From Dietary Fiber to Host Physiology: Short-Chain Fatty Acids as Key Bacterial Metabolites

doi:10.1016/J.CELL.2016.05.041

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From Dietary Fiber to Host Physiology: Short-Chain Fatty Acids as Key Bacterial Metabolites

Journal Article•DOI•

From Dietary Fiber to Host Physiology: Short-Chain Fatty Acids as Key Bacterial Metabolites

Ara Koh¹, Filipe De Vadder¹, Petia Kovatcheva-Datchary¹, Fredrik Bäckhed², Fredrik Bäckhed¹ - Show less +1 more•Institutions (2)

University of Gothenburg¹, University of Copenhagen²

02 Jun 2016-Cell (Elsevier)-Vol. 165, Iss: 6, pp 1332-1345

TL;DR: Data is reviewed supporting the diverse functional roles carried out by a major class of bacterial metabolites, the short-chain fatty acids (SCFAs), which affect various physiological processes and may contribute to health and disease.

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About: This article is published in Cell.The article was published on 2016-06-02 and is currently open access. It has received 3363 citations till now.

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Journal Article•DOI•

Expert consensus document: The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics

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Glenn R. Gibson¹, Robert W. Hutkins, Mary Ellen Sanders, Susan L. Prescott², Raylene A. Reimer³, Seppo Salminen⁴, Karen P. Scott⁵, Catherine Stanton⁶, Kelly S. Swanson⁷, Patrice D. Cani⁸, Kristin Verbeke, Gregor Reid⁹ - Show less +8 more•Institutions (9)

University of Reading¹, University of Western Australia², University of Calgary³, University of Turku⁴, University of Aberdeen⁵, Teagasc⁶, University of Illinois at Urbana–Champaign⁷, Université catholique de Louvain⁸, University of Western Ontario⁹

14 Jun 2017-Nature Reviews Gastroenterology & Hepatology

TL;DR: The goal of this Consensus Statement is to engender appropriate use of the term 'prebiotic' by relevant stakeholders so that consistency and clarity can be achieved in research reports, product marketing and regulatory oversight of the category.

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Abstract: With the continued interest in the role of the gut microbiota in health, attention has now turned to how to harness the microbiota for the benefit of the host. This Consensus Statement outlines the definition and scope of the term 'prebiotic' as determined by an expert panel convened by the International Scientific Association for Probiotics and Prebiotics in December 2016. In December 2016, a panel of experts in microbiology, nutrition and clinical research was convened by the International Scientific Association for Probiotics and Prebiotics to review the definition and scope of prebiotics. Consistent with the original embodiment of prebiotics, but aware of the latest scientific and clinical developments, the panel updated the definition of a prebiotic: a substrate that is selectively utilized by host microorganisms conferring a health benefit. This definition expands the concept of prebiotics to possibly include non-carbohydrate substances, applications to body sites other than the gastrointestinal tract, and diverse categories other than food. The requirement for selective microbiota-mediated mechanisms was retained. Beneficial health effects must be documented for a substance to be considered a prebiotic. The consensus definition applies also to prebiotics for use by animals, in which microbiota-focused strategies to maintain health and prevent disease is as relevant as for humans. Ultimately, the goal of this Consensus Statement is to engender appropriate use of the term 'prebiotic' by relevant stakeholders so that consistency and clarity can be achieved in research reports, product marketing and regulatory oversight of the category. To this end, we have reviewed several aspects of prebiotic science including its development, health benefits and legislation.

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2,863 citations

Journal Article•DOI•

The Microbiota-Gut-Brain Axis

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John F. Cryan¹, Kenneth J. O’Riordan¹, Caitlin S. M. Cowan¹, Kiran V. Sandhu¹, Thomaz F.S. Bastiaanssen, Marcus Boehme, Martín Gabriel Codagnone, Sofia Cussotto, Christine Fülling, Anna V. Golubeva, Katherine E. Guzzetta, Minal Jaggar, Caitriona M. Long-Smith, Joshua M. Lyte, Jason A. Martin, Alicia Molinero-Perez, Gerard M. Moloney, Emanuela Morelli, Enrique Morillas, Rory C. O'Connor, Joana S Cruz-Pereira, Veronica L. Peterson, Kieran Rea, Nathaniel L. Ritz, Eoin Sherwin, Simon Spichak, Emily M. Teichman, Marcel van de Wouw, Ana Paula Ventura-Silva, Shauna E. Wallace-Fitzsimons, Niall P. Hyland, Gerard Clarke, Timothy G. Dinan - Show less +29 more•Institutions (1)

University College Cork¹

01 Oct 2019-Physiological Reviews

TL;DR: Future studies will focus on understanding the mechanisms underlying the microbiota-gut-brain axis and attempt to elucidate microbial-based intervention and therapeutic strategies for neuropsychiatric disorders.

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Abstract: The importance of the gut-brain axis in maintaining homeostasis has long been appreciated. However, the past 15 yr have seen the emergence of the microbiota (the trillions of microorganisms within ...

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1,775 citations

Journal Article•DOI•

Formation of propionate and butyrate by the human colonic microbiota

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Petra Louis, Harry J. Flint

01 Jan 2017-Environmental Microbiology

TL;DR: This overview emphasizes the important role played by cross-feeding of intermediary metabolites (in particular lactate, succinate and 1,2-propanediol) between different gut bacteria.

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Abstract: The human gut microbiota ferments dietary non-digestible carbohydrates into short-chain fatty acids (SCFA). These microbial products are utilized by the host and propionate and butyrate in particular exert a range of health-promoting functions. Here an overview of the metabolic pathways utilized by gut microbes to produce these two SCFA from dietary carbohydrates and from amino acids resulting from protein breakdown is provided. This overview emphasizes the important role played by cross-feeding of intermediary metabolites (in particular lactate, succinate and 1,2-propanediol) between different gut bacteria. The ecophysiology, including growth requirements and responses to environmental factors, of major propionate and butyrate producing bacteria are discussed in relation to dietary modulation of these metabolites. A detailed understanding of SCFA metabolism by the gut microbiota is necessary to underpin effective strategies to optimize SCFA supply to the host.

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1,379 citations

Cites background from "From Dietary Fiber to Host Physiolo..."

...They are taken up efficiently by the gut mucosa and have important impacts upon 38 host physiology as sources of energy, as regulators of gene expression and as signaling molecules that are 39 recognized by specific receptors (Morrison & Preston, 2016; Koh et al., 2016)....
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...They are taken up efficiently by the gut mucosa and have important impacts upon host physiology as sources of energy, as regulators of gene expression and as signaling molecules that are recognized by specific receptors (Morrison & Preston, 2016; Koh et al., 2016)....
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Journal Article•DOI•

Gut bacteria selectively promoted by dietary fibers alleviate type 2 diabetes

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Liping Zhao¹, Liping Zhao², Feng Zhang², Xiaoying Ding², Guojun Wu², Yan Y. Lam¹, Xuejiao Wang², Huaqing Fu², Xinhe Xue², Chunhua Lu, Jilin Ma, Lihua Yu, Chengmei Xu, Zhongying Ren, Ying Xu, Songmei Xu, Hongli Shen, Xiuli Zhu, Yu Shi, Qingyun Shen, Weiping Dong², Rui Liu², Yunxia Ling², Yue Zeng², Xing-peng Wang², Qianpeng Zhang², Jing Wang², Linghua Wang², Yanqiu Wu², Benhua Zeng³, Hong Wei³, Menghui Zhang², Yongde Peng², Chenhong Zhang² - Show less +30 more•Institutions (3)

Rutgers University¹, Shanghai Jiao Tong University², Third Military Medical University³

09 Mar 2018-Science

TL;DR: It is found that adopting a high-fiber diet promoted the growth of SCFA-producing organisms in diabetic humans and had better improvement in hemoglobin A1c levels, partly via increased glucagon-like peptide-1 production.

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Abstract: The gut microbiota benefits humans via short-chain fatty acid (SCFA) production from carbohydrate fermentation, and deficiency in SCFA production is associated with type 2 diabetes mellitus (T2DM). We conducted a randomized clinical study of specifically designed isoenergetic diets, together with fecal shotgun metagenomics, to show that a select group of SCFA-producing strains was promoted by dietary fibers and that most other potential producers were either diminished or unchanged in patients with T2DM. When the fiber-promoted SCFA producers were present in greater diversity and abundance, participants had better improvement in hemoglobin A1c levels, partly via increased glucagon-like peptide-1 production. Promotion of these positive responders diminished producers of metabolically detrimental compounds such as indole and hydrogen sulfide. Targeted restoration of these SCFA producers may present a novel ecological approach for managing T2DM.

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1,298 citations

Journal Article•DOI•

The Impact of Dietary Fiber on Gut Microbiota in Host Health and Disease.

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Kassem Makki¹, Edward C. Deehan², Jens Walter², Fredrik Bäckhed³, Fredrik Bäckhed¹ - Show less +1 more•Institutions (3)

Sahlgrenska University Hospital¹, University of Alberta², University of Copenhagen³

13 Jun 2018-Cell Host & Microbe

TL;DR: This review will focus on dietary fibers, which interact directly with gut microbes and lead to the production of key metabolites such as short-chain fatty acids, and discuss how dietary fiber impacts gut microbial ecology, host physiology, and health.

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1,216 citations

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Journal Article•DOI•

An obesity-associated gut microbiome with increased capacity for energy harvest

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Peter J. Turnbaugh¹, Ruth E. Ley, Michael A. Mahowald, Vincent Magrini¹, Elaine R. Mardis¹, Jeffrey I. Gordon - Show less +2 more•Institutions (1)

Washington University in St. Louis¹

21 Dec 2006-Nature

TL;DR: It is demonstrated through metagenomic and biochemical analyses that changes in the relative abundance of the Bacteroidetes and Firmicutes affect the metabolic potential of the mouse gut microbiota and indicates that the obese microbiome has an increased capacity to harvest energy from the diet.

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Abstract: The worldwide obesity epidemic is stimulating efforts to identify host and environmental factors that affect energy balance. Comparisons of the distal gut microbiota of genetically obese mice and their lean littermates, as well as those of obese and lean human volunteers have revealed that obesity is associated with changes in the relative abundance of the two dominant bacterial divisions, the Bacteroidetes and the Firmicutes. Here we demonstrate through metagenomic and biochemical analyses that these changes affect the metabolic potential of the mouse gut microbiota. Our results indicate that the obese microbiome has an increased capacity to harvest energy from the diet. Furthermore, this trait is transmissible: colonization of germ-free mice with an 'obese microbiota' results in a significantly greater increase in total body fat than colonization with a 'lean microbiota'. These results identify the gut microbiota as an additional contributing factor to the pathophysiology of obesity.

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10,126 citations

"From Dietary Fiber to Host Physiolo..." refers background in this paper

...SCFA may constitute an important energy source in humans (Bergman, 1990), and it has been suggested that increased energy harvest, associated with increased polysaccharide degradation in the gut, could contribute to the obese phenotype in genetically obese mice (Turnbaugh et al., 2006)....
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Journal Article•DOI•

Origin and Physiological Roles of Inflammation

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Ruslan Medzhitov¹•Institutions (1)

Yale University¹

23 Jul 2008-Nature

TL;DR: This work has shown that tissue stress or malfunction induces an adaptive response that is intermediate between the basal homeostatic state and a classic inflammatory response, which is referred to here as para-inflammation.

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Abstract: Inflammation underlies a wide variety of physiological and pathological processes. Although the pathological aspects of many types of inflammation are well appreciated, their physiological functions are mostly unknown. The classic instigators of inflammation - infection and tissue injury - are at one end of a large range of adverse conditions that induce inflammation, and they trigger the recruitment of leukocytes and plasma proteins to the affected tissue site. Tissue stress or malfunction similarly induces an adaptive response, which is referred to here as para-inflammation. This response relies mainly on tissue-resident macrophages and is intermediate between the basal homeostatic state and a classic inflammatory response. Para-inflammation is probably responsible for the chronic inflammatory conditions that are associated with modern human diseases.

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4,832 citations

"From Dietary Fiber to Host Physiolo..." refers background in this paper

...In normal conditions in which commensalhost interaction is nicely balanced, removal of commensals by antibiotics will erase the beneficial effect of SCFAs, contributing to CRC development....
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...Chronic inflammation is a well-established risk factor for colorectal cancer (CRC) (Medzhitov, 2008)....
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...Abbreviations: EEC, enteroendocrine cell; LP, lamina propria; Tregs, regulatory T cells; GLP-1, glucagon like peptide-1; PYY, peptide YY; IBD, inflammatory bowel disease; Teff, effector T cell; DCs, dendritic cells; b-D-OHB, b-D-hydroxybutyrate; CRC, colorectal cancer; VEGF, vascular endothelial growth factor; microbial metabolite-mediated signalinga, signaling through the receptors by microbially produced metabolites (not endogenously produced from the host). propria macrophages (Chang et al., 2014) and differentiation of dendritic cells from bone marrow stem cells (Singh et al., 2010) via HDAC inhibition, making our immune system hyporesponsive to beneficial commensals....
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...Context-Dependent Effects of Microbiota on CRC Depending on the cellular context of the host (i.e., inflammation-driven or acquisition of stemcell-like character), antibiotics and/or SCFAs can function as anti-inflammatory or pro-inflammatory....
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Journal Article•DOI•

Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases

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Daniel N. Frank¹, Allison L. St. Amand, Robert A. Feldman, Edgar C. Boedeker, Noam Harpaz, Norman R. Pace - Show less +2 more•Institutions (1)

University of Colorado Boulder¹

21 Aug 2007-Proceedings of the National Academy of Sciences of the United States of America

TL;DR: Patient stratification by GI microbiota provides further evidence that CD represents a spectrum of disease states and suggests that treatment of some forms of IBD may be facilitated by redress of the detected microbiological imbalances.

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Abstract: The two primary human inflammatory bowel diseases, Crohn's disease (CD) and ulcerative colitis (UC), are idiopathic relapsing disorders characterized by chronic inflammation of the intestinal tract. Although several lines of reasoning suggest that gastrointestinal (GI) microbes influence inflammatory bowel disease (IBD) pathogenesis, the types of microbes involved have not been adequately described. Here we report the results of a culture-independent rRNA sequence analysis of GI tissue samples obtained from CD and UC patients, as well as non-IBD controls. Specimens were obtained through surgery from a variety of intestinal sites and included both pathologically normal and abnormal states. Our results provide comprehensive molecular-based analysis of the microbiota of the human small intestine. Comparison of clone libraries reveals statistically significant differences between the microbiotas of CD and UC patients and those of non-IBD controls. Significantly, our results indicate that a subset of CD and UC samples contained abnormal GI microbiotas, characterized by depletion of commensal bacteria, notably members of the phyla Firmicutes and Bacteroidetes. Patient stratification by GI microbiota provides further evidence that CD represents a spectrum of disease states and suggests that treatment of some forms of IBD may be facilitated by redress of the detected microbiological imbalances.

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3,967 citations

"From Dietary Fiber to Host Physiolo..." refers background in this paper

...More specifically, butyrate seems to be related to a protective role based on a significant decrease in the number of butyrate-producing bacteria in the colon of patients with ulcerative colitis and colon cancer (Frank et al., 2007; Wang et al., 2012) and an amelioration of experimental colitis (AOM (azoxymethane)/DSS treatment) through GPR109A (Singh et al....
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...…role based on a significant decrease in the number of butyrate-producing bacteria in the colon of patients with ulcerative colitis and colon cancer (Frank et al., 2007; Wang et al., 2012) and an amelioration of experimental colitis (AOM (azoxymethane)/DSS treatment) through GPR109A (Singh et al.,…...
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Journal Article•DOI•

The Microbial Metabolites, Short-Chain Fatty Acids, Regulate Colonic Treg Cell Homeostasis

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Patrick M. Smith¹, Michael R. Howitt¹, Nicolai Panikov¹, Monia Michaud¹, Carey Ann Gallini¹, Mohammad Bohlooly-Y², Jonathan N. Glickman¹, Wendy S. Garrett - Show less +4 more•Institutions (2)

Harvard University¹, AstraZeneca²

02 Aug 2013-Science

TL;DR: This study determined that short-chain fatty acids, gut microbiota–derived bacterial fermentation products, regulate the size and function of the colonic Treg pool and protect against colitis in a Ffar2-dependent manner in mice, revealing that a class of abundant microbial metabolites underlies adaptive immune microbiota coadaptation and promotes colonic homeostasis and health.

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Abstract: Regulatory T cells (T regs ) that express the transcription factor Foxp3 are critical for regulating intestinal inflammation. Candidate microbe approaches have identified bacterial species and strain-specific molecules that can affect intestinal immune responses, including species that modulate T reg responses. Because neither all humans nor mice harbor the same bacterial strains, we posited that more prevalent factors exist that regulate the number and function of colonic T regs . We determined that short-chain fatty acids, gut microbiota–derived bacterial fermentation products, regulate the size and function of the colonic T reg pool and protect against colitis in a Ffar2 -dependent manner in mice. Our study reveals that a class of abundant microbial metabolites underlies adaptive immune microbiota coadaptation and promotes colonic homeostasis and health.

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3,733 citations

"From Dietary Fiber to Host Physiolo..." refers background or result in this paper

...In contrast to the earlier study showing the expression of GPR43 in colonic Tregs and myeloid cells (Smith et al., 2013), Park and co-authors reported that T cells do not significantly express GPR43 and thus GPR43 is not functional in regulating cytokine expression in T cells, which is rather…...
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...Recent studies have shown the effects of SCFAs on Treg cell expansion/generation via SCFAs-GPCR or their HDAC-inhibiting ability (Figure 2 and 3) (Arpaia et al., 2013; Furusawa et al., 2013; Singh et al., 2014; Smith et al., 2013)....
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Journal Article•DOI•

Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells

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Yukihiro Furusawa¹, Yuuki Obata¹, Shinji Fukuda², Takaho A. Endo, Gaku Nakato, Daisuke Takahashi, Yumiko Nakanishi², Chikako Uetake, Keiko Kato³, Tamotsu Kato, Masumi Takahashi, Noriko N. Fukuda², Shinnosuke Murakami², Eiji Miyauchi, Shingo Hino⁴, Koji Atarashi⁵, Satoshi Onawa, Yumiko Fujimura¹, Trevor Lockett⁶, Julie M. Clarke⁶, David L. Topping⁶, Masaru Tomita², Shohei Hori, Osamu Ohara, Tatsuya Morita⁴, Haruhiko Koseki³, Jun Kikuchi³, Kenya Honda, Koji Hase¹, Hiroshi Ohno³ - Show less +26 more•Institutions (6)

University of Tokyo¹, Keio University², Yokohama City University³, Shizuoka University⁴, National Presto Industries⁵, Commonwealth Scientific and Industrial Research Organisation⁶

19 Dec 2013-Nature

TL;DR: It is shown that a large bowel microbial fermentation product, butyrate, induces the differentiation of colonic Treg cells in mice and ameliorated the development of colitis induced by adoptive transfer of CD4+ CD45RBhi T cells in Rag1−/− mice.

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Abstract: Gut commensal microbes shape the mucosal immune system by regulating the differentiation and expansion of several types of T cell. Clostridia, a dominant class of commensal microbe, can induce colonic regulatory T (Treg) cells, which have a central role in the suppression of inflammatory and allergic responses. However, the molecular mechanisms by which commensal microbes induce colonic Treg cells have been unclear. Here we show that a large bowel microbial fermentation product, butyrate, induces the differentiation of colonic Treg cells in mice. A comparative NMR-based metabolome analysis suggests that the luminal concentrations of short-chain fatty acids positively correlates with the number of Treg cells in the colon. Among short-chain fatty acids, butyrate induced the differentiation of Treg cells in vitro and in vivo, and ameliorated the development of colitis induced by adoptive transfer of CD4(+) CD45RB(hi) T cells in Rag1(-/-) mice. Treatment of naive T cells under the Treg-cell-polarizing conditions with butyrate enhanced histone H3 acetylation in the promoter and conserved non-coding sequence regions of the Foxp3 locus, suggesting a possible mechanism for how microbial-derived butyrate regulates the differentiation of Treg cells. Our findings provide new insight into the mechanisms by which host-microbe interactions establish immunological homeostasis in the gut.

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3,596 citations

"From Dietary Fiber to Host Physiolo..." refers background in this paper

...Thus, the metabolic shift in activated T cells will make them sensitive to SCFA-mediated HDAC inhibition, which may result in increased FoxP3 induction through acetylation at FoxP3 locus (Arpaia et al., 2013; Furusawa et al., 2013)....
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...Recent studies have shown the effects of SCFAs on Treg cell expansion/generation via SCFAs-GPCR or their HDAC-inhibiting ability (Figure 2 and 3) (Arpaia et al., 2013; Furusawa et al., 2013; Singh et al., 2014; Smith et al., 2013)....
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