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

Ariza, 2012, The succinate receptor as a novel therapeutic target for oxidative and metabolic stress-related conditions, Front. Endocrinol. (Lausanne), 3, 22, 10.3389/fendo.2012.00022

Arpaia, 2013, Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation, Nature, 504, 451, 10.1038/nature12726

Belcheva, 2014, Gut microbial metabolism drives transformation of MSH2-deficient colon epithelial cells, Cell, 158, 288, 10.1016/j.cell.2014.04.051

Bergman, 1990, Energy contributions of volatile fatty acids from the gastrointestinal tract in various species, Physiol. Rev., 70, 567, 10.1152/physrev.1990.70.2.567

Bjursell, 2011, Improved glucose control and reduced body fat mass in free fatty acid receptor 2-deficient mice fed a high-fat diet, Am. J. Physiol. Endocrinol. Metab., 300, E211, 10.1152/ajpendo.00229.2010

Boskey, 2001, Origins of vaginal acidity: high D/L lactate ratio is consistent with bacteria being the primary source, Hum. Reprod., 16, 1809, 10.1093/humrep/16.9.1809

Braniste, 2014, The gut microbiota influences blood-brain barrier permeability in mice, Sci. Transl. Med., 6, 263ra158, 10.1126/scitranslmed.3009759

Brown, 2003, The Orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids, J. Biol. Chem., 278, 11312, 10.1074/jbc.M211609200

Brusselle, 2013, Eosinophils in the spotlight: Eosinophilic airway inflammation in nonallergic asthma, Nat. Med., 19, 977, 10.1038/nm.3300

Cai, 2008, Role of GPR81 in lactate-mediated reduction of adipose lipolysis, Biochem. Biophys. Res. Commun., 377, 987, 10.1016/j.bbrc.2008.10.088

Cani, 2007, Selective increases of bifidobacteria in gut microflora improve high-fat-diet-induced diabetes in mice through a mechanism associated with endotoxaemia, Diabetologia, 50, 2374, 10.1007/s00125-007-0791-0

Chambers, 2015, Effects of targeted delivery of propionate to the human colon on appetite regulation, body weight maintenance and adiposity in overweight adults, Gut, 64, 1744, 10.1136/gutjnl-2014-307913

Chang, 2014, The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition, Proc. Natl. Acad. Sci. USA, 111, 2247, 10.1073/pnas.1322269111

Cresci, 2010, Colonic gene expression in conventional and germ-free mice with a focus on the butyrate receptor GPR109A and the butyrate transporter SLC5A8, J. Gastrointest. Surg., 14, 449, 10.1007/s11605-009-1045-x

Cummings, 1991, The control and consequences of bacterial fermentation in the human colon, J. Appl. Bacteriol., 70, 443, 10.1111/j.1365-2672.1991.tb02739.x

Cummings, 1987, Short chain fatty acids in human large intestine, portal, hepatic and venous blood, Gut, 28, 1221, 10.1136/gut.28.10.1221

de Martel, 2012, Global burden of cancers attributable to infections in 2008: a review and synthetic analysis, Lancet Oncol., 13, 607, 10.1016/S1470-2045(12)70137-7

De Vadder, 2014, Microbiota-generated metabolites promote metabolic benefits via gut-brain neural circuits, Cell, 156, 84, 10.1016/j.cell.2013.12.016

De Vadder, 2015, Vasoactive intestinal peptide is a local mediator in a gut-brain neural axis activating intestinal gluconeogenesis, Neurogastroenterol. Motil., 27, 443, 10.1111/nmo.12508

Dewulf, 2013, Insight into the prebiotic concept: lessons from an exploratory, double blind intervention study with inulin-type fructans in obese women, Gut, 62, 1112, 10.1136/gutjnl-2012-303304

Donohoe, 2012, The Warburg effect dictates the mechanism of butyrate-mediated histone acetylation and cell proliferation, Mol. Cell, 48, 612, 10.1016/j.molcel.2012.08.033

Duncan, 2002, Acetate utilization and butyryl coenzyme A (CoA):acetate-CoA transferase in butyrate-producing bacteria from the human large intestine, Appl. Environ. Microbiol., 68, 5186, 10.1128/AEM.68.10.5186-5190.2002

Erny, 2015, Host microbiota constantly control maturation and function of microglia in the CNS, Nat. Neurosci., 18, 965, 10.1038/nn.4030

Flint, 2012, The role of the gut microbiota in nutrition and health, Nat. Rev. Gastroenterol. Hepatol., 9, 577, 10.1038/nrgastro.2012.156

Frank, 2007, Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases, Proc. Natl. Acad. Sci. USA, 104, 13780, 10.1073/pnas.0706625104

Freeland, 2010, Acute effects of intravenous and rectal acetate on glucagon-like peptide-1, peptide YY, ghrelin, adiponectin and tumour necrosis factor-alpha, Br. J. Nutr., 103, 460, 10.1017/S0007114509991863

Frost, 2014, The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism, Nat. Commun., 5, 3611, 10.1038/ncomms4611

Furusawa, 2013, Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells, Nature, 504, 446, 10.1038/nature12721

Gao, 2009, Butyrate improves insulin sensitivity and increases energy expenditure in mice, Diabetes, 58, 1509, 10.2337/db08-1637

Garrote, 2015, Is lactate an undervalued functional component of fermented food products?, Front. Microbiol., 6, 629, 10.3389/fmicb.2015.00629

Haraguchi, 2014, Cecal succinate elevated by some dietary polyphenols may inhibit colon cancer cell proliferation and angiogenesis, J. Agric. Food Chem., 62, 5589, 10.1021/jf501142k

He, 2004, Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors, Nature, 429, 188, 10.1038/nature02488

Hetzel, 2003, Acryloyl-CoA reductase from Clostridium propionicum. An enzyme complex of propionyl-CoA dehydrogenase and electron-transferring flavoprotein, Eur. J. Biochem., 270, 902, 10.1046/j.1432-1033.2003.03450.x

Holgate, 2011, The sentinel role of the airway epithelium in asthma pathogenesis, Immunol. Rev., 242, 205, 10.1111/j.1600-065X.2011.01030.x

Hudson, 2012, Extracellular ionic locks determine variation in constitutive activity and ligand potency between species orthologs of the free fatty acid receptors FFA2 and FFA3, J. Biol. Chem., 287, 41195, 10.1074/jbc.M112.396259

Hurst, 2014, The short chain fatty acids, butyrate and propionate, have differential effects on the motility of the guinea pig colon, Neurogastroenterol. Motil., 26, 1586, 10.1111/nmo.12425

Johnstone, 2002, Histone-deacetylase inhibitors: novel drugs for the treatment of cancer, Nat. Rev. Drug Discov., 1, 287, 10.1038/nrd772

Kaiko, 2016, The colonic crypt protects stem cells from microbiota-derived metabolites, Cell, 165, 10.1016/j.cell.2016.05.018

Kamada, 2013, Role of the gut microbiota in immunity and inflammatory disease, Nat. Rev. Immunol., 13, 321, 10.1038/nri3430

Kim, 2009, The HDAC inhibitor, sodium butyrate, stimulates neurogenesis in the ischemic brain, J. Neurochem., 110, 1226, 10.1111/j.1471-4159.2009.06212.x

Kimura, 2011, Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41), Proc. Natl. Acad. Sci. USA, 108, 8030, 10.1073/pnas.1016088108

Kimura, 2013, The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43, Nat. Commun., 4, 1829, 10.1038/ncomms2852

Kovatcheva-Datchary, 2015, Dietary Fiber-Induced Improvement in Glucose Metabolism Is Associated with Increased Abundance of Prevotella, Cell Metab., 22, 971, 10.1016/j.cmet.2015.10.001

Le Poul, 2003, Functional characterization of human receptors for short chain fatty acids and their role in polymorphonuclear cell activation, J. Biol. Chem., 278, 25481, 10.1074/jbc.M301403200

Liang, 2010, Butyrate promotes induced pluripotent stem cell generation, J. Biol. Chem., 285, 25516, 10.1074/jbc.M110.142059

Lin, 2012, Butyrate and propionate protect against diet-induced obesity and regulate gut hormones via free fatty acid receptor 3-independent mechanisms, PLoS ONE, 7, e35240, 10.1371/journal.pone.0035240

Liu, 2009, Lactate inhibits lipolysis in fat cells through activation of an orphan G-protein-coupled receptor, GPR81, J. Biol. Chem., 284, 2811, 10.1074/jbc.M806409200

Louis, 2004, Restricted distribution of the butyrate kinase pathway among butyrate-producing bacteria from the human colon, J. Bacteriol., 186, 2099, 10.1128/JB.186.7.2099-2106.2004

Louis, 2014, The gut microbiota, bacterial metabolites and colorectal cancer, Nat. Rev. Microbiol., 12, 661, 10.1038/nrmicro3344

Lupton, 2004, Microbial degradation products influence colon cancer risk: the butyrate controversy, J. Nutr., 134, 479, 10.1093/jn/134.2.479

Macfarlane, 2012, Bacteria, colonic fermentation, and gastrointestinal health, J. AOAC Int., 95, 50

Macia, 2015, Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome, Nat. Commun., 6, 6734, 10.1038/ncomms7734

Maslowski, 2009, Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43, Nature, 461, 1282, 10.1038/nature08530

Mazmanian, 2008, A microbial symbiosis factor prevents intestinal inflammatory disease, Nature, 453, 620, 10.1038/nature07008

Medzhitov, 2008, Origin and physiological roles of inflammation, Nature, 454, 428, 10.1038/nature07201

Meijer-Severs, 1987, Short-chain fatty acids and succinate in feces of healthy human volunteers and their correlation with anaerobe cultural counts, Scand. J. Gastroenterol., 22, 672, 10.3109/00365528709011141

Newgard, 2009, A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance, Cell Metab., 9, 311, 10.1016/j.cmet.2009.02.002

Nilsson, 2003, Identification of a free fatty acid receptor, FFA2R, expressed on leukocytes and activated by short-chain fatty acids, Biochem. Biophys. Res. Commun., 303, 1047, 10.1016/S0006-291X(03)00488-1

Nøhr, 2013, GPR41/FFAR3 and GPR43/FFAR2 as cosensors for short-chain fatty acids in enteroendocrine cells vs FFAR3 in enteric neurons and FFAR2 in enteric leukocytes, Endocrinology, 154, 3552, 10.1210/en.2013-1142

Nøhr, 2015, Expression of the short chain fatty acid receptor GPR41/FFAR3 in autonomic and somatic sensory ganglia, Neuroscience, 290, 126, 10.1016/j.neuroscience.2015.01.040

Park, 2015, Short-chain fatty acids induce both effector and regulatory T cells by suppression of histone deacetylases and regulation of the mTOR-S6K pathway, Mucosal Immunol., 8, 80, 10.1038/mi.2014.44

Ragsdale, 2008, Acetogenesis and the Wood-Ljungdahl pathway of CO(2) fixation, Biochim. Biophys. Acta., 1784, 1873, 10.1016/j.bbapap.2008.08.012

Reid, 2003, Oral use of Lactobacillus rhamnosus GR-1 and L. fermentum RC-14 significantly alters vaginal flora: randomized, placebo-controlled trial in 64 healthy women, FEMS Immunol. Med. Microbiol., 35, 131, 10.1016/S0928-8244(02)00465-0

Rey, 2010, Dissecting the in vivo metabolic potential of two human gut acetogens, J. Biol. Chem., 285, 22082, 10.1074/jbc.M110.117713

Ridaura, 2013, Gut microbiota from twins discordant for obesity modulate metabolism in mice, Science, 341, 1241214, 10.1126/science.1241214

Robertson, 2005, Insulin-sensitizing effects of dietary resistant starch and effects on skeletal muscle and adipose tissue metabolism, Am. J. Clin. Nutr., 82, 559, 10.1093/ajcn/82.3.559

Rubic, 2008, Triggering the succinate receptor GPR91 on dendritic cells enhances immunity, Nat. Immunol., 9, 1261, 10.1038/ni.1657

Russell, 2011, High-protein, reduced-carbohydrate weight-loss diets promote metabolite profiles likely to be detrimental to colonic health, Am. J. Clin. Nutr., 93, 1062, 10.3945/ajcn.110.002188

Russell, 2012, Early life antibiotic-driven changes in microbiota enhance susceptibility to allergic asthma, EMBO Rep., 13, 440, 10.1038/embor.2012.32

Samuel, 2008, Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, Gpr41, Proc. Natl. Acad. Sci. USA, 105, 16767, 10.1073/pnas.0808567105

Sanchez, 2009, Arabinoxylan-oligosaccharides (AXOS) affect the protein/carbohydrate fermentation balance and microbial population dynamics of the Simulator of Human Intestinal Microbial Ecosystem, Microb. Biotechnol., 2, 101, 10.1111/j.1751-7915.2008.00064.x

Schnorr, 2014, Gut microbiome of the Hadza hunter-gatherers, Nat. Commun., 5, 3654, 10.1038/ncomms4654

Schwiertz, 2010, Microbiota and SCFA in lean and overweight healthy subjects, Obesity (Silver Spring), 18, 190, 10.1038/oby.2009.167

Scott, 2006, Whole-genome transcription profiling reveals genes up-regulated by growth on fucose in the human gut bacterium “Roseburia inulinivorans”, J. Bacteriol., 188, 4340, 10.1128/JB.00137-06

Shi, 2011, HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells, J. Exp. Med., 208, 1367, 10.1084/jem.20110278

Singh, 2010, Blockade of dendritic cell development by bacterial fermentation products butyrate and propionate through a transporter (Slc5a8)-dependent inhibition of histone deacetylases, J. Biol. Chem., 285, 27601, 10.1074/jbc.M110.102947

Singh, 2014, Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis, Immunity, 40, 128, 10.1016/j.immuni.2013.12.007

Smith, 1997, Dissimilatory amino Acid metabolism in human colonic bacteria, Anaerobe, 3, 327, 10.1006/anae.1997.0121

Smith, 2013, The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis, Science, 341, 569, 10.1126/science.1241165

Sonnenburg, 2016, Diet-induced extinctions in the gut microbiota compound over generations, Nature, 529, 212, 10.1038/nature16504

Soret, 2010, Short-chain fatty acids regulate the enteric neurons and control gastrointestinal motility in rats, Gastroenterology, 138, 1772, 10.1053/j.gastro.2010.01.053

Taggart, 2005, (D)-beta-Hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor PUMA-G, J. Biol. Chem., 280, 26649, 10.1074/jbc.C500213200

Tang, 2011, G-protein-coupled receptor for short-chain fatty acids suppresses colon cancer, Int. J. Cancer, 128, 847, 10.1002/ijc.25638

Thangaraju, 2009, GPR109A is a G-protein-coupled receptor for the bacterial fermentation product butyrate and functions as a tumor suppressor in colon, Cancer Res., 69, 2826, 10.1158/0008-5472.CAN-08-4466

Thorburn, 2015, Evidence that asthma is a developmental origin disease influenced by maternal diet and bacterial metabolites, Nat. Commun., 6, 7320, 10.1038/ncomms8320

Tolhurst, 2012, Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2, Diabetes, 61, 364, 10.2337/db11-1019

Trompette, 2014, Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis, Nat. Med., 20, 159, 10.1038/nm.3444

Tunaru, 2003, PUMA-G and HM74 are receptors for nicotinic acid and mediate its anti-lipolytic effect, Nat. Med., 9, 352, 10.1038/nm824

Turnbaugh, 2006, An obesity-associated gut microbiome with increased capacity for energy harvest, Nature, 444, 1027, 10.1038/nature05414

Venter, 1990, Effects of dietary propionate on carbohydrate and lipid metabolism in healthy volunteers, Am. J. Gastroenterol., 85, 549

Videla, 1994, Role of intestinal microflora in chronic inflammation and ulceration of the rat colon, Gut, 35, 1090, 10.1136/gut.35.8.1090

Vital, 2014, Revealing the bacterial butyrate synthesis pathways by analyzing (meta)genomic data, MBio, 5, e00889, 10.1128/mBio.00889-14

Wall, 2009, Metabolic activity of the enteric microbiota influences the fatty acid composition of murine and porcine liver and adipose tissues, Am. J. Clin. Nutr., 89, 1393, 10.3945/ajcn.2008.27023

Wang, 2012, Structural segregation of gut microbiota between colorectal cancer patients and healthy volunteers, ISME J., 6, 320, 10.1038/ismej.2011.109

Wise, 2003, Molecular identification of high and low affinity receptors for nicotinic acid, J. Biol. Chem., 278, 9869, 10.1074/jbc.M210695200

Yajima, 2011, Non-neuronal release of ACh plays a key role in secretory response to luminal propionate in rat colon, J. Physiol., 589, 953, 10.1113/jphysiol.2010.199976

Yamashita, 2007, Improvement of obesity and glucose tolerance by acetate in Type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats, Biosci. Biotechnol. Biochem., 71, 1236, 10.1271/bbb.60668

Yin, 2014, Niche-independent high-purity cultures of Lgr5+ intestinal stem cells and their progeny, Nat. Methods, 11, 106, 10.1038/nmeth.2737

Yoo, 2011, Synergistic effects of sodium butyrate, a histone deacetylase inhibitor, on increase of neurogenesis induced by pyridoxine and increase of neural proliferation in the mouse dentate gyrus, Neurochem. Res., 36, 1850, 10.1007/s11064-011-0503-5

Zaiss, 2015, The Intestinal Microbiota Contributes to the Ability of Helminths to Modulate Allergic Inflammation, Immunity, 43, 998, 10.1016/j.immuni.2015.09.012