Immunomodulatory potential of gut microbiome-derived short-chain fatty acids (SCFAs)
Intestinal microbiota is an element of the bacterial ecosystem in all mammalian organisms. These microorganisms play a very important part in the development, functioning, and modulation of the immune system from the moment of birth. In recent years, owing to the use of modern sequencing techniques, the microbiome composition in healthy people has been identified based on bacterial 16S rRNA analysis. Currently, more and more attention is being given to the influence of microorganisms on the host’s cellular metabolism. Analysis of microbial metabolites, among them short-chain fatty acids (SCFAs), and disruption of intestinal microbiota homeostasis in terms of their effects on molecular regulatory mechanisms of immune reactions will surely improve the understanding of the etiology of many common diseases. SCFAs, mainly butyrate, propionate, and acetate, occur in specific amounts, and their proportions can change, depending on the diet, age and diseases. The levels of SCFAs are substantially influenced by the ratio of commensal intestinal bacteria, the disturbance of which (dysbiosis) can lead to a disproportion between the SCFAs produced. SCFAs are regarded as mediators in the communication between the intestinal microbiome and the immune system. The signal they produce is transferred, among others, in immune cells via free fatty acid receptors (FFARs), which belong to the family of G protein-coupled receptors (GPCRs). It has been also confirmed that SCFAs inhibit the activity of histone deacetylase (HDAC) – an enzyme involved in post-translational modifications, namely the process of deacetylation and, what is new, the process of histone crotonylation. These properties of SCFAs have an effect on their immunomodulatory potential i.e. maintaining the anti/pro-inflammatory balance. SCFAs act not only locally in the intestines colonized by commensal bacteria, but also influence the intestinal immune cells, and modulate immune response by multi-protein inflammasome complexes. SCFAs have been confirmed to contribute to the maintenance of the immune homeostasis of the urinary system (kidneys), respiratory system (lungs), central nervous system, and the sight organ.
Alex S, Lange K, Amolo T, Grinstead JS, Haakonsson AK, Szalowska E, Kersten S (2013) Short-chain fatty acids stimulate angiopoietin-like 4 synthesis in human colon adenocarcinoma cells by activating peroxisome proliferator-activated receptor. Mol CellBiol 33: 1303–1316. https://doi.org/10.1128/MCB.00858-12.
Ang Z, Xiong D, Wu M, Ding J L (2018) FFAR2-FFAR3 receptor heteromerization modulates short-chain fatty acid sensing. FASEB J 32: 289–303. https://doi.org/10.1096/fj.201700252RR.
Astakhova L, Ngara M, Babich O, Prosekov A, Asyakina L, Dyshlyuk L, Matskova L (2016) Short chain fatty acids (SCFA) reprogram gene expression in human malignant epithelial and lymphoid cells. PLoS One 11: e0154102. https://doi.org/10.1371/journal.pone.0154102.
Bolognini D, Tobin AB, Milligan G, Moss CE (2016) The pharmacology and function of receptors for short-chain fatty acids. Mol Pharmacol 89: 388–398. https://doi.org/10.1124/mol.115.102301.
Brown AJ, Goldsworthy SM, Barnes AA, Eilert MM, Tcheang L, Daniels D, Dowell SJ (2003) The orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J Biol Chem 278: 11312–11319. https://doi.org/10.1074/jbc.M211609200.
Cait A, Hughes MR, Antignano F, Cait J, Dimitriu PA, Maas KR, Mohn WW (2017) Microbiome-driven allergic lung inflammation is ameliorated by short-chain fatty acids. Mucosal Immunol 11: 785-795. https://doi.org/10.1038/mi.2017.75.
Chow J, Mazmanian SK (2010) A Pathobiont of the Microbiota Balances Host Colonization and Intestinal Inflammation. Cell Host Microbe 7: 265–276. https://doi.org/10.1016/j.chom.2010.03.004.
Human Microbiome Project Consortium (2012) Structure, function and diversity of the healthy human microbiome. Nature 486: 207–214. https://doi.org/10.1038/nature11234.
Cotillard A, Kennedy SP, Kong LC, Prifti E, Pons N, Le Chatelier E, Layec S (2013) Dietary intervention impact on gut microbial gene richness. Nature 500: 585–588. https://doi.org/10.1038/nature12480.
D’Souza WN, Douangpanya J, Mu S, Jaeckel P, Zhang M, Maxwell JR, Hsu H (2017) Differing roles for short chain fatty acids and GPR43 agonism in the regulation of intestinal barrier function and immune responses. PLoS One 12: e0180190. https://doi.org/10.1371/journal.pone.0180190.
Duncan S H, Barcenilla A, Stewart CS, Pryde SE, Flint HJ (2002) Acetate utilization and butyryl coenzyme A (CoA):acetate-CoA transferase in butyrate-producing bacteria from the human large intestine. Appl Environ Microbiol 68: 5186–5190. https://doi.org/10.1128/AEM.68.10.5186-5190.2002.
Fellows R, Denizot J, Stellato C, Cuomo A, Jain P, Stoyanova E, Varga-Weisz P (2018) Microbiota derived short chain fatty acids promote histone crotonylation in the colon through histone deacetylases. Nat Commun 9: 105. https://doi.org/10.1038/s41467-017-02651-5.
Fransen F, van Beek AA, Borghuis T, Aidy S El, Hugenholtz F, van der Gaast – de Jongh C, de Vos P (2017) Aged gut microbiota contributes to systemical inflammaging after transfer to germ-free mice. Fron Immunol 8: 1385. https://doi.org/10.3389/fimmu.2017.01385.
Grabarska A, Dmoszyńska-Graniczka M, Nowosadzka E, Stepulak A (2013) Histone deacetylase inhibitors – molecular mechanisms of actions and clinical applications. Postepy Hig Med Dosw 67: 722–735. https://doi.org/10.5604/17322693.1061381.
Huang W, Guo HL, Deng X, Zhu TT, Xiong JF, Xu YH, Xu Y (2017) Short-chain fatty acids inhibit oxidative stress and inflammation in mesangial cells induced by high glucose and lipopolysaccharide. Exp Clin Endocrinol Diabetes 125: 98–105. https://doi.org/10.1055/s-0042-121493.
Kimura I, Inoue D, Maeda T, Hara T, Ichimura A, Miyauchi S, Tsujimoto G (2011) Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41). Proc Natl Acad Sci 108: 8030–8035. https://doi.org/10.1073/pnas.1016088108.
Kobayashi M, Mikami D, Kimura H, Kamiyama K, Morikawa Y, Yokoi S, Iwano M (2017) Short-chain fatty acids, GPR41 and GPR43 ligands, inhibit TNF-α-induced MCP-1 expression by modulating p38 and JNK signaling pathways in human renal cortical epithelial cells. Biochem Biophys Res Commun 486: 499–505. https://doi.org/10.1016/j.bbrc.2017.03.071.
Koh A, De Vadder F, Kovatcheva-Datchary P, Bäckhed F (2016) From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites. Cell 165: 1332–1345. https://doi.org/10.1016/j.cell.2016.05.041.
Korek E, Krauss H (2015) Novel adipokines: their potential role in the pathogenesis of obesity and metabolic disorders. Postepy Hig Med Dosw 69: 799–810. https://doi.org/10.5604/17322693.1161415.
Korem T, Zeevi D, Suez J, Weinberger A, Avnit-Sagi T, Pompan-Lotan M, Segal E (2015) Growth dynamics of gut microbiota in health and disease inferred from single metagenomic samples. Science 349: 1101–1106. https://doi.org/10.1126/science.aac4812.
Le Chatelier E, Nielsen T, Qin J, Prifti E, Hildebrand F, Falony G, Pedersen O (2013) Richness of human gut microbiome correlates with metabolic markers. Nature 500: 541–546. https://doi.org/10.1038/nature12506.
Levy M, Thaiss CA, Zeevi D, Dohnalová L, Zilberman-Schapira G, Mahdi JA, Elinav E (2015) Microbiota-modulated metabolites shape the intestinal microenvironment by regulating NLRP6 inflammasome signaling. Cell 163: 1428–1443. https://doi.org/10.1016/j.cell.2015.10.048.
Lloyd-Price J, Mahurkar A, Rahnavard G, Crabtree J, Orvis J, Hall A B, Huttenhower C (2017) Strains, functions and dynamics in the expanded Human Microbiome Project. Nature 550: 61. https://doi.org/10.1038/nature23889.
Lu Y, Fan C, Li P, Lu Y, Chang X, Qi K (2016) Short chain fatty acids prevent high-fat-diet-induced obesity in mice by regulating G protein-coupled receptors and gut microbiota. Sci Rep 6: 37589. https://doi.org/10.1038/srep37589.
Macia L, Tan J, Vieira A T, Leach K, Stanley D, Luong S, Mackay CR (2015) Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome. Nat Commun 6: 6734. https://doi.org/10.1038/ncomms7734.
Mackowiak PA (2013) Recycling metchnikoff: probiotics, the intestinal microbiome and the quest for long life. Front public Heal 1: 52. https://doi.org/10.3389/fpubh.2013.00052
Maier L, Pruteanu M, Kuhn M, Zeller G, Telzerow A, Anderson EE, Brochado. AR, Fernandez KC, Dose H, Mori H, Patil KR, Bork P, Typas A (2018) Extensive impact of non-antibiotic drugs on human gut bacteria. Nature https://doi.org/10.1038/nature25979.
Malaisé Y, Menard S, Cartier C, Gaultier E, Lasserre F, Lencina C, Guzylack-Piriou L (2017) Gut dysbiosis and impairment of immune system homeostasis in perinatally-exposed mice to Bisphenol A precede obese phenotype development. Sci Rep 7: 14472. https://doi.org/10.1038/s41598-017-15196-w.
Mamantopoulos M, Ronchi F, Van Hauwermeiren F, Vieira-Silva S, Yilmaz B, Martens L, Wullaert A (2017) NLRP6- and ASC-dependent inflammasomes do not shape the commensal gut microbiota composition. Immunity 47: 339–348. https://doi.org/10.1016/j.immuni.2017.07.011.
Milligan G, Shimpukade B, Ulven T, Hudson BD (2017) Complex pharmacology of free fatty acid receptors. Chem Rev 117: 67–110. https://doi.org/10.1021/acs.chemrev.6b00056.
Moser AM, Spindelboeck W, Strohmaier H, Enzinger C, Gattringer T, Fuchs S, Khalil M (2017) Mucosal biopsy shows immunologic changes of the colon in patients with early MS. Neurol - Neuroimmunol Neuroinflammation 4: e362. https://doi.org/10.1212/NXI.0000000000000362.
Nagpal R, Tsuji H, Takahashi T, Nomoto K, Kawashima K, Nagata S, Yamashiro Y (2017) Ontogenesis of the gut microbiota composition in healthy, full-term, vaginally born and breast-fed infants over the first 3 years of life: a quantitative bird’s-eye view. Front Microbiol 8: 1388. https://doi.org/10.3389/fmicb.2017.01388.
Nakajima A, Nakatani A, Hasegawa S, Irie J, Ozawa K, Tsujimoto G, Kimura I (2017) The short chain fatty acid receptor GPR43 regulates inflammatory signals in adipose tissue M2-type macrophages. PLoS One 12: e0179696. https://doi.org/10.1371/journal.pone.0179696.
Nakamura YK, Janowitz C, Metea C, Asquith M, Karstens L, Rosenbaum J T, Lin P (2017) Short chain fatty acids ameliorate immune-mediated uveitis partially by altering migration of lymphocytes from the intestine. Sci Rep 7: 11745. https://doi.org/10.1038/s41598-017-12163-3.
Nastasi C, Candela M, Bonefeld C M, Geisler C, Hansen M, Krejsgaard T, Woetmann A (2015) The effect of short-chain fatty acids on human monocyte-derived dendritic cells. Scientific Reports 5: 16148. https://doi.org/10.1038/srep16148.
Ohira H, Tsutsui W, Fujioka Y (2017) Are short chain fatty acids in gut microbiota defensive players for inflammation and atherosclerosis? Journal Atheroscler Thromb 24: 660–672. https://doi.org/10.5551/jat.RV17006.
Park J, Goergen CJ, HogenEsch H, Kim CH (2016) Chronically elevated levels of short-chain fatty acids induce t cell-mediated ureteritis and hydronephrosis. J Immunol 196: 2388–2400. https://doi.org/10.4049/jimmunol.1502046.
Park J, Kim M, Kang SG, Jannasch AH, Cooper B, Patterson J, Kim CH (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: 80–93. https://doi.org/10.1038/mi.2014.44.
Perry RJ, Peng L, Barry NA, Cline GW, Zhang D, Cardone RL, Shulman GI (2016) Acetate mediates a microbiome–brain–β-cell axis to promote metabolic syndrome. Nature 534: 213–217. https://doi.org/10.1038/nature18309.
Pluznick JL (2016) Gut microbiota in renal physiology: focus on short-chain fatty acids and their receptors. Kidney Int, 90: 1191–1198. https://doi.org/10.1016/j.kint.2016.06.033
Pluznick JL, Protzko RJ, Gevorgyan H, Peterlin Z, Sipos A, Han J, Caplan MJ (2013) Olfactory receptor responding to gut microbiota-derived signals plays a role in renin secretion and blood pressure regulation. Proc Natl Acad Sci 110: 4410–4415. https://doi.org/10.1073/pnas.1215927110.
Pryde SE, Duncan SH, Hold GL, Stewart CS, Flint HJ (2002) The microbiology of butyrate formation in the human colon. FEMS Microbiol Lett 217: 133–139. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/12480096.
Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, Wang J (2010) A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464: 59–65. https://doi.org/10.1038/nature08821.
Ragsdale SW, Pierce E (2008) Acetogenesis and the Wood–Ljungdahl pathway of CO2 fixation. Biochim Biophys Acta - Proteins Proteomics 1784: 1873–1898. https://doi.org/10.1016/j.bbapap.2008.08.012.
Ratsimandresy RA, Indramohan M, Dorfleutner A, Stehlik C (2017) The AIM2 inflammasome is a central regulator of intestinal homeostasis through the IL-18/IL-22/STAT3 pathway. Cell Mol Immunol 14: 127–142. https://doi.org/10.1038/cmi.2016.35.
Reichardt N, Duncan SH, Young P, Belenguer A, McWilliam Leitch C, Scott KP, Louis P (2014) Phylogenetic distribution of three pathways for propionate production within the human gut microbiota. ISME J 8: 1323–1335. https://doi.org/10.1038/ismej.2014.14
Rodríguez-Carrio J, Salazar N, Margolles A, González S, Gueimonde M, de Los Reyes-Gavilán CG, Suárez A (2017) Free fatty acids profiles are related to gut microbiota signatures and short-chain fatty acids. Front Immunol 8: 823. https://doi.org/10.3389/fimmu.2017.00823.
Rooks MG, Garrett WS (2016) Gut microbiota, metabolites and host immunity. Nat Rev Immunol 16: 341–352. https://doi.org/10.1038/nri.2016.42.
Sabari BR, Tang Z, Huang H, Yong-Gonzalez V, Molina H, Kong HE, Allis CD (2015) Intracellular crotonyl-coa stimulates transcription through p300-catalyzed histone crotonylation. Mol Cell 58: 203–215. https://doi.org/10.1016/j.molcel.2015.02.029.
Schwiertz A, Taras D, Schäfer K, Beijer S, Bos NA, Donus C, Hardt PD (2010) Microbiota and SCFA in Lean and Overweight Healthy Subjects. Obesity 18: 190–195. https://doi.org/10.1038/oby.2009.167.
Tramontano M, Andrejev S, Pruteanu M, Klünemann M, Kuhn M, Galardini M, Patil KR (2018) Nutritional preferences of human gut bacteria reveal their metabolic idiosyncrasies. Nat Microbiol 3: 514–522. https://doi.org/10.1038/s41564-018-0123-9
Vital M, Howe AC, Tiedje JM (2014) Revealing the bacterial butyrate synthesis pathways by analyzing (meta)genomic data. MBio 5: e00889. https://doi.org/10.1128/mBio.00889-14.
Xiong Y, Miyamoto N, Shibata K, Valasek MA, Motoike T, Kedzierski RM, Yanagisawa M (2004) Short-chain fatty acids stimulate leptin production in adipocytes through the G protein-coupled receptor GPR41. Proc Natl Acad Sci 101: 1045–1050. https://doi.org/10.1073/pnas.2637002100.
Xu M, Pokrovskii M, Ding Y, Yi R, Au C, Harrison OJ, Littman DR (2018) c-MAF-dependent regulatory T cells mediate immunological tolerance to a gut pathobiont. Nature 554: 373–377. https://doi.org/10.1038/nature25500.
Yuan X, Wang L, Bhat OM, Lohner H, Li PL (2018) Differential effects of short chain fatty acids on endothelial Nlrp3 inflammasome activation and neointima formation: Antioxidant action of butyrate. Redox Biol 16: 21–31. https://doi.org/10.1016/j.redox.2018.02.007.
Acta Biochimica Polonica is an OpenAccess quarterly and publishes four issues a year. All contents are distributed under the Creative Commons Attribution-ShareAlike 4.0 International (CC BY 4.0) license. Everybody may use the content following terms: Attribution — You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use.
Copyright for all published papers © stays with the authors.
Copyright for the journal: © Polish Biochemical Society.