, the impairment of microbiota composition and increased susceptibility to inflammatory diseases such as inflammatory bowel diseases (IBDs) or colon cancer. On the other hand, in rural areas where the diet is closer to the Paleolithic diet comprising of fruit and vegetables enriched in fibers and RS, the prevalence of these inflammatory diseases is low while SCFA and presence of SCFA-producing bacteria are significantly more elevated (De Filippo et al., 2010). These data aligns with a “diet hypothesis” which suggests that adequate intake of fiber promotes a healthy microbiota that significantly reduces the prevalence of inflammatory diseases, notably through the release of SCFA (Macia et al., 2012; Maslowski & Mackay, 2011). Despite intense public health efforts to promote the beneficial effects of a healthy diet in Western countries, the incidence of obesity and inflammatory diseases are still increasing suggesting that other approaches must be explored. One alternative could be to provide food supplements such as the prebiotic inulin-type fructans, which have been shown to promote Bifidobacteria at the expense of Roseburia species and of Clostridium cluster XIVa in mice (Dewulf et al., 2011). The other alternative would be to directly introduce a cocktail of beneficial bacteria including the SCFA producer Bifidobacteria into solution, such as yogurt, similar to how some currently available probiotics products are consumed. One study has shown that gavage of mice with B. longum increased the production of acetate (Xiong et al., 2004) and reduced their susceptibility to infection. Another study showed that mice inoculated with VSL#3 (commercial formula containing eight naturally occurring probiotic strains of bacteria) showed protection against acute DSS-induced colitis (Mennigen et al., 2009). This suggests that even if all the mechanisms behind the use of probiotics are not fully understood, such as their rate of survival or site of action, they remain to be a very promising therapeutic strategy. 1.2. Transport of SCFAs As discussed, while the majority of SCFAs are generated and utilized within the vicinity of the gut, a small proportion of propionate and acetate reaches the liver where they can be used as substrates for the energy-producing tricarboxylic acid cycle and efficiently metabolized to produce glucose. A small percent of SCFAs in the gut exists as unionized forms and can directly cross The Role of Short-Chain Fatty Acids in Health and Disease 97 the epithelial barrier. However, most exists in an ionized state and requires specialized transporters for their uptake. Therefore, the passage of the majority of SCFAs across the mucosa involves active transport mediated by two main receptors: the monocarboxylate transporter 1 (MCT-1) and the sodium-coupled monocarboxylate transporter 1 (SMCT-1) receptors. Both MCT-1 and SMCT-1 are highly expressed on colonocytes and also along the entire gastrointestinal tract including the small intestine and the cecum (Iwanaga, Takebe, Kato, Karaki, & Kuwahara, 2006). Additionally, MCT-1 is also highly expressed on lymphocytes suggesting the importance of intracellular SCFA uptake by these cells (Halestrap & Wilson, 2012). Additionally, SMCT-1 is expressed on the kidney and thyroid gland. SMCT-1 binds SCFAs in order of affinity butyrate > propionate > acetate (Ganapathy, Gopal, Miyauchi, & Prasad, 2005). Unabsorbed SCFAs are excreted. 2. SCFA SENSING AND SIGNAL TRANSDUCTION The ability of SCFAs to modulate biological responses of the host depends on two major mechanisms. The first involves the direct inhibition of histone deacetylases HDACs to directly regulate gene expression. Intrinsic HDAC inhibitor (HDACi) activity is particularly characteristic of the SCFAs butyrate and propionate. The second mechanism for SCFA effects is signaling through G-protein-coupled receptors (GPCRs). The major GPCRs activated by SCFAs are GPR41, GPR43, and GPR109A. 2.1. HDAC inhibitors Acetylation of lysine residues within histones induces gene activation by facilitating the access of transcription factors to promoter regions (MacDonald & Howe, 2009). HDACs remove acetyl groups from histones (Kim & Bae, 2011); as such, inhibition of HDAC activity or expression can increase gene transcription by increasing histone acetylation. SCFAs inhibit HDAC activity, and may therefore alter gene expression in a wide variety of cells. Of all the SCFAs, butyrate is considered to be the most potent inhibitor of HDAC activity. Indeed, butyrate exhibits a stronger HDAC inhibitory activity than propionate as demonstrated in both HeLa (Boffa, Vidali, Mann, & Allfrey, 1978) and colon cancer cell lines whereas acetate appeared to have very little or no or effect (Hinnebusch, Meng, Wu, Archer, & Hodin, 2002; Kiefer, BeyerSehlmeyer, & Pool-Zobel, 2006; Waldecker, Kautenburger, Daumann, Busch, & Schrenk, 2008). However, this lack of effect on HDACs by acetate may be tissue dependent, since others have shown that acetate can inhibit 98 Jian Tan et al. HDACs. In one study, treatment of hepatoma tissue (Sealy & Chalkley, 1978) with acetate, propionate, or butyrate leads to a global increase in histone acetylation. In the same vein, orally administered acetate has been shown to inhibit both HDAC2 activity and protein expression in the rodent brain (Soliman & Rosenberger, 2011). Thus, HDAC inhibition by SCFAs depends not only on the type of SCFA but also on which tissue or cell type they are acting. 2.1.1 Mechanism behind SCFA-mediated HDAC inhibition While the exact mechanism behind SCFA inhibition of HDACs is not known, SCFAs might either act directly on HDACs by entering into the cells via transporters or indirectly through the activation of GPCRs (see below). Transporters such as SMCT-1 could be good candidates. Indeed, expression of SMCT-1 was required for butyrate- and propionate-induced blockade of murine dendritic cell development, which correlated with a global increase in HDAC inhibition and DNA acetylation (Singh et al., 2010). Thus, the transport of SCFAs into cells via SMCT-1 may account for the observed global inhibition of HDACs by propionate and butyrate and the subsequent blockade of enzymatic activity. Direct inhibitory activity of SCFAs on HDACs has been highlighted by the fact that while one butyrate molecule is a noncompetitive inhibitor that does not interfere with the binding of HDACs to their substrates, two molecules of butyrate may competitively occupy the hydrophobic cleft of the active site of HDACs (Cousens, Gallwitz, & Alberts, 1979). This is similar to the action of the well-characterized HDACi trichostatin A (TSA) (Davie, 2003). Apart from a direct effect of SCFAs on HDACs, another interesting hypothesis is that they may have an indirect effect through GPCRs. Indeed, activation of GPR41 in Chinese hamster ovary cell lines suppressed histone acetylation possibly through the inhibition of HDACs (Wu, Zhou, Hu, & Dong, 2012). Thus, GPR41 but also GPR43 or GPR109 might contribute to HDAC inhibition mediated by SCFAs. Whether the SCFAs directly or indirectly block HDAC activation remains elusive and extensive research will be necessary to clarify these points. 2.1.2 Immunological relevance of SCFA-mediated HDAC inhibition When SCFA-mediated HDAC inhibition can be established or associated, the overwhelming result is an anti-inflammatory immune phenotype (Table 3.1). Indeed, treatment of human macrophages with 1 mM of acetate in vitro significantly reduced their global HDAC activity and increased global histone acetylation correlating with decreased production of inflammatory cytokines IL-6, The Role of Short-Chain Fatty Acids in Health and Disease 99 IL-8, and TNFa (Kendrick et al., 2010). Similarly, butyrate and propionate decreased LPS-induced TNFa production in vitro from human peripheral blood mononuclear cells (PMBCs) in a similar manner to TSA (Usami et al., 2008). These results suggest an active control of the release of proinflammatory cytokines by SCFAs through HDAC inhibition in both rodents and humans. Activation of NF-kB is one of the major pathways involved in the release of inflammatory cytokines (Hayden, West, & Ghosh, 2006). Butyrate and propionate were shown to reduce NF-kB activity in PBMCs in a similar manner to TSA (Usami et al., 2008) suggesting that the anti-inflammatory effect of SCFAs might be mediated through the modulation of NF-kB via HDAC inhibition. However, a direct effect of these SCFAs on histone acetylation in PMBCs has not been shown. Finally, global inhibition of HDAC activity was also observed in rodent neutrophils after addition of acetate, propionate, or butyrate in vitro with increasing strength, respectively (Vinolo et al., 2011). In monocytes, butyrate and propionate, but not acetate, decreased LPS-induced TNFa expression and NOS expression in rodent neutrophils (Vinolo et al., 2011). This suggests that acetate might not mediate its anti-inflammatory effects through HDAC inhibition but rather through GPCR activation, as we have reported (Maslowski et al., 2009). Finally, HDAC inhibition by SCFAs is not restricted to cells of the innate immune system. Lymphocytes, in particular regulatory T cells (Tregs), may also be affected by HDAC inhibition. Indeed, HDAC inhibition, particularly HDAC9, increased expression of the forkhead box P3 (Foxp3) transcription factor in mice, which subsequently increased proliferative and functional capabilities of Tregs (Lucas et al., 2009; Tao et al., 2007). In vitro, addition of butyrate on human Treg was shown to moderately diminish their proliferation while increased their inhibitory capacities on T cell proliferation through a CTLA-4-mediated mechanism (Akimova et al., 2010). Furthermore, effector CD4þ T cells could be anergized via the HDACi activities of butyrate, which occurred independently of Treg (Fontenelle & Gilbert, 2012). Although global HDAC activity is often associated with SCFA-mediated immunomodulation, specific HDAC inhibition or expression is rarely investigated and provides an avenue for further research. 2.2. G-protein-coupled receptors 2.2.1 GPR43 GPR43, also known as free fatty acid receptor 2 (FFA2/FFAR2), is the primary receptor for the SCFA acetate. GPR43 recognizes an extensive range of SCFAs including propionate, butyrate, caproate, and valerate and while propionate was reported to be the most potent activator of GPR43, acetate is the Table 3.1 HDAC specific immunomodulation of the immune system HDAC No. Immunological function HDAC1 • • • HDAC2 • • Reduces TNF-induced NF-kB-dependent reporter gene expression via direct interaction with corepressor p65 and p50 Repression of IL-12 expression Increases expression of NF-kB-independent genes References Ashburner, Westerheide, and Baldwin (2001), Zhong, May, Jimi, and Ghosh (2002), Viatour et al. (2003), and Lu et al. (2005) Ashburner et al. (2001) and Kong, Reduces TNF-induced NF-kB-dependent reporter gene expression indeFang, Li, Fang, and Xu (2009) pendent of interaction with p65 Repression of major histocompatibility class II transactivator (CIITA) activity and subsequent repression of activation in macrophages HDAC3 • • • • Repression of NF-kB signaling by sequestration of NF-kB to the cytoplasm Increases expression of NF-kB-independent genes Required for inflammatory gene expression in macrophages Increased HDAC3 is associated with reduced apoptotic T lymphocytes from a reduction in p53 expression (tumor suppressor) Chen, Fischle, Verdin, and Greene (2001), Viatour et al. (2003), and Zhang, Shi, Wang, and Sriram (2011) HDAC7 • • • Transcriptionally represses macrophage genes during B cell development Enhances Foxp3 function Histone deacetylation of the Foxp3 promoter Bruna Barneda-Zahonero et al. (2013), Li et al. (2007), and Lal and Bromberg (2009) HDAC8 • Induces apoptosis of T cell lymphoma dependent on phospholipase C-g1 signaling Balasubramanian et al. (2008) HDAC9 • Inhibits proliferation and suppressive function of Tregs and is downregulated Tao et al. (2007) during TCR stimulation of Tregs HDAC9 knock-out mice have increased numbers of Tregs compared to WT. • HDAC11 • • • Villagra et al. (2009) Regulates IL-10 expression from APCs Increasing HDAC11 caused an increase in IL-10 and promoted the restoration of responsiveness in tolerant CD4þ T cells Reducing HDAC11 increased IL-10 expression in APCs and impaired antigenspecific T cell responses The Role of Short-Chain Fatty Acids in Health and Disease 101 most selective (Le Poul et al., 2003). GPR43 expression has been identified along the entire gastrointestinal tract, including cells of both the immune and nervous system. In the intestinal tract, GPR43 is highly expressed on intestinal peptide YY (PYY) and glucagon-like peptide 1 (GLP-1) (Tolhurst et al., 2012) producing endocrine L-cells of the ileum and colon (Vangaveti, Shashidhar, Jarrod, Baune, & Kennedy, 2010) as well as on colonocytes and enterocytes of the small and large intestine. Direct infusion of SCFAs in the colon of rats and rabbits induced the release of PYY, possibly through their binding on GPR43, that exerted anorexigenic effects (Roelofsen, Priebe, & Vonk, 2010) and GPR43 knock-out (Gpr43 / ) mice have decreased SCFA-induced release of GLP-1, a key hormone controlling insulin release (Tolhurst et al., 2012). While SCFAs might modulate body weight via central effects by reducing food intake through secretion of PYY and GLP-1, they can also directly act in periphery on the adipose tissue. Indeed, high fat diet has been shown to upregulate GPR43 expression in subcutaneous adipose tissue in parallel with increased fat storage in adipocytes. On the other hand, supplementation of the diet with inulin-type fructans, fermentable carbohydrates, blunted the weight gain and the overexpression of GPR43 due to high fat feeding, suggesting that SCFAs might modulate adiposity (Dewulf et al., 2011). Moreover, inhibition of GPR43 expression in the adipocyte cell line 3T3-L1 using small interfering RNA inhibited their differentiation suggesting a possible role of GPR43 in adipocyte development (Dewulf et al., 2013). While RS consumption in rats leads to activation of the hypothalamic anorexigenic pathway shown by the increased expression of proopiomelanocortin in the arcuate nucleus, GPR43 does not seem to be expressed in the arcuate nucleus or other region of the hypothalamus (Sleeth, Thompson, Ford, Zac-Varghese, & Frost, 2010). More broadly, to our knowledge, there is no report of GPR43 expression in the central or peripheral nervous system. In the immune system, GPR43 is expressed on eosinophils, basophils (Le Poul et al., 2003), neutrophils, monocytes, dendritic cells (Cox et al., 2009; Le Poul et al., 2003), and mucosal mast cells (Karaki et al., 2008) suggesting a broad role of SCFAs in immune responses. It is highly expressed in murine hemopoietic tissues such as the bone marrow and spleen suggesting the potential role for GPR43 in modulating the development or differentiation of immune cells (Maslowski et al., 2009; Senga et al., 2003). Finally, a recent study has shown the expression of GPR43 in myometrium and fetal membranes after the onset of labor and a significant upregulation of GPR43 in preterm fetal membranes with evidence of 102 Jian Tan et al. infection. This study also suggests an anti-inflammatory role of SCFAs through GPR43 that may reduce the risk of preterm labor induced by pathogens (Voltolini et al., 2012). This anti-inflammatory role of GPR43 is in accordance with our findings on the exacerbated inflammatory phenotypes of Gpr43 / mice in colitis and arthritis models (Maslowski et al., 2009). 2.2.2 GPR41 Identified at the same time as GPR43, GPR41, also known as free fatty acid receptor 3 (FFA3/FFAR3), is a receptor for acetate and propionate and to a lesser degree butyrate. Like GPR43, it also recognizes other SCFAs including caproate and valerate, but to a lesser degree. GPR41 is expressed in the colonic mucosa in PYY but not GPR43-expressing cells. GPR41 is also expressed in the colonic smooth muscle and SCFAs induce phasic contraction of these muscles in a GPR41-dependent manner with the following order of potency: propionate butyrate > acetate (Tazoe et al., 2009). SCFAs stimulate sympathetic activation through GPR41 activation by acting on the sympathetic ganglion. This effect is abolished under fasted conditions by ketone bodies (Kimura et al., 2011). Based on these results, GPR41 agonists could be used as potential antiobesity therapeutics. Moreover, the expression of GPR41 in adipose tissue and its potency to induce the release of the anorexigenic hormone leptin when activated by SCFAs confirms its beneficial effects on body weight (Xiong et al., 2004). The former findings are still controversial as Hong and colleagues did not find GPR41 expression on adipocytes and suggest that this effect on leptin release is mediated through GPR43. Langerhans cells in the pancreas also express GPR41 but its functional role in these cells is unknown. Finally, GPR41 is expressed in spleen and in PBMC but its role on immune cells remains uninvestigated. 2.2.3 GPR109A GPR109a, also known as Niacin receptor 1, is a high affinity niacin (Vitamin B3) receptor and related to its low affinity analog GPR109B, which is only expressed in humans. Although niacin is the primary ligand of GPR109A, physiological concentrations of niacin do not reach a threshold required to activate the receptor (Wanders et al., 2012). However, butyrate is a suitable candidate ligand with the ability to bind GPR109A with low affinity in millimolar concentration (Thangaraju et al., 2009). GPR109A transcript is highly expressed in adipocytes but declines with age (Thangaraju et al., 2009). To a lesser extent, GPR109A is also expressed on immune cells such as dermal dendritic cells, monocytes, macrophages, and neutrophils (Wanders et al., 2012). The Role of Short-Chain Fatty Acids in Health and Disease 103 Activation of GPR109A in adipocytes has been shown to suppress lipolysis and lowering of plasma-free fatty acid levels (Kang, Kim, & Youn, 2011). The role of GPR109A in immune responses, and gut homeostasis, is yet to be reported. A summary of the major SCFA receptors, associated ligand, and their functions is presented in Table 3.2. 3. VARIED FUNCTIONS OF SCFAs SCFAs, particularly butyrate, are key promoters of colonic heath and integrity. Butyrate is the major and preferred metabolic substrate for colonocytes providing at least 60–70% of their energy requirements necessary for their proliferation and differentiation (Suzuki et al., 2008). As such, colonocytes of germ-free mice, deficient in SCFAs, are highly energy deprived, as indicated by decreased expression of key enzymes involved in fatty acid metabolism in mitochondria (Tazoe et al., 2008). Consequently, these cells have a marked deficit of mitochondrial respiration, as shown by a decreased NADH/NADþ ratio, in ATP production as well as of oxidative phosphorylation, which can lead to autophagy. Addition of butyrate to colonocytes isolated from germ-free mice normalized this deficit (Donohoe et al., 2011). Apart from being a major energy source for colonocytes, SCFAs in the gut perform various physiological functions including dictating colonic mobility, colonic blood flow, and gastrointestinal pH, which can influence uptake and absorption of electrolytes and nutrients (Tazoe et al., 2008). These effects could be mediated through the activation of GPCRs as discussed earlier. Finally, the physiological roles of SCFAs are broader than a local effect on the gut on enterocytes and on digestive function; they indeed play major immunological roles both systemically and locally in the gut that will be further expanded in the following sections. 3.1. Anti-inflammatory and antitumorigenic roles SCFAs are well known for their anti-inflammatory functions by modulating immune cell chemotaxis, reactive oxygen species (ROS) release as well as cytokine release. Butyrate elicits anti-inflammatory effects via inhibition of IL-12 and upregulation of IL-10 production in human monocytes (Saemann et al., 2000), repressing production of proinflammatory molecules TNFa, IL-1b, nitric oxide (Ni et al., 2010), and reduction of NF-ĸB activity (Ni et al., 2010; Segain et al., 2000). The active suppression of NF-ĸB activity was shown by all three major SCFAs in order of potency being butyrate > propionate > acetate in Colo320DM cells (Tedelind, Westberg, Table 3.2 Summary of the major short-chain fatty acids-activated GPCR including its ligand, expression, and function GPCR Ligands Expression Roles Reference(s) GPR41 Adipocytes, various immune SCFA (C2–C7) cells, and enteroendocrine Formate, acetate, propionate, butyrate, L cells and pentanoate Leptin production, sympathetic activation Kimura et al. (2011) and Xiong et al. (2004) GPR43 Adipocytes, various Immune SCFA (C2–C7) cells, enteroendocrine L cells, Formate, acetate, propionate, butyrate, gut epithelium, fetal membrane and pentanoate Anorexigenic effects via secretion of PYY and GLP-1, anti-inflammatory, and antitumorigenic Cherbut et al. (1998), Maslowski et al. (2009), Tang, Chen, Jiang, Robbins, and Nie (2011), Suzuki, Yoshida, and Hara (2008), Tazoe et al. (2008), Le Poul et al. (2003), Cox et al. (2009), and Voltolini et al. (2012) Adipocytes, various immune cells, intestinal epithelial cells, upregulated in hepatocytes during inflammation, epidermis in squamous carcinoma High-density lipoprotein metabolism, cAMP reduction in adipocytes, DC trafficking, anti-inflammatory, and antitumorigenic Li, Hatch, et al. 2010, Li, Millar, Brownell, Briand, and Rader (2010), Bermudez et al. (2011), Ingersoll et al. (2012), Thangaraju et al. (2009), and Wanders et al. (2012) GPR109a SCFAs (C4–C8), particularly butyrate Nicotinate The Role of Short-Chain Fatty Acids in Health and Disease 105 Kjerrulf, & Vidal, 2007). Suppression of NF-ĸB activity and also TNFa production by SCFAs is also commonly observed in LPS-activated PMBCs such as neutrophils (Aoyama, Kotani, & Usami, 2010). This is consistent with the findings that butyrate could inhibit high mobility group box-1 (Aoyama et al., 2010), a nuclear transcription factor downstream of NF-ĸB signaling involved in eliciting inflammatory roles and promoting cellular proliferation that could promote cancer (Tang, Kang, Zeh Iii, & Lotze, 2010). Furthermore, butyrate (and also propionate) could induce apoptosis of neutrophils in nonactivated and LPS- or TNFa-activated neutrophil apoptosis by caspase-8 and caspase-9 pathways (Aoyama et al., 2010). Under inflammatory conditions, addition of acetate has been shown to inhibit human neutrophil migration toward C5a or fMLP in a GPR43dependent manner as phenylacetamide, a human GPR43 agonist mimicked these effects (Vinolo et al., 2011). In vivo, migration of neutrophils toward the peritoneum was exacerbated in Gpr43 / mice when mice were challenged with C5a or fMLP, confirming the critical role of GPR43 as regulator of cell chemotaxis. It is, however, puzzling that under noninflammatory conditions, SCFAs attract both mouse and human neutrophils through a mechanism involving GPR43 activation (Le Poul et al., 2003; Maslowski et al., 2009; Vinolo et al., 2009). This illustrates the dual effects of SCFAs on chemotaxis and the phenomenon that SCFAs might attract inflammatory cells under basal conditions requires further investigation. SCFAs can enforce the epithelial barrier by affecting the mucus layer, epithelial cell survival, as well as tight junction proteins, and will be discussed in a later section of this chapter. SCFAs might enforce this epithelial barrier by increasing the infiltration of immune cells in the lamina propria. The most common immune mechanism known to induce content leakage from the gut is through the release of neutralizing IgA; however, the increase in phagocytes in the lamina propria might also be an important unexplored mechanism. Other than suppressing neutrophil functions, butyrate (and to a degree acetate and propionate) can inhibit IL-2 production and lymphocyte proliferation in culture (Cavaglieri et al., 2003). SCFAs not only modulate cell migration but also their activity. As discussed earlier SCFAs are potent anti-inflammatory mediators, by inhibiting the release of proinflammatory cytokines from macrophages and neutrophils. Acetate was shown to promote the release of ROS when added on mouse neutrophils by activating GPR43 (Maslowski et al., 2009). ROS are efficient bactericidal factors involved in the clearance of pathogens. Thus, SCFAs might be key regulators of inflammatory diseases by tightly controlling the migration of immune cells toward inflammatory sites as well 106 Jian Tan et al. as modulating their activation state, enabling accelerated pathogen clearance through ROS activation. As discussed earlier, all these processes would decrease host injury, which would not only allow for the survival of the host but also for survival of the SCFA-producing bacteria. Butyrate has been associated with anticancer activity on a variety of human cancer cell lines. Treatment of human hepatoma cells in vitro increased expression of cell cycle inhibitory genes and appeared to reverse malignant phenotype, which has been associated with a reduction in telomerase activity via HDAC inhibition (Nakamura et al., 2001; Wakabayashi et al., 2005). Telomerase activity can maintain cancer cell proliferation, thereby providing a possible target for butyrate-induced antitumor effects. Furthermore, activation of GPR109a on human colon cancer cells by butyrate has been associated with increased apoptosis independent of HDAC inhibition and increased expression of the butyrate transporter MCT-1 (Borthakur et al., 2012; Thangaraju et al., 2009). Butyrate-induced GPR109a activation may directly inhibit colon cancer growth by inducing apoptosis or may act indirectly via increased MCT-1 expression and subsequent increase of butyrate transport into the cell. Expression of the butyrate transporter SMCT-1 on colon cancer cells is essential for its antitumorigenic function and correlates with global increases to histone acetylation (Gupta, Martin, Prasad, & Ganapathy, 2006). In addition, SMCT-1 is downregulated in human colon cancer cells, further accentuating the role of SMCT-1 in colon cancer (Miyauchi, Gopal, Fei, & Ganapathy, 2004). SMCT-1 may therefore transport butyrate into colonic cells and prevent development of a cancerous phenotype, though the involvement of HDAC inhibition remains largely unknown. Even if the mechanisms behind the beneficial role of SCFAs on cancer are not fully understood, it is widely accepted that intake of fiber lowers risk of cancer, especially colorectal cancer. The analysis of 25 studies demonstrated that cereals and whole grain intake was associated with reduced risk of colorectal cancer supporting the potential beneficial role of SCFAs in cancer (Aune et al., 2011). 3.2. SCFAs and antimicrobial activities Free fatty acids (such as medium- and short-chain fatty acids) exhibit intrinsic broad-spectrum antimicrobial activity and are used as such in the agriculture industry. For example, propionate is routinely used as an antimicrobial additive in food (Arora, Sharma, & Frost, 2011) while in vivo administration of butyrate is used to control Salmonella infections (Fernandez-Rubio et al., 2009). Several key mechanisms were attributed to the antimicrobial The Role of Short-Chain Fatty Acids in Health and Disease 107 activities of free fatty acids including disruption of osmotic and pH balance, nutrient uptake, and energy generation and their working concentrations were well below the toxicity threshold to host cells (Dewulf et al., 2011). This was shown in a study by Hong et al. (2005) demonstrating that formic acid, acetate, propionate, butyrate, and hexanoic acid exerted various biocidal (lethal) or biostatic (growth inhibitory) effects on oral microorganisms at concentrations as low as micromolar. Propionate and hexanoic acid can also exert antimicrobial activities by promoting host antimicrobial peptide expression (Alva-Murillo, Ochoa-Zarzosa, & Lopez-Meza, 2012). Similarly, host defense peptides of the innate immune system were potently induced by oral treatment of butyrate and were responsible for the clearance of Salmonella enteritidis without triggering a proinflammatory response indicated by a lack of IL-1b production (Sunkara, Jiang, & Zhang, 2012). In humans, the activity of cathelicidin, an antimicrobial agent released by polymorphonuclear leukocytes was induced by butyrate, possibly via its HDAC inhibitory activities (Kida, Shimizu, & Kuwano, 2006). A recent study has shown that the antimicrobial activities of individual SCFAs were relatively inert toward species of bacteria that produced them but were otherwise potent toward other microorganisms (Alva-Murillo et al., 2012). Therefore, the production of SCFAs themselves may play a significant role in the shaping of the gut microbial ecology; however, the precise effects of SCFAs on bacterial selection require further investigation. 3.3. SCFAs and gut integrity Gut integrity is an essential factor in maintaining mucosal homeostasis. It is ensured by an efficient separation between the gut luminal contents and the host, which is partly due to an effective epithelial barrier. Disruption of gut integrity has been attributed to various intestinal diseases such as inflammatory bowel disease, celiac diseases, irritable bowel syndrome (Voltolini et al., 2012), and colorectal cancer (Tolhurst et al., 2012). It is interesting to note that alteration of gut integrity seems to have much broader health implications than locally in the gut. Indeed, a phenomenon called “leaky gut,” characterized by increased gut permeability, is associated with diseases such as asthma or type 1 diabetes (T1D) showing that an effective physical separation of host tissues from the gut microbiota is critical for general health. A layer of mucus forms a physical barrier that separates the epithelium from the luminal environment, and this contributes to gut integrity by limiting physical access of bacteria to the epithelium, thus limiting prospects for 108 Jian Tan et al. breach and inflammation (Tolhurst et al., 2012). Mucus is comprised of secretory (MUC2, MUC5A/B, MUC6) and epithelial membrane-bound (MUC1, MUC3A/B, MUC4, MUC12, MUC13, MUC15, MUC16, and MUC17) mucin glycoproteins (Cherbut et al., 1998; Tolhurst et al., 2012). Deficiencies in mucins exacerbate various intestinal diseases such as mucositis but can be remediated via oral supplementation of butyrate, which modulates gut permeability (Ferreira et al., 2012). Consistent with this, supplementation of either butyrate or propionate could induce both MUC2 mRNA expression and MUC2 secretion in human goblet-like cell line LS174T (Burger-van Paassen et al., 2009) suggesting that SCFAs might be critical bacterial products promoting gut integrity. However, whether the mechanisms behind these effects are through HDAC inhibition or via the stimulation of GPR41, GPR43, or GPR109 has not been elucidated. Functional tight junction proteins, such as ZO-1 and occludin between epithelial cells, are also required for maintaining gut integrity by limiting gut permeability (Balda & Matter, 2008). As mentioned earlier, increased gut permeability is a common feature in diseases such as food allergy and asthma (Hijazi et al., 2004; Perrier & Corthesy, 2011), however, whether it is the cause or the consequence of these diseases remains largely unresolved. In vitro, butyrate supplementation to Caco-2 cell monolayers enhances the transepithelial resistance (TER), which is a marker of gut integrity, by accelerating the assembly of tight junction proteins ZO-1 and occludin dependent on AMPK activation without altering their expression levels (Tolhurst et al., 2012). In vivo, mice treated with B. longum, a probiotic strain of bacteria that releases large amounts of acetate, decreased the translocation of Shiga toxin from enterohemorrhagic Escherichia coli O157:H7 toward the bloodstream and thus increased survival (Xiong et al., 2004). In vitro, this study shows that while acetate per se did not affect the TER of Caco-2 cells, it did increase their survival when they were coinfected with this pathogen resulting in increased gut integrity. Finally, it has been shown in numerous studies that obesity or inflammatory bowel disease, that dysbiosis is associated with increased gut permeability. These conditions are probably associated with much lower concentrations of SCFAs in both the GI tract and the blood. Apart from acting on the epithelial layer, SCFAs might promote gut integrity by maintaining symbiosis. Indeed, by lowering the luminal pH, SCFAs can directly promote the growth of symbionts, and on the other hand inhibit growth of pathobionts (Roy, Kien, Bouthillier, & Levy, 2006). However, some opportunistic pathobionts have evolved to take advantage of the presence of SCFAs. Indeed it has been The Role of Short-Chain Fatty Acids in Health and Disease 109 shown that butyrate promotes virulence gene factor expression in pathogenic E. coli and thus, colonize the colon where levels of butyrate are the highest (Nakanishi et al., 2009). Furthermore, SCFAs (particularly butyrate) could also induce the production of flagella and regulate its motility function in enterohemorrhagic E. coli (Herold, Paton, Srimanote, & Paton, 2009; Tobe, Nakanishi, & Sugimoto, 2011). From an evolutionary point of view, it is not surprising that beneficial bacteria protect the host, notably by maintaining gut homeostasis to ensure their own survival. Our view is that vertebrates have evolved systems that allow bacterial metabolites such as SCFAs to regulate immunity and gut physiology. Expression of GPR43 on innate/inflammatory immune cells and the gut epithelium is an excellent example of this relationship. In Western countries where consumption of dietary fiber is low, boosting the levels of SCFAs appears as a promising new approach to promote gut integrity and homeostasis. SCFAs or HDAC/GPR43 agonists might find uses to treat or prevent a broad range of diseases from cancers to allergies and autoimmune diseases. 4. INTEGRATIVE VIEW OF THE GUT MICROBIOTA, SCFAs, AND DISEASE The incidence of both inflammatory and autoimmune diseases has increased dramatically in Westernized countries over the past several decades. While both genetic and environmental factors influence the induction of such diseases, the contribution of diet and the relevance of SCFAs have only been appreciated recently. The effect of SCFAs on various inflammatory and autoimmune diseases will be discussed below. IBDs such as Crohn’s disease (CD) and ulcerative colitis (UC) are characterized by inflammation of the gastrointestinal tract and colonic mucosa. The induction of IBDs is multifactorial with genetic, environmental, and microbial components. The increased incidence of IBD in developed countries over the last 20 years is too rapid to be explained by genetic changes. However, what has dramatically changed over the last 20 years is the lifestyle, particularly the introduction of Western style diets, which are generally low in fiber, and rich in fat and digestible sugars. Thus, “Western” diets could be driving this increase of IBD in Western countries (Shapira, Agmon-Levin, & Shoenfeld, 2010). As mentioned previously, changes in diet can lead to rapid changes in the composition of gut microbiota, which in turn could influence the relative 110 Jian Tan et al. amounts of the different SCFAs produced. Observations in both mice and humans support the link between diet, SCFA production via the gut microbiota, and IBDs. Indeed, metagenomic analyses of fecal bacteria have shown significant dysbiosis in patients suffering from CD or UC, where there is a lower representation of Bacteroidetes and Firmicutes, typical commensal bacterial species, especially Clostridial clusters IV (C. leptum subgroup) and XIVa (Clostridium coccoides subgroup) compared to healthy individuals (Frank et al., 2007). Whether this dysbiosis is causative or a consequence of IBD is unknown, however, targeting the microbiota through antibiotic treatments has shown promising results by decreasing bacterial infiltration to tissues. Combined treatment with probiotics and prebiotics also appears beneficial in IBD, however, the use of anti-, pro-, and prebiotics as treatments for IBD is yet to be fully established (Sartor, 2004). An emerging and promising therapeutic approach is fecal transplantation, which has been highly successful in some Clostridium difficile-infected patients (Borody, Brandt, Paramsothy, & Agrawal, 2013; Brandt, 2012), as well as some UC patients (Damman, Miller, Surawicz, & Zisman, 2012). In mouse models, the role of the microbiota in the development of DSS-induced colitis, a mouse model of ulcerative colitis, has been demonstrated. While under SPF conditions, IL-10-deficient mice developed exacerbated colitis, whereas they were protected under germ-free conditions (Sellon et al., 1998). These results suggest that IL-10-deficient mice have a colitogenic microbiota. Although it has not been shown in humans, we can speculate that patients with IBD may also house a colitogenic microbiota that if transmitted from mother to child at birth may confer susceptibility to CD (Akolkar et al., 1997). Interestingly, in parallel with the dysbiosis, two studies have shown that IBD was correlated with lower levels of SCFAs in feces by nuclear magnetic resonance spectroscopy (Marchesi et al., 2007) and by HPLC with acetate (162.0 mM/g), propionate (65.6 mM/g), and butyrate (86.9 mM/g) in the feces of IBD patients compared to healthy individuals (209.7, 93.3, and 176.0 mM/g, respectively) (Huda-Faujan et al., 2010). Given these differences, SCFAs may play an important role in the pathogenesis of IBD. However, the stage of these diseases at which SCFAs are lowered, before the first signs of inflammation, early signs, or once the diseases are clearly established, remains unknown. Sabatino et al. (2005) explored the therapeutic effect of administering butyrate orally to patients with CD. Administration of 4 g of butyrate per day for 8 weeks via an enteric-coated tablet induced clinical improvement and remission in 53% of patients where butyrate successfully The Role of Short-Chain Fatty Acids in Health and Disease 111 downregulated mucosal levels of NF-kB and IL-1b. Mouse studies have also shown that SCFAs were beneficial in colitis as mice treated with butyrate had reduced inflammation in their colonic mucosa with reduced neutrophil infiltration (Vieira et al., 2012) and treatment with acetate had similar beneficial effects (Maslowski et al., 2009). Moreover, lack of SCFA signaling through GPR43 in Gpr43 / mice exacerbated the development of colitis (Maslowski et al., 2009). Thus, normalizing levels of SCFAs as well as remediating dysbiosis may have synergistic and beneficial effects in the treatment of IBD. The beneficial anti-inflammatory effects of SCFAs extend beyond the gut. Indeed, Brown et al. (2011) completed a metagenomic analysis of the gut microbiome of T1D matched case–control subjects. 16S rRNA sequencing revealed a larger proportion of bacterial species producing butyrate in controls compared to individuals suffering from T1D. This confirms the notion that in healthy individuals, the presence of butyrate-producing bacteria might maintain gut integrity, while in T1D patients, nonbutyrate-producing bacteria impede the synthesis of mucin, which could lead to increased gut permeability. In rats, oral treatment with butyrate during the preweaning period tended to delay the development of diabetes (Li, Hatch, et al., 2010) suggesting that butyrate might play a role. In this study, only one dose of butyrate was investigated, thus alternative dosing strategies and perhaps in combination with other SCFAs such as acetate would be necessary to draw firmer conclusions about the effects of SCFAs on diabetes development. Moreover, analysis of fecal microbiota revealed that Myd88 / NOD mice, which are protected from diabetes development under SPF conditions, had an increase in Bacteroidetes species when housed under SPF conditions (Wen et al., 2008). Bacteroidetes produce large amounts of SCFAs, thus protection from T1D in these Myd88 / NOD mice under SPF conditions could be via the anti-inflammatory effects provided by SCFAs. Similarly, fecal microbiota of patients suffering from rheumatoid arthritis (RA), another autoimmune disease, revealed that RA patients had significantly less Bifidobacteria and Bacteroides species compared to patients suffering from fibromyalgia, a noninflammatory musculoskeletal disease (Vaahtovuo, Munukka, Korkeamaki, Luukkainen, & Toivanen, 2008). Thus, low levels of SCFAs might contribute or result from the development of RA; however, prospective studies that assess the production of SCFAs in RA patients as well as other inflammatory diseases would be of great interest to determine if a defect in SCFA levels contributes to disease onset. 112 Jian Tan et al. Finally, Böttcher et al. (2000) compared the production of SCFAs in allergic and nonallergic children and found that allergic infants had lower levels of propionate, acetate, and butyrate in their feces compared to nonallergic individuals. This may account for the observation that Gpr43 / mice exhibit exacerbated development of allergic airway inflammation (Maslowski et al., 2009). These results suggest that SCFAs might play a protective role in allergic disease. This would support a diet/fiber deficiency model (Maslowski et al., 2009) for the increase in inflammatory diseases in Western countries. 5. PERSPECTIVE The incidence of autoimmunity, IBD, and allergy has increased dramatically in Western and Westernized countries. This increase parallels a decrease in the consumption of fiber and indigestible starches. Carefully designed studies are now required to evaluate the effect of diet, independent of other possible contributing factors (i.e., hygiene, infection, sunlight, etc.). These studies will be critical for determining the role of diet, particularly fiber and SCFAs, in the development of Western diseases. If indeed diet and the resulting changes to the gut microbiota underlie certain Western lifestyle diseases, then there is enormous potential for prevention or correction through diet, probiotics, or new drugs targeting metabolite sensing mechanisms such as HDACs or GPCRs. REFERENCES Akimova, T., Ge, G., Golovina, T., Mikheeva, T., Wang, L., Riley, J. L., et al. (2010). Histone/protein deacetylase inhibitors increase suppressive functions of human FOXP3 þ Tregs. Clinical Immunology, 136, 348. Akolkar, P. N., Gulwani-Akolkar, B., Heresbach, D., Lin, X. Y., Fisher, S., Katz, S., et al. (1997). Differences in risk of Crohn’s disease in offspring of mothers and fathers with inflammatory bowel disease. The American Journal of Gastroenterology, 92, 2241. Alva-Murillo, N., Ochoa-Zarzosa, A., & Lopez-Meza, J. E. (2012). Short chain fatty acids (propionic and hexanoic) decrease Staphylococcus aureus internalization into bovine mammary epithelial cells and modulate antimicrobial peptide expression. Veterinary Microbiology, 155, 324. Aoyama, M., Kotani, J., & Usami, M. (2010). Butyrate and propionate induced activated or non-activated neutrophil apoptosis via HDAC inhibitor activity but without activating GPR-41/GPR-43 pathways. Nutrition, 26, 653. Arora, T., Sharma, R., & Frost, G. (2011). Propionate. Anti-obesity and satiety enhancing factor? Appetite, 56, 511. Ashburner, B. P., Westerheide, S. D., & Baldwin, A. S. (2001). The p65 (RelA) subunit of NF-kB interacts with the histone deacetylase (HDAC) corepressors HDAC1 and HDAC2 to negatively regulate gene expression. Molecular and Cellular Biology, 21, 7065. Aune, D., Chan, D. S., Lau, R., Vieira, R., Greenwood, D. C., Kampman, E., et al. (2011). Dietary fibre, whole grains, and risk of colorectal cancer: Systematic review and doseresponse meta-analysis of prospective studies. BMJ, 343, d6617. The Role of Short-Chain Fatty Acids in Health and Disease 113 Balasubramanian, S., Ramos, J., Luo, W., Sirisawad, M., Verner, E., & Buggy, J. J. (2008). A novel histone deacetylase 8 (HDAC8)-specific inhibitor PCI-34051 induces apoptosis in T-cell lymphomas. Leukemia, 22, 1026. Balda, M. S., & Matter, K. (2008). Tight junctions at a glance. Journal of Cell Science, 121, 3677. Bermudez, Y., Benavente, C. A., Meyer, R. G., Coyle, W. R., Jacobson, M. K., & Jacobson, E. L. (2011). Nicotinic acid receptor abnormalities in human skin cancer: Implications for a role in epidermal differentiation. PLoS One, 6, e20487. Boffa, L. C., Vidali, G., Mann, R. S., & Allfrey, V. G. (1978). Suppression of histone deacetylation in vivo and in vitro by sodium butyrate. Journal of Biological Chemistry, 253, 3364. Borody, T. J., Brandt, L. J., Paramsothy, S., & Agrawal, G. (2013). Fecal microbiota transplantation: A new standard treatment option for Clostridium difficile infection. Expert Review of Anti-Infective Therapy, 11, 447. Borthakur, A., Priyamvada, S., Kumar, A., Natarajan, A. A., Gill, R. K., Alrefai, W. A., et al. (2012). A novel nutrient sensing mechanism underlies substrate-induced regulation of monocarboxylate transporter-1. American Journal of Physiology: Gastrointestinal and Liver Physiology, 303, G1126. Böttcher, M. F., Nordin, E. K., Sandin, A., Midtvedt, T., & Björkstén, B. (2000). Microflora-associated characteristics in faeces from allergic and nonallergic infants. Clinical & Experimental Allergy, 30, 1591. Brandt, L. J. (2012). Fecal transplantation for the treatment of Clostridium difficile infection. Gastroenterology & Hepatology (N Y), 8, 191. Brown, C. T., Davis-Richardson, A. G., Giongo, A., Gano, K. A., Crabb, D. B., Mukherjee, N., et al. (2011). Gut microbiome metagenomics analysis suggests a functional model for the development of autoimmunity for type 1 diabetes. PLoS ONE, 6, e25792. Bruna Barneda-Zahonero, L. R.-G., Collazo, Olga, Rafati, Haleh, Abul, B. M. M. K., Islam, Lars H., Bussmann, Alessandro di Tullio, et al. (2013). HDAC7 is a repressor of myeloid genes whose downregulation is required for transdifferentiation of pre-B cells into macrophages. PLOS Genetics, 9. Burger-van Paassen, N., Vincent, A., Puiman, P. J., van der Sluis, M., Bouma, J., Boehm, G., et al. (2009). The regulation of intestinal mucin MUC2 expression by short-chain fatty acids: Implications for epithelial protection. The Biochemical Journal, 420, 211. Cavaglieri, C. R., Nishiyama, A., Fernandes, L. C., Curi, R., Miles, E. A., & Calder, P. C. (2003). Differential effects of short-chain fatty acids on proliferation and production of pro- and anti-inflammatory cytokines by cultured lymphocytes. Life Sciences, 73, 1683. Chen, L.-F., Fischle, W., Verdin, E., & Greene, W. C. (2001). Duration of nuclear NF-kB action regulated by reversible acetylation. Science, 293, 1653. Cherbut, C., Ferrier, L., Roze, C., Anini, Y., Blottiere, H., Lecannu, G., et al. (1998). Shortchain fatty acids modify colonic motility through nerves and polypeptide YY release in the rat. The American Journal of Physiology, 275, G1415. Cousens, L. S., Gallwitz, D., & Alberts, B. M. (1979). Different accessibilities in chromatin to histone acetylase. The Journal of Biological Chemistry, 254, 1716. Cox, M. A., Jackson, J., Stanton, M., Rojas-Triana, A., Bober, L., Laverty, M., et al. (2009). Short-chain fatty acids act as antiinflammatory mediators by regulating prostaglandin E(2) and cytokines. World Journal of Gastroenterology, 15, 5549. Cronin,M.,Ventura,M.,Fitzgerald,G.F.,&vanSinderen,D.(2011).Progressingenomics,metabolism and biotechnology of bifidobacteria. International Journal of Food Microbiology, 149, 4. Damman, C. J., Miller, S. I., Surawicz, C. M., & Zisman, T. L. (2012). The microbiome and inflammatory bowel disease: Is there a therapeutic role for fecal microbiota transplantation? The American Journal of Gastroenterology, 107, 1452. 114 Jian Tan et al. Davidson, A. L., & Chen, J. (2004). ATP-binding cassette transporters in bacteria. Annual Review of Biochemistry, 73, 241. Davie, J. R. (2003). Inhibition of histone deacetylase activity by butyrate. Journal of Nutrition, 133, 2485S. De Filippo, C., Cavalieri, D., Di Paola, M., Ramazzotti, M., Poullet, J. B., Massart, S., et al. (2010). Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proceedings of the National Academy of Sciences of the United States of America, 107, 14691. Dewulf, E. M., Cani, P. D., Neyrinck, A. M., Possemiers, S., Van Holle, A., Muccioli, G. G., et al. (2011). Inulin-type fructans with prebiotic properties counteract GPR43 overexpression and PPARgamma-related adipogenesis in the white adipose tissue of highfat diet-fed mice. The Journal of Nutritional Biochemistry, 22, 712. Dewulf, E. M., Ge, Q., Bindels, L. B., Sohet, F. M., Cani, P. D., Brichard, S. M., et al. (2013). Evaluation of the relationship between GPR43 and adiposity in human. Nutrition & Metabolism (London), 10, 11. Donohoe, D. R., Garge, N., Zhang, X., Sun, W., O’Connell, T. M., Bunger, M. K., et al. (2011). The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon. Cell Metabolism, 13, 517. Duncan, S. H., Holtrop, G., Lobley, G. E., Calder, A. G., Stewart, C. S., & Flint, H. J. (2004). Contribution of acetate to butyrate formation by human faecal bacteria. The British Journal of Nutrition, 91, 915. Englyst, H. N., Kingman, S. M., & Cummings, J. H. (1992). Classification and measurement of nutritionally important starch fractions. European Journal of Clinical Nutrition, 46(Suppl. 2), S33. Fast, A. G., & Papoutsakis, E. T. (2012). Stoichiometric and energetic analyses of non-photosynthetic CO2-fixation pathways to support synthetic biology strategies for production of fuels and chemicals. Current Opinion in Chemical Engineering, 1, 380. Fernandez-Rubio, C., Ordonez, C., Abad-Gonzalez, J., Garcia-Gallego, A., Honrubia, M. P., Mallo, J. J., et al. (2009). Butyric acid-based feed additives help protect broiler chickens from Salmonella Enteritidis infection. Poultry Science, 88, 943. Ferreira, T. M., Leonel, A. J., Melo, M. A., Santos, R. R., Cara, D. C., Cardoso, V. N., et al. (2012). Oral supplementation of butyrate reduces mucositis and intestinal permeability associated with 5-Fluorouracil administration. Lipids, 47, 669. Fontenelle, B., & Gilbert, K. M. (2012). n-Butyrate anergized effector CD4 þ T cells independent of regulatory T cell generation or activity. Scandinavian Journal of Immunology, 76, 457. Frank, D. N., St. Amand, A. L., Feldman, R. A., Boedeker, E. C., Harpaz, N., & Pace, N. R. (2007). Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proceedings of the National Academy of Sciences, 104, 13780. Fukuda, S., Toh, H., Hase, K., Oshima, K., Nakanishi, Y., Yoshimura, K., et al. (2011). Bifidobacteria can protect from enteropathogenic infection through production of acetate. Nature, 469, 543. Ganapathy, V., Gopal, E., Miyauchi, S., & Prasad, P. D. (2005). Biological functions of SLC5A8, a candidate tumour suppressor. Biochemical Society Transactions, 33, 237. Guilloteau, P., Martin, L., Eeckhaut, V., Ducatelle, R., Zabielski, R., & Van Immerseel, F. (2010). From the gut to the peripheral tissues: The multiple effects of butyrate. Nutrition Research Reviews, 23, 366. Gupta, N., Martin, P. M., Prasad, P. D., & Ganapathy, V. (2006). SLC5A8 (SMCT1)mediated transport of butyrate forms the basis for the tumor suppressive function of the transporter. Life Sciences, 78, 2419. The Role of Short-Chain Fatty Acids in Health and Disease 115 Halestrap, A. P., & Wilson, M. C. (2012). The monocarboxylate transporter family—Role and regulation. IUBMB Life, 64, 109. Hamer, H. M., Jonkers, D., Venema, K., Vanhoutvin, S., Troost, F. J., & Brummer, R. J. (2008). Review article: The role of butyrate on colonic function. Alimentary Pharmacology & Therapeutics, 27, 104. Hayden, M. S., West, A. P., & Ghosh, S. (2006). NF-kappaB and the immune response. Oncogene, 25, 6758. Herold, S., Paton, J. C., Srimanote, P., & Paton, A. W. (2009). Differential effects of shortchain fatty acids and iron on expression of iha in Shiga-toxigenic Escherichia coli. Microbiology, 155, 3554. Hijazi, Z., Molla, A. M., Al-Habashi, H., Muawad, W. M., Molla, A. M., & Sharma, P. N. (2004). Intestinal permeability is increased in bronchial asthma. Archives of Disease in Childhood, 89, 227. Hinnebusch, B. F., Meng, S., Wu, J. T., Archer, S. Y., & Hodin, R. A. (2002). The effects of short-chain fatty acids on human colon cancer cell phenotype are associated with histone hyperacetylation. The Journal of Nutrition, 132, 1012. Hong, Y. H., Nishimura, Y., Hishikawa, D., Tsuzuki, H., Miyahara, H., Gotoh, C., et al. (2005). Acetate and propionate short chain fatty acids stimulate adipogenesis via GPCR43. Endocrinology, 146, 5092. Hoverstad, T., & Midtvedt, T. (1986). Short-chain fatty acids in germfree mice and rats. The Journal of Nutrition, 116, 1772. Huda-Faujan, N., Abdulamir, A. S., Fatimah, A. B., Anas, O. M., Shuhaimi, M., Yazid, A. M., et al. (2010). The impact of the level of the intestinal short chain Fatty acids in inflammatory bowel disease patients versus healthy subjects. The Open Biochemistry Journal, 4, 53. Ingersoll, M. A., Potteaux, S., Alvarez, D., Hutchison, S. B., van Rooijen, N., & Randolph, G. J. (2012). Niacin inhibits skin dendritic cell mobilization in a GPR109A independent manner but has no impact on monocyte trafficking in atherosclerosis. Immunobiology, 5, 548–557. Iwanaga, T., Takebe, K., Kato, I., Karaki, S., & Kuwahara, A. (2006). Cellular expression of monocarboxylate transporters (MCT) in the digestive tract of the mouse, rat, and humans, with special reference to slc5a8. Biomedical Research, 27, 243. Kang, I., Kim, S. W., & Youn, J. H. (2011). Effects of nicotinic acid on gene expression: Potential mechanisms and implications for wanted and unwanted effects of the lipidlowering drug. The Journal of Clinical Endocrinology and Metabolism, 96, 3048. Karaki, S., Tazoe, H., Hayashi, H., Kashiwabara, H., Tooyama, K., Suzuki, Y., et al. (2008). Expression of the short-chain fatty acid receptor, GPR43, in the human colon. Journal of Molecular Histology, 39, 135. Kendrick, S. F. W., O’Boyle, G., Mann, J., Zeybel, M., Palmer, J., Jones, D. E. J., et al. (2010). Acetate, the key modulator of inflammatory responses in acute alcoholic hepatitis. Hepatology, 51, 1988. Kida, Y., Shimizu, T., & Kuwano, K. (2006). Sodium butyrate up-regulates cathelicidin gene expression via activator protein-1 and histone acetylation at the promoter region in a human lung epithelial cell line, EBC-1. Molecular Immunology, 43, 1972. Kiefer, J., Beyer-Sehlmeyer, G., & Pool-Zobel, B. L. (2006). Mixtures of SCFA, composed according to physiologically available concentrations in the gut lumen, modulate histone acetylation in human HT29 colon cancer cells. The British Journal of Nutrition, 96, 803. Kim, H. J., & Bae, S. C. (2011). Histone deacetylase inhibitors: Molecular mechanisms of action and clinical trials as anti-cancer drugs. American Journal of Translational Research, 3, 166. Kimura, I., Inoue, D., Maeda, T., Hara, T., Ichimura, A., Miyauchi, S., et al. (2011). Shortchain fatty acids and ketones directly regulate sympathetic nervous system via G protein- 116 Jian Tan et al. coupled receptor 41 (GPR41). Proceedings of the National Academy of Sciences of the United States of America, 108, 8030. King, D. E., Mainous, A. G., 3rd., & Lambourne, C. A. (2012). Trends in dietary fiber intake in the United States, 1999–2008. Journal of the Academy of Nutrition and Dietetics, 112, 642. Kong, X., Fang, M., Li, P., Fang, F., & Xu, Y. (2009). HDAC2 deacetylates class II transactivator and suppresses its activity in macrophages and smooth muscle cells. Journal of Molecular and Cellular Cardiology, 46, 292. Lal, G., & Bromberg, J. S. (2009). Epigenetic mechanisms of regulation of Foxp3 expression. Blood, 114, 3727. Le Poul, E., Loison, C., Struyf, S., Springael, J. Y., Lannoy, V., Decobecq, M. E., et al. (2003). Functional characterization of human receptors for short chain fatty acids and their role in polymorphonuclear cell activation. The Journal of Biological Chemistry, 278, 25481. Li, N., Hatch, M., Wasserfall, C. H., Douglas-Escobar, M., Atkinson, M. A., Schatz, D. A., et al. (2010). Butyrate and type 1 diabetes mellitus: Can we fix the intestinal leak? Journal of Pediatric Gastroenterology and Nutrition, 51, 414. Li, X., Millar, J. S., Brownell, N., Briand, F., & Rader, D. J. (2010). Modulation of HDL metabolism by the niacin receptor GPR109A in mouse hepatocytes. Biochemical Pharmacology, 80, 1450. Li, B., Samanta, A., Song, X., Iacono, K. T., Bembas, K., Tao, R., et al. (2007). FOXP3 interactions with histone acetyltransferase and class II histone deacetylases are required for repression. Proceedings of the National Academy of Sciences of the United States of America, 104, 4571. Lu, J., Sun, H., Wang, X., Liu, C., Xu, X., Li, F., et al. (2005). Interleukin-12 p40 promoter activity is regulated by the reversible acetylation mediated by HDAC1 and p300. Cytokine, 31, 46. Lucas, J. L., Mirshahpanah, P., Haas-Stapleton, E., Asadullah, K., Zollner, T. M., & Numerof, R. P. (2009). Induction of Foxp3 þ regulatory T cells with histone deacetylase inhibitors. Cellular Immunology, 257, 97. MacDonald, V. E., & Howe, L. J. (2009). Histone acetylation: Where to go and how to get there. Epigenetics, 4, 139. Macfarlane, S., & Macfarlane, G. T. (2003). Regulation of short-chain fatty acid production. The Proceedings of the Nutrition Society, 62, 67. Macia, L., Thorburn, A. N., Binge, L. C., Marino, E., Rogers, K. E., Maslowski, K. M., et al. (2012). Microbial influences on epithelial integrity and immune function as a basis for inflammatory diseases. Immunological Reviews, 245, 164. Mahowald, M. A., Rey, F. E., Seedorf, H., Turnbaugh, P. J., Fulton, R. S., Wollam, A., et al. (2009). Characterizing a model human gut microbiota composed of members of its two dominant bacterial phyla. Proceedings of the National Academy of Sciences of the United States of America, 106, 5859. Marchesi, J. R., Holmes, E., Khan, F., Kochhar, S., Scanlan, P., Shanahan, F., et al. (2007). Rapid and noninvasive metabonomic characterization of inflammatory bowel disease. Journal of Proteome Research, 6, 546. Maslowski, K. M., & Mackay, C. R. (2011). Diet, gut microbiota and immune responses. Nature Immunology, 12, 5. Maslowski, K. M., Vieira, A. T., Ng, A., Kranich, J., Sierro, F., Yu, D., et al. (2009). Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature, 461, 1282. Mennigen, R., Nolte, K., Rijcken, E., Utech, M., Loeffler, B., Senninger, N., et al. (2009). Probiotic mixture VSL#3 protects the epithelial barrier by maintaining tight junction protein expression and preventing apoptosis in a murine model of colitis. American Journal of Physiology: Gastrointestinal and Liver Physiology, 296, G1140. The Role of Short-Chain Fatty Acids in Health and Disease 117 Miller, T. L., & Wolin, M. J. (1996). Pathways of acetate, propionate, and butyrate formation by the human fecal microbial flora. Applied and Environmental Microbiology, 62, 1589. Miyauchi, S., Gopal, E., Fei, Y. J., & Ganapathy, V. (2004). Functional identification of SLC5A8, a tumor suppressor down-regulated in colon cancer, as a Na(þ)-coupled transporter for short-chain fatty acids. The Journal of Biological Chemistry, 279, 13293. Nakamura, M., Saito, H., Ebinuma, H., Wakabayashi, K., Saito, Y., Takagi, T., et al. (2001). Reduction of telomerase activity in human liver cancer cells by a histone deacetylase inhibitor. Journal of Cellular Physiology, 187, 392. Nakanishi, N., Tashiro, K., Kuhara, S., Hayashi, T., Sugimoto, N., & Tobe, T. (2009). Regulation of virulence by butyrate sensing in enterohaemorrhagic Escherichia coli. Microbiology, 155, 521. Ni, Y. F., Wang, J., Yan, X. L., Tian, F., Zhao, J. B., Wang, Y. J., et al. (2010). Histone deacetylase inhibitor, butyrate, attenuates lipopolysaccharide-induced acute lung injury in mice. Respiratory Research, 11, 33. Pan, X. D., Chen, F. Q., Wu, T. X., Tang, H. G., & Zhao, Z. Y. (2009). Prebiotic oligosaccharides change the concentrations of short-chain fatty acids and the microbial population of mouse bowel. Journal of Zhejiang University: Science B, 10, 258. Park, Y., Subar, A. F., Hollenbeck, A., & Schatzkin, A. (2011). Dietary fiber intake and mortality in the NIH-AARP diet and health study. Archives of Internal Medicine, 171, 1061. Perrier, C., & Corthesy, B. (2011). Gut permeability and food allergies. Clinical and Experimental Allergy, 41, 20. Pokusaeva, K., Fitzgerald, G. F., & van Sinderen, D. (2011). Carbohydrate metabolism in Bifidobacteria. Genes & Nutrition, 6, 285. Pomare, E. W., Branch, W. J., & Cummings, J. H. (1985). Carbohydrate fermentation in the human colon and its relation to acetate concentrations in venous blood. The Journal of Clinical Investigation, 75, 1448. Postma, P. W., Lengeler, J. W., & Jacobson, G. R. (1993). Phosphoenolpyruvate:carbohydrate phosphotransferase systems of bacteria. Microbiological Reviews, 57, 543. Ragsdale, S. W., & Pierce, E. (2008). Acetogenesis and the Wood-Ljungdahl pathway of CO(2) fixation. Biochimica et Biophysica Acta, 1784, 1873. Roelofsen, H., Priebe, M. G., & Vonk, R. J. (2010). The interaction of short-chain fatty acids with adipose tissue: Rlevance for prevention of type 2 diabetes. Beneficial Microbes, 1, 433. Roy, C. C., Kien, C. L., Bouthillier, L., & Levy, E. (2006). Short-chain fatty acids: Ready for prime time? Nutrition in Clinical Practice, 21, 351. Sabatino, A. D., Morera, R., Ciccocioppo, R., Cazzola, P., Gotti, S., Tinozzi, F. P., et al. (2005). Oral butyrate for mildly to moderately active Crohn’s disease. Alimentary Pharmacology & Therapeutics, 22, 789. Saemann, M. D., Bohmig, G. A., Osterreicher, C. H., Burtscher, H., Parolini, O., Diakos, C., et al. (2000). 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, 2380. Sartor, R. B. (2004). Therapeutic manipulation of the enteric microflora in inflammatory bowel diseases: Antibiotics, probiotics, and prebiotics. Gastroenterology, 126, 1620. Sealy, L., & Chalkley, R. (1978). The effect of sodium butyrate on histone modification. Cell, 14, 115. Segain, J. P., Raingeard de la Bletiere, D., Bourreille, A., Leray, V., Gervois, N., Rosales, C., et al. (2000). Butyrate inhibits inflammatory responses through NFkappaB inhibition: Implications for Crohn’s disease. Gut, 47, 397. Sellon, R. K., Tonkonogy, S., Schultz, M., Dieleman, L. A., Grenther, W., Balish, E., et al. (1998). Resident enteric bacteria are necessary for development of spontaneous colitis and immune system activation in interleukin-10-deficient mice. Infection and Immunity, 66, 5224. 118 Jian Tan et al. Senga, T., Iwamoto, S., Yoshida, T., Yokota, T., Adachi, K., Azuma, E., et al. (2003). LSSIG is a novel murine leukocyte-specific GPCR that is induced by the activation of STAT3. Blood, 101, 1185. Shapira, Y., Agmon-Levin, N., & Shoenfeld, Y. (2010). Defining and analyzing geoepidemiology and human autoimmunity. Journal of Autoimmunity, 34, J168. Singh, N., Thangaraju, M., Prasad, P. D., Martin, P. M., Lambert, N. A., Boettger, T., et al. (2010). Blockade of dendritic cell development by bacterial fermentation products butyrate and propionate through a transporter (Slc5a8)-dependent inhibition of histone deacetylases. The Journal of Biological Chemistry, 285, 27601. Sleeth, M. L., Thompson, E. L., Ford, H. E., Zac-Varghese, S. E., & Frost, G. (2010). Free fatty acid receptor 2 and nutrient sensing: A proposed role for fibre, fermentable carbohydrates and short-chain fatty acids in appetite regulation. Nutrition Research Reviews, 23, 135. Soliman, M. L., & Rosenberger, T. A. (2011). Acetate supplementation increases brain histone acetylation and inhibits histone deacetylase activity and expression. Molecular and Cellular Biochemistry, 352, 173. Sunkara, L. T., Jiang, W., & Zhang, G. (2012). Modulation of antimicrobial host defense peptide gene expression by free fatty acids. PLoS One, 7, e49558. Suzuki, T., Yoshida, S., & Hara, H. (2008). Physiological concentrations of short-chain fatty acids immediately suppress colonic epithelial permeability. The British Journal of Nutrition, 100, 297. Tang, Y., Chen, Y., Jiang, H., Robbins, G. T., & Nie, D. (2011). G-protein-coupled receptor for short-chain fatty acids suppresses colon cancer. International Journal of Cancer, 128, 847. Tang, D., Kang, R., Zeh Iii, H. J., & Lotze, M. T. (2010). High-mobility group box 1 and cancer. Biochimica et Biophysica Acta (BBA)—Gene Regulatory Mechanisms, 1799, 131. Tao, R., de Zoeten, E. F., Ozkaynak, E., Chen, C., Wang, L., Porrett, P. M., et al. (2007). Deacetylase inhibition promotes the generation and function of regulatory T cells. Nature Medicine, 13, 1299. Tazoe, H., Otomo, Y., Kaji, I., Tanaka, R., Karaki, S. I., & Kuwahara, A. (2008). Roles of short-chain fatty acids receptors, GPR41 and GPR43 on colonic functions. Journal of Physiology and Pharmacology, 59(Suppl. 2), 251. Tazoe, H., Otomo, Y., Karaki, S., Kato, I., Fukami, Y., Terasaki, M., et al. (2009). Expression of short-chain fatty acid receptor GPR41 in the human colon. Biomedical Research, 30, 149. Tedelind, S., Westberg, F., Kjerrulf, M., & Vidal, A. (2007). Anti-inflammatory properties of the short-chain fatty acids acetate and propionate: A study with relevance to inflammatory bowel disease. World Journal of Gastroenterology, 13, 2826. Thangaraju, M., Cresci, G. A., Liu, K., Ananth, S., Gnanaprakasam, J. P., Browning, D. D., et al. (2009). GPR109A is a G-protein-coupled receptor for the bacterial fermentation product butyrate and functions as a tumor suppressor in colon. Cancer Research, 69, 2826. Tobe, T., Nakanishi, N., & Sugimoto, N. (2011). Activation of motility by sensing shortchain fatty acids via two steps in a flagellar gene regulatory cascade in enterohemorrhagic Escherichia coli. Infection and Immunity, 79, 1016. Tolhurst, G., Heffron, H., Lam, Y. S., Parker, H. E., Habib, A. M., Diakogiannaki, E., et al. (2012). Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes, 61, 364. Usami, M., Kishimoto, K., Ohata, A., Miyoshi, M., Aoyama, M., Fueda, Y., et al. (2008). Butyrate and trichostatin A attenuate nuclear factor kappaB activation and tumor necrosis factor alpha secretion and increase prostaglandin E2 secretion in human peripheral blood mononuclear cells. Nutrition Research, 28, 321. Vaahtovuo, J., Munukka, E., Korkeamaki, M., Luukkainen, R., & Toivanen, P. (2008). Fecal microbiota in early rheumatoid arthritis. The Journal of Rheumatology, 35, 1500. The Role of Short-Chain Fatty Acids in Health and Disease 119 Vangaveti, V., Shashidhar, V., Jarrod, G., Baune, B. T., & Kennedy, R. L. (2010). Free fatty acid receptors: Emerging targets for treatment of diabetes and its complications. Therapeutic Advances in Endocrinology and Metabolism, 1, 165. Viatour, P., Legrand-Poels, S., van Lint, C., Warnier, M., Merville, M.-P., Gielen, J., et al. (2003). Cytoplasmic IkBa increases NF-kB-independent transcription through binding to histone deacetylase (HDAC) 1 and HDAC3. Journal of Biological Chemistry, 278, 46541. Vieira, E. L., Leonel, A. J., Sad, A. P., Beltrao, N. R., Costa, T. F., Ferreira, T. M., et al. (2012). Oral administration of sodium butyrate attenuates inflammation and mucosal lesion in experimental acute ulcerative colitis. The Journal of Nutritional Biochemistry, 23, 430. Villagra, A., Cheng, F., Wang, H. W., Suarez, I., Glozak, M., Maurin, M., et al. (2009). The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance. Nature Immunology, 10, 92. Vinolo, M. A., Rodrigues, H. G., Hatanaka, E., Hebeda, C. B., Farsky, S. H., & Curi, R. (2009). Short-chain fatty acids stimulate the migration of neutrophils to inflammatory sites. Clinical Science (London, England), 117, 331. Vinolo, M. A., Rodrigues, H. G., Hatanaka, E., Sato, F. T., Sampaio, S. C., & Curi, R. (2011). Suppressive effect of short-chain fatty acids on production of proinflammatory mediators by neutrophils. The Journal of Nutritional Biochemistry, 22, 849. Voltolini, C., Battersby, S., Etherington, S. L., Petraglia, F., Norman, J. E., & Jabbour, H. N. (2012). A novel antiinflammatory role for the short-chain fatty acids in human labor. Endocrinology, 153, 395. Wakabayashi, K., Saito, H., Kaneko, F., Nakamoto, N., Tada, S., & Hibi, T. (2005). Gene expression associated with the decrease in malignant phenotype of human liver cancer cells following stimulation with a histone deacetylase inhibitor. International Journal of Oncology, 26, 233. Waldecker, M., Kautenburger, T., Daumann, H., Busch, C., & Schrenk, D. (2008). Inhibition of histone-deacetylase activity by short-chain fatty acids and some polyphenol metabolites formed in the colon. The Journal of Nutritional Biochemistry, 19, 587. Wanders, D., Graff, E. C., & Judd, R. L. (2012). Effects of high fat diet on GPR109A and GPR81 gene expression. Biochemical and Biophysical Research Communications, 425, 278. Wen, L., Ley, R. E., Volchkov, P. Y., Stranges, P. B., Avanesyan, L., Stonebraker, A. C., et al. (2008). Innate immunity and intestinal microbiota in the development of Type 1 diabetes. Nature, 455, 1109. Westermann, P., Ahring, B. K., & Mah, R. A. (1989). Acetate production by methanogenic bacteria. Applied and Environmental Microbiology, 55, 2257. Wong, J. M., de Souza, R., Kendall, C. W., Emam, A., & Jenkins, D. J. (2006). Colonic health: Fermentation and short chain fatty acids. Journal of Clinical Gastroenterology, 40, 235. Wu, J., Zhou, Z., Hu, Y., & Dong, S. (2012). Butyrate-induced GPR41 activation inhibits histone acetylation and cell growth. Journal of Genetics and Genomics, 39, 375. Xiong, Y., Miyamoto, N., Shibata, K., Valasek, M. A., Motoike, T., Kedzierski, R. M., et al. (2004). Short-chain fatty acids stimulate leptin production in adipocytes through the G protein-coupled receptor GPR41. Proceedings of the National Academy of Sciences of the United States of America, 101, 1045. Zhang, F., Shi, Y., Wang, L., & Sriram, S. (2011). Role of HDAC3 on p53 expression and apoptosis in T cells of patients with multiple sclerosis. PLoS One, 6, e16795. Zhong, H., May, M. J., Jimi, E., & Ghosh, S. (2002). The phosphorylation status of nuclear NF-ºB determines its association with CBP/p300 or HDAC-1. Molecular cell, 9, 625. Zoetendal, E. G., Raes, J., van den Bogert, B., Arumugam, M., Booijink, C. C., Troost, F. J., et al. (2012). The human small intestinal microbiota is driven by rapid uptake and conversion of simple carbohydrates. The ISME Journal, 6, 1415.

RELATED PAPERS

RELATED TOPICS

Log In

The Role of Short-Chain Fatty Acids in Health and Disease

The Role of Short-Chain Fatty Acids in Health and Disease

Related Papers

RELATED PAPERS

RELATED TOPICS