Regulation of immune cell function by short-chain fatty acids

Renan Corrêa-Oliveira, José Luís Fachi, Aline Vieira, Fabio Takeo Sato, Marco Aurélio R Vinolo, Renan Corrêa-Oliveira, José Luís Fachi, Aline Vieira, Fabio Takeo Sato, Marco Aurélio R Vinolo

Abstract

Short-chain fatty acids (SCFAs) are bacterial fermentation products, which are chemically composed by a carboxylic acid moiety and a small hydrocarbon chain. Among them, acetic, propionic and butyric acids are the most studied, presenting, respectively, two, three and four carbons in their chemical structure. These metabolites are found in high concentrations in the intestinal tract, from where they are uptaken by intestinal epithelial cells (IECs). The SCFAs are partially used as a source of ATP by these cells. In addition, these molecules act as a link between the microbiota and the immune system by modulating different aspects of IECs and leukocytes development, survival and function through activation of G protein coupled receptors (FFAR2, FFAR3, GPR109a and Olfr78) and by modulation of the activity of enzymes and transcription factors including the histone acetyltransferase and deacetylase and the hypoxia-inducible factor. Considering that, it is not a surprise, the fact that these molecules and/or their targets are suggested to have an important role in the maintenance of intestinal homeostasis and that changes in components of this system are associated with pathological conditions including inflammatory bowel disease, obesity and others. The aim of this review is to present a clear and updated description of the effects of the SCFAs derived from bacteria on host immune system, as well as the molecular mechanisms involved on them.

Figures

Figure 1
Figure 1
Cellular signaling pathways activated by the short-chain fatty acids. These bacterial metabolites activate membrane receptors called GPCRs (as FFAR2, FFAR3, GPR109a and Olfr78). They are also able to reach the cytoplasm of the cells through transporters (Slc16a1 and Slc5a8) or passive diffusion across the plasma membrane (mainly, the non-ionized form) and they modulate the activity of several enzymes and transcription factors including the HIF, HDACs and histone acetyltransferase (HAT). SCFAs modify several cellular processes including gene expression, chemotaxis, differentiation, proliferation and apoptosis through these mechanisms.
Figure 2
Figure 2
The SCFAs are bacterial fermentation products found in high concentrations in the intestine. These metabolites act as a link between the microbiota and the immune system. IECs uptake SCFAs through passive (mainly, the non-ionized form) and active mechanisms. Once inside the cells, they are partially used as a source of energy (1). In addition, these SCFAs increase the expression of antimicrobial peptides secreted to the external surface by epithelial cells (2) and modulate their production of immune mediators including IL-18, a key cytokine for the repair and maintenance of epithelial integrity, and others cytokines and chemokines (3). SCFAs can also regulate the differentiation, recruitment and activation of immune cells: including neutrophil (4), DCs (5), macrophages (6) and T lymphocytes (7). In this context, SCFAs interact with neutrophils and modulate their recruitment, effector function and survival at the tissues (4). In general, these bacterial metabolites present anti-inflammatory effects including reduction of some pro-inflammatory cytokines such as TNF-α and IL-12 production by macrophages and DCs, and change their capacity to capture antigens and stimulate T cells. In addition, the SCFAs also modulate the proliferation and differentiation of T lymphocytes through direct effects on these cells (for example, inducing the generation of Tregs) (7).

References

    1. Brestoff JR, Artis D. Commensal bacteria at the interface of host metabolism and the immune system. Nat Immunol 2013; 14: 676–684.
    1. Sommer F, Backhed F. The gut microbiota—masters of host development and physiology. Nat Rev Microbiol 2013; 11: 227–238.
    1. Kamada N, Seo SU, Chen GY, Nunez G. Role of the gut microbiota in immunity and inflammatory disease. Nat Rev Immunol 2013; 13: 321–335.
    1. Trompette A, Gollwitzer ES, Yadava K, Sichelstiel AK, Sprenger N, Ngom-Bru C et al. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat Med 2014; 20: 159–166.
    1. Ferreira CM, Vieira AT, Vinolo MA, Oliveira FA, Curi R, Martins Fdos S. The central role of the gut microbiota in chronic inflammatory diseases. J Immunol Res 2014; 2014: 689492.
    1. Srinivasan S, Hoffman NG, Morgan MT, Matsen FA, Fiedler TL, Hall RW et al. Bacterial communities in women with bacterial vaginosis: high resolution phylogenetic analyses reveal relationships of microbiota to clinical criteria. PLoS ONE 2012; 7: e37818.
    1. Maslowski KM, Vieira AT, Ng A, Kranich J, Sierro F, Yu D et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 2009; 461: 1282–1286.
    1. Atarashi K, Nishimura J, Shima T, Umesaki Y, Yamamoto M, Onoue M et al. ATP drives lamina propria T(H)17 cell differentiation. Nature 2008; 455: 808–812.
    1. Wong JM, de Souza R, Kendall CW, Emam A, Jenkins DJ. Colonic health: fermentation and short chain fatty acids. J Clin Gastroenterol 2006; 40: 235–243.
    1. Lu XJ, Chen J, Yu CH, Shi YH, He YQ, Zhang RC et al. LECT2 protects mice against bacterial sepsis by activating macrophages via the CD209a receptor. J Exp Med 2013; 210: 5–13.
    1. Mirmonsef P, Gilbert D, Zariffard MR, Hamaker BR, Kaur A, Landay AL et al. The effects of commensal bacteria on innate immune responses in the female genital tract. Am J Reprod Immunol 2011; 65: 190–195.
    1. Donohoe DR, Collins LB, Wali A, Bigler R, Sun W, Bultman SJ. The warburg effect dictates the mechanism of butyrate-mediated histone acetylation and cell proliferation. Mol Cell 2012; 48: 612–626.
    1. Vinolo MA, Rodrigues HG, Nachbar RT, Curi R. Regulation of inflammation by short chain Fatty acids. Nutrients 2011; 3: 858–876.
    1. Vinolo MA, Hirabara SM, Curi R. G-protein-coupled receptors as fat sensors. Curr Opin Clin Nutr Metab Care 2012; 15: 112–116.
    1. Kelly CJ, Zheng L, Campbell EL, Saeedi B, Scholz CC, Bayless AJ et al. Crosstalk between microbiota-derived short-chain fatty acids and intestinal epithelial HIF augments tissue barrier function. Cell Host Microbe 2015; 17: 662–671.
    1. Pluznick J. A novel SCFA receptor, the microbiota, and blood pressure regulation. Gut Microbes 2014; 5: 202–207.
    1. Thangaraju M, Cresci GA, Liu K, Ananth S, Gnanaprakasam JP, Browning DD et al. GPR109A is a G-protein-coupled receptor for the bacterial fermentation product butyrate and functions as a tumor suppressor in colon. Cancer Res 2009; 69: 2826–2832.
    1. den Besten G, van Eunen K, Groen AK, Venema K, Reijngoud DJ, Bakker BM. The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. J Lipid Res 2013; 54: 2325–2340.
    1. Peterson LW, Artis D. Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat Rev Immunol 2014; 14: 141–153.
    1. Donohoe DR, Garge N, Zhang X, Sun W, O'Connell TM, Bunger MK et al. The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon. Cell Metab 2011; 13: 517–526.
    1. Comalada M, Bailon E, de Haro O, Lara-Villoslada F, Xaus J, Zarzuelo A et al. The effects of short-chain fatty acids on colon epithelial proliferation and survival depend on the cellular phenotype. J Cancer Res Clin Oncol 2006; 132: 487–497.
    1. Raqib R, Sarker P, Bergman P, Ara G, Lindh M, Sack DA et al. Improved outcome in shigellosis associated with butyrate induction of an endogenous peptide antibiotic. Proc Natl Acad Sci USA 2006; 103: 9178–9183.
    1. Raqib R, Sarker P, Mily A, Alam NH, Arifuzzaman AS, Rekha RS et al. Efficacy of sodium butyrate adjunct therapy in shigellosis: a randomized, double-blind, placebo-controlled clinical trial. BMC Infect Dis 2012; 12: 111.
    1. Zeng X, Sunkara LT, Jiang W, Bible M, Carter S, Ma X et al. Induction of porcine host defense peptide gene expression by short-chain fatty acids and their analogs. PLoS one 2013; 8: e72922.
    1. Sunkara LT, Jiang W, Zhang G. Modulation of antimicrobial host defense peptide gene expression by free fatty acids. PLoS ONE 2012; 7: e49558.
    1. Kim MH, Kang SG, Park JH, Yanagisawa M, Kim CH. Short-chain fatty acids activate GPR41 and GPR43 on intestinal epithelial cells to promote inflammatory responses in mice. Gastroenterology 2013; 145: 396–406 e391-310.
    1. Macia L, Tan J, Vieira AT, Leach K, Stanley D, Luong S et al. Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome. Nat Commun 2015; 6: 6734.
    1. Singh N, Gurav A, Sivaprakasam S, Brady E, Padia R, Shi H et al. Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity 2014; 40: 128–139.
    1. Iraporda C, Errea A, Romanin DE, Cayet D, Pereyra E, Pignataro O et al. Lactate and short chain fatty acids produced by microbial fermentation downregulate proinflammatory responses in intestinal epithelial cells and myeloid cells. Immunobiology 2015; 220: 1161–1169.
    1. Asarat M, Vasiljevic T, Apostolopoulos V, Donkor O. Short-chain fatty acids regulate secretion of IL-8 from human intestinal epithelial cell lines in vitro. Immunol Invest 2015; 44: 678–693.
    1. Kelly CJ, Glover LE, Campbell EL, Kominsky DJ, Ehrentraut SF, Bowers BE et al. Fundamental role for HIF-1alpha in constitutive expression of human beta defensin-1. Mucosal Immunol 2013; 6: 1110–1118.
    1. Saeedi BJ, Kao DJ, Kitzenberg DA, Dobrinskikh E, Schwisow KD, Masterson JC et al. HIF-dependent regulation of claudin-1 is central to intestinal epithelial tight junction integrity. Mol Biol Cell 2015; 26: 2252–2262.
    1. Rodrigues HG, Takeo Sato F, Curi R, Vinolo MA. Fatty acids as modulators of neutrophil recruitment, function and survival. Eur J Pharmacol, (e-pub ahead of print 15 May 2015; doi:10.1016/j.ejphar.2015.03.098).
    1. Vinolo MA, Rodrigues HG, Hatanaka E, Hebeda CB, Farsky SH, Curi R. Short-chain fatty acids stimulate the migration of neutrophils to inflammatory sites. Clin Sci (Lond) 2009; 117: 331–338.
    1. Vinolo MA, Rodrigues HG, Hatanaka E, Sato FT, Sampaio SC, Curi R. Suppressive effect of short-chain fatty acids on production of proinflammatory mediators by neutrophils. J Nutr Biochem 2011; 22: 849–855.
    1. Sina C, Gavrilova O, Forster M, Till A, Derer S, Hildebrand F et al. G protein-coupled receptor 43 is essential for neutrophil recruitment during intestinal inflammation. J Immunol 2009; 183: 7514–7522.
    1. Vinolo MA, Ferguson GJ, Kulkarni S, Damoulakis G, Anderson K, Bohlooly YM et al. SCFAs induce mouse neutrophil chemotaxis through the GPR43 receptor. PLoS ONE 2011; 6: e21205.
    1. Tedelind S, Westberg F, Kjerrulf M, Vidal A. Anti-inflammatory properties of the short-chain fatty acids acetate and propionate: a study with relevance to inflammatory bowel disease. World J Gastroenterol 2007; 13: 2826–2832.
    1. Mirmonsef P, Zariffard MR, Gilbert D, Makinde H, Landay AL, Spear GT. Short-chain fatty acids induce pro-inflammatory cytokine production alone and in combination with toll-like receptor ligands. Am J Reprod Immunol 2012; 67: 391–400.
    1. Cox MA, Jackson J, Stanton M, Rojas-Triana A, Bober L, Laverty M et al. Short-chain fatty acids act as antiinflammatory mediators by regulating prostaglandin E(2) and cytokines. World J Gastroenterol 2009; 15: 5549–5557.
    1. Bailon E, Cueto-Sola M, Utrilla P, Rodriguez-Cabezas ME, Garrido-Mesa N, Zarzuelo A et al. Butyrate in vitro immune-modulatory effects might be mediated through a proliferation-related induction of apoptosis. Immunobiology 2010; 215: 863–873.
    1. Liu L, Li L, Min J, Wang J, Wu H, Zeng Y et al. Butyrate interferes with the differentiation and function of human monocyte-derived dendritic cells. Cell Immunol 2012; 277: 66–73.
    1. Vinolo MA, Rodrigues H, Festuccia WT, Crisma A, Alves V, Martins A et al. Tributyrin attenuates obesity-associated inflammation and insulin resistance in high-fat fed mice. Am J Physiol Endocrinol Metab 2012; 303: E272–E282.
    1. Maa MC, Chang MY, Hsieh MY, Chen YJ, Yang CJ, Chen ZC et al. Butyrate reduced lipopolysaccharide-mediated macrophage migration by suppression of Src enhancement and focal adhesion kinase activity. J Nutr Biochem 2010; 21: 1186–1192.
    1. Chang PV, Hao L, Offermanns S, Medzhitov R. The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition. Proc Natl Acad Sci USA 2014; 111: 2247–2252.
    1. Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA, Bohlooly YM et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 2013; 341: 569–573.
    1. Schauber J, Svanholm C, Termen S, Iffland K, Menzel T, Scheppach W et al. Expression of the cathelicidin LL-37 is modulated by short chain fatty acids in colonocytes: relevance of signalling pathways. Gut 2003; 52: 735–741.
    1. Ochoa-Zarzosa A, Villarreal-Fernandez E, Cano-Camacho H, Lopez-Meza JE. Sodium butyrate inhibits Staphylococcus aureus internalization in bovine mammary epithelial cells and induces the expression of antimicrobial peptide genes. Microb Pathog 2009; 47: 1–7.
    1. Sunkara LT, Achanta M, Schreiber NB, Bommineni YR, Dai G, Jiang W et al. Butyrate enhances disease resistance of chickens by inducing antimicrobial host defense peptide gene expression. PLoS One 2011; 6: e27225.
    1. Millard AL, Mertes PM, Ittelet D, Villard F, Jeannesson P, Bernard J. Butyrate affects differentiation, maturation and function of human monocyte-derived dendritic cells and macrophages. Clin Exp Immunol 2002; 130: 245–255.
    1. Berndt BE, Zhang M, Owyang SY, Cole TS, Wang TW, Luther J et al. Butyrate increases IL-23 production by stimulated dendritic cells. Am J Physiol Gastrointest Liver Physiol 2012; 303: G1384–G1392.
    1. Andrade-Oliveira V, Amano MT, Correa-Costa M, Castoldi A, Felizardo RJ, de Almeida DC et al. Gut bacteria products prevent AKI induced by ischemia-reperfusion. J Am Soc Nephrol 2015; 26: 1877–1888.
    1. Singh N, Thangaraju M, Prasad PD, Martin PM, Lambert NA, Boettger T et al. Blockade of dendritic cell development by bacterial fermentation products butyrate and propionate through a transporter (Slc5a8)-dependent inhibition of histone deacetylases. J Biol Chem 2010; 285: 27601–27608.
    1. Gurav A, Sivaprakasam S, Bhutia YD, Boettger T, Singh N, Ganapathy V. Slc5a8, a Na+-coupled high-affinity transporter for short-chain fatty acids, is a conditional tumour suppressor in colon that protects against colitis and colon cancer under low-fibre dietary conditions. Biochem J 2015; 469: 267–278.
    1. Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J, deRoos P et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 2013; 504: 451–455.
    1. Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G, Takahashi D et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 2013; 504: 446–450.
    1. Thorburn AN, McKenzie CI, Shen S, Stanley D, Macia L, Mason LJ et al. Evidence that asthma is a developmental origin disease influenced by maternal diet and bacterial metabolites. Nat Commun 2015; 6: 7320.
    1. Park J, Kim M, Kang SG, Jannasch AH, Cooper B, Patterson J et al. 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 2015; 8: 80–93.
    1. Zimmerman MA, Singh N, Martin PM, Thangaraju M, Ganapathy V, Waller JL et al. Butyrate suppresses colonic inflammation through HDAC1-dependent Fas upregulation and Fas-mediated apoptosis of T cells. Am J Physiol Gastrointest Liver Physiol 2012; 302: G1405–G1415.
    1. Park J, Goergen CJ, HogenEsch H, Kim CH. Chronically elevated levels of short-chain fatty acids induce T cell-mediated ureteritis and hydronephrosis. J Immunol 2016; 196: 2388–2400.

Source: PubMed

Sponsorer och medarbetare

Medicinska tillstånd

Läkemedelsinterventioner

3
Prenumerera