Browse > Article
http://dx.doi.org/10.4110/in.2014.14.6.277

Gut Microbiota-Derived Short-Chain Fatty Acids, T Cells, and Inflammation  

Kim, Chang H. (Laboratory of Immunology and Hematopoiesis, Department of Comparative Pathobiology, Purdue Veterinary Medicine, Weldon School of Biomedical Engineering, Center for Cancer Research, Purdue University)
Park, Jeongho (Laboratory of Immunology and Hematopoiesis, Department of Comparative Pathobiology, Purdue Veterinary Medicine, Weldon School of Biomedical Engineering, Center for Cancer Research, Purdue University)
Kim, Myunghoo (Laboratory of Immunology and Hematopoiesis, Department of Comparative Pathobiology, Purdue Veterinary Medicine, Weldon School of Biomedical Engineering, Center for Cancer Research, Purdue University)
Publication Information
IMMUNE NETWORK / v.14, no.6, 2014 , pp. 277-288 More about this Journal
Abstract
T cells are central players in the regulation of adaptive immunity and immune tolerance. In the periphery, T cell differentiation for maturation and effector function is regulated by a number of factors. Various factors such as antigens, co-stimulation signals, and cytokines regulate T cell differentiation into functionally specialized effector and regulatory T cells. Other factors such as nutrients, micronutrients, nuclear hormones and microbial products provide important environmental cues for T cell differentiation. A mounting body of evidence indicates that the microbial metabolites short-chain fatty acids (SCFAs) have profound effects on T cells and directly and indirectly regulate their differentiation. We review the current status of our understanding of SCFA functions in regulation of peripheral T cell activity and discuss their impact on tissue inflammation.
Keywords
Short-chain fatty acids; Th1; Th17; IL-10; FoxP3; Microbiota; Inflammation; Colitis; Microbial metabolites;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Liu, X., R. I. Nurieva, and C. Dong. 2013. Transcriptional regulation of follicular T-helper (Tfh) cells. Immunol. Rev. 252: 139-145.   DOI
2 Tripathi, S. K. and R. Lahesmaa. 2014. Transcriptional and epigenetic regulation of T-helper lineage specification. Immunol. Rev. 261: 62-83.   DOI
3 Bonelli, M., H. Y. Shih, K. Hirahara, K. Singelton, A. Laurence, A. Poholek, T. Hand, Y. Mikami, G. Vahedi, Y. Kanno, and J. J. O'Shea. 2014. Helper T cell plasticity: impact of extrinsic and intrinsic signals on transcriptomes and epigenomes. Curr. Top. Microbiol. Immunol. 381: 279-326.
4 Man, K., M. Miasari, W. Shi, A. Xin, D. C. Henstridge, S. Preston, M. Pellegrini, G. T. Belz, G. K. Smyth, M. A. Febbraio, S. L. Nutt, and A. Kallies. 2013. The transcription factor IRF4 is essential for TCR affinity-mediated metabolic programming and clonal expansion of T cells. Nat. Immunol. 14: 1155-1165.   DOI
5 Nakayama, T., and M. Yamashita. 2010. The TCR-mediated signaling pathways that control the direction of helper T cell differentiation. Semin. Immunol. 22: 303-309.   DOI
6 Nurieva, R. I., X. Liu, and C. Dong. 2009. Yin-Yang of costimulation: crucial controls of immune tolerance and function. Immunol. Rev. 229: 88-100.   DOI
7 Ishii N., T. Takahashi, P. Soroosh, and K. Sugamura. 2010. OX40-OX40 ligand interaction in T-cell-mediated immunity and immunopathology. Adv. Immunol. 105: 63-98.   DOI
8 Ford, M. L., and C. P. Larsen. 2009. Translating costimulation blockade to the clinic: lessons learned from three pathways. Immunol. Rev. 229: 294-306.   DOI
9 Nicolaou, A., C. Mauro, P. Urquhart, and F. Marelli-Berg. 2014. Polyunsaturated Fatty Acid-derived lipid mediators and T cell function. Front Immunol. 5: 75.
10 Arpaia, N., C. Campbell, X. Fan, S. Dikiy, d. van, V, P. deRoos, H. Liu, J. R. Cross, K. Pfeffer, P. J. Coffer, and A. Y. Rudensky. 2013. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504: 451-455.   DOI   ScienceOn
11 Kang, S. G., H. W. Lim, O. M. Andrisani, H. E. Broxmeyer, and C. H. Kim. 2007. Vitamin A metabolites induce gut-homing $FoxP3^+$ regulatory T cells. J. Immunol. 179: 3724-3733.   DOI
12 Mucida, D., Y. Park, G. Kim, O. Turovskaya, I. Scott, M. Kronenberg, and H. Cheroutre. 2007. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317: 256-260.   DOI   ScienceOn
13 Park, J., M. Kim, S. G. Kang, A. H. Jannasch, B. Cooper, J. Patterson, and C. H. Kim. 2014. 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. doi: 10.1038/mi.2014.44.
14 Smith, P. M., M. R. Howitt, N. Panikov, M. Michaud, C. A. Gallini, Y. Bohlooly, J. N. Glickman, and W. S. Garrett. 2013. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341: 569-573.   DOI   ScienceOn
15 Furusawa, Y., Y. Obata, S. Fukuda, T. A. Endo, G. Nakato, D. Takahashi, Y. Nakanishi, C. Uetake, K. Kato, T. Kato, M. Takahashi, N. N. Fukuda, S. Murakami, E. Miyauchi, S. Hino, K. Atarashi, S. Onawa, Y. Fujimura, T. Lockett, J. M. Clarke, D. L. Topping, M. Tomita, S. Hori, O. Ohara, T. Morita, H. Koseki, J. Kikuchi, K. Honda, K. Hase, and H. Ohno. 2013. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504: 446-450.   DOI   ScienceOn
16 Macfarlane, S., and G. T. Macfarlane. 2003. Regulation of short-chain fatty acid production. Proc. Nutr. Soc. 62: 67-72.   DOI
17 Reichardt, N., S. H. Duncan, P. Young, A. Belenguer, L. C. McWilliam, K. P. Scott, H. J. Flint, and P. Louis. 2014. Phylogenetic distribution of three pathways for propionate production within the human gut microbiota. ISME. J. 8: 1323-1335.   DOI
18 Barcenilla, A., S. E. Pryde, J. C. Martin, S. H. Duncan, C. S. Stewart, C. Henderson, and H. J. Flint. 2000. Phylogenetic relationships of butyrate-producing bacteria from the human gut. Appl. Environ. Microbiol. 66: 1654-1661.   DOI
19 Charrier, C., G. J. Duncan, M. D. Reid, G. J. Rucklidge, D. Henderson, P. Young, V. J. Russell, R. I. Aminov, H. J. Flint, and P. Louis. 2006. A novel class of CoA-transferase involved in short-chain fatty acid metabolism in butyrate-producing human colonic bacteria. Microbiology 152: 179-185.   DOI
20 Miller, T. L., and M. J. Wolin. 1996. Pathways of acetate, propionate, and butyrate formation by the human fecal microbial flora. Appl. Environ. Microbiol. 62: 1589-1592.
21 Louis, P., G. L. Hold, and H. J. Flint. 2014. The gut microbiota, bacterial metabolites and colorectal cancer. Nat. Rev. Microbiol. 12: 661-672.   DOI
22 Miyauchi, S., E. Gopal, Y. J. Fei, and V. Ganapathy. 2004. Functional identification of SLC5A8, a tumor suppressor down-regulated in colon cancer, as a Na(+)-coupled transporter for short-chain fatty acids. J. Biol. Chem. 279: 13293-13296.   DOI
23 Yanase, H., K. Takebe, J. Nio-Kobayashi, H. Takahashi-Iwanaga, and T. Iwanaga. 2008. Cellular expression of a sodium-dependent monocarboxylate transporter (Slc5a8) and the MCT family in the mouse kidney. Histochem. Cell Biol. 130: 957-966.   DOI
24 Halestrap, A. P., X. Wang, R. C. Poole, V. N. Jackson, and N. T. Price. 1997. Lactate transport in heart in relation to myocardial ischemia. Am. J. Cardiol. 80: 17A-25A.   DOI
25 Kim, M. H., S. G. Kang, J. H. Park, M. Yanagisawa, and C. H. Kim. 2013. Short-chain fatty acids activate GPR41 and GPR43 on intestinal epithelial cells to promote inflammatory responses in mice. Gastroenterology 145: 396-406.   DOI
26 Eberle, J. A., P. Widmayer, and H. Breer. 2014. Receptors for short-chain fatty acids in brush cells at the "gastric groove". Front Physiol. 5: 152.
27 Tazoe, H., Y. Otomo, S. Karaki, I. Kato, Y. Fukami, M. Terasaki, and A. Kuwahara. 2009. Expression of short-chain fatty acid receptor GPR41 in the human colon. Biomed. Res. 30: 149-156.   DOI
28 Nohr, M. K., M. H. Pedersen, A. Gille, K. L. Egerod, M. S. Engelstoft, A. S. Husted, R. M. Sichlau, K. V. Grunddal, S. S. Poulsen, S. Han, R. M. Jones, S. Offermanns, and T. W. Schwartz. 2013. GPR41/FFAR3 and GPR43/FFAR2 as co-sensors for short-chain fatty acids in enteroendocrine cells vs FFAR3 in enteric neurons and FFAR2 in enteric leukocytes. Endocrinology 154: 3552-3564.   DOI
29 Wang, A., R. M. Akers, and H. Jiang. 2012. Short communication: Presence of G protein-coupled receptor 43 in rumen epithelium but not in the islets of Langerhans in cattle. J. Dairy Sci. 95: 1371-1375.   DOI
30 Zaibi, M. S., C. J. Stocker, J. O'Dowd, A. Davies, M. Bellahcene, M. A. Cawthorne, A. J. Brown, D. M. Smith, and J. R. Arch. 2010. Roles of GPR41 and GPR43 in leptin secretory responses of murine adipocytes to short chain fatty acids. FEBS Lett. 584: 2381-2386.   DOI
31 Bahar, H. K., A. Veprik, N. Rubins, O. Naaman, and M. D. Walker. 2012. GPR41 gene expression is mediated by internal ribosome entry site (IRES)-dependent translation of bicistronic mRNA encoding GPR40 and GPR41 proteins. J. Biol. Chem. 287: 20154-20163.   DOI
32 Pluznick, J. L., R. J. Protzko, H. Gevorgyan, Z. Peterlin, A. Sipos, J. Han, I. Brunet, L. X. Wan, F. Rey, T. Wang, S. J. Firestein, M. Yanagisawa, J. I. Gordon, A. Eichmann, J. Peti-Peterdi, and M. J. Caplan. 2013. Olfactory receptor responding to gut microbiota-derived signals plays a role in renin secretion and blood pressure regulation. Proc. Natl. Acad. Sci. U. S. A. 110: 4410-4415.   DOI
33 Sina, C., O. Gavrilova, M. Forster, A. Till, S. Derer, F. Hildebrand, B. Raabe, A. Chalaris, J. Scheller, A. Rehmann, A. Franke, S. Ott, R. Hasler, S. Nikolaus, U. R. Folsch, S. Rose-John, H. P. Jiang, J. Li, S. Schreiber, and P. Rosenstiel. 2009. G protein-coupled receptor 43 is essential for neutrophil recruitment during intestinal inflammation. J. Immunol. 183: 7514-7522.   DOI   ScienceOn
34 Voltolini, C., S. Battersby, S. L. Etherington, F. Petraglia, J. E. Norman, and H. N. Jabbour. 2012. A novel antiinflammatory role for the short-chain fatty acids in human labor. Endocrinology 153: 395-403.   DOI
35 Thangaraju, M., G. A. Cresci, K. Liu, S. Ananth, J. P. Gnanaprakasam, D. D. Browning, J. D. Mellinger, S. B. Smith, G. J. Digby, N. A. Lambert, P. D. Prasad, and V. Ganapathy. 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: 2826-2832.   DOI   ScienceOn
36 Zoller, H. F., and W. M. Clark. 1921. The production of volatile fatty acids by bacteria of the dysentery group. J. Gen. Physiol. 3: 325-330.   DOI
37 Topping, D. L., and P. M. Clifton. 2001. Short-chain fatty acids and human colonic function: roles of resistant starch and nonstarch polysaccharides. Physiol. Rev. 81: 1031-1064.   DOI
38 Finnie, I. A., A. D. Dwarakanath, B. A. Taylor, and J. M. Rhodes. 1995. Colonic mucin synthesis is increased by sodium butyrate. Gut 36: 93-99.   DOI
39 Tazoe, H., Y. Otomo, I. Kaji, R. Tanaka, S. I. Karaki, and A. Kuwahara. 2008. Roles of short-chain fatty acids receptors, GPR41 and GPR43 on colonic functions. J. Physiol. Pharmacol. 59 Suppl 2: 251-262.
40 Tan, J., C. McKenzie, M. Potamitis, A. N. Thorburn, C. R. Mackay, and L. Macia. 2014. The role of short-chain fatty acids in health and disease. Adv. Immunol. 121: 91-119.   DOI
41 Wang, A., Z. Gu, B. Heid, R. M. Akers, and H. Jiang. 2009. Identification and characterization of the bovine G protein-coupled receptor GPR41 and GPR43 genes. J. Dairy Sci. 92: 2696-2705.   DOI
42 Le, P. E., C. Loison, S. Struyf, J. Y. Springael, V. Lannoy, M. E. Decobecq, S. Brezillon, V. Dupriez, G. Vassart, D. J. Van, M. Parmentier, and M. Detheux. 2003. Functional characterization of human receptors for short chain fatty acids and their role in polymorphonuclear cell activation. J. Biol. Chem. 278: 25481-25489.   DOI   ScienceOn
43 Cani, P. D., A. Everard, and T. Duparc. 2013. Gut microbiota, enteroendocrine functions and metabolism. Curr. Opin. Pharmacol. 13: 935-940.   DOI
44 Licciardi, P. V., K. Ververis, and T. C. Karagiannis. 2011. Histone deacetylase inhibition and dietary short-chain Fatty acids. ISRN. Allergy 2011: 869647.
45 Yin, L., G. Laevsky, and C. Giardina. 2001. Butyrate suppression of colonocyte NF-kappa B activation and cellular proteasome activity. J. Biol. Chem. 276: 44641-44646.   DOI
46 Eftimiadi, C., E. Buzzi, M. Tonetti, P. Buffa, D. Buffa, M. T. van Steenbergen, G. J. de, and G. A. Botta. 1987. Short-chain fatty acids produced by anaerobic bacteria alter the physiological responses of human neutrophils to chemotactic peptide. J. Infect. 14: 43-53.   DOI
47 Carretta, M. D., I. Conejeros, M. A. Hidalgo, and R. A. Burgos. 2013. Propionate induces the release of granules from bovine neutrophils. J. Dairy Sci. 96: 2507-2520.   DOI
48 Kendrick, S. F., G. O'Boyle, J. Mann, M. Zeybel, J. Palmer, D. E. Jones, and C. P. Day. 2010. Acetate, the key modulator of inflammatory responses in acute alcoholic hepatitis. Hepatology 51: 1988-1997.   DOI
49 Luhrs, H., T. Gerke, J. G. Muller, R. Melcher, J. Schauber, F. Boxberge, W. Scheppach, and T. Menzel. 2002. Butyrate inhibits NF-kappaB activation in lamina propria macrophages of patients with ulcerative colitis. Scand. J. Gastroenterol. 37: 458-466.   DOI
50 Park, J. S., E. J. Lee, J. C. Lee, W. K. Kim, and H. S. Kim. 2007. Anti-inflammatory effects of short chain fatty acids in IFN-gamma-stimulated RAW 264.7 murine macrophage cells: involvement of NF-kappaB and ERK signaling pathways. Int. Immunopharmacol. 7: 70-77.   DOI   ScienceOn
51 Arora, T., R. Sharma, and G. Frost. 2011. Propionate. Anti-obesity and satiety enhancing factor? Appetite 56: 511-515.   DOI
52 Hong, Y. H., Y. Nishimura, D. Hishikawa, H. Tsuzuki, H. Miyahara, C. Gotoh, K. C. Choi, D. D. Feng, C. Chen, H. G. Lee, K. Katoh, S. G. Roh, and S. Sasaki. 2005. Acetate and propionate short chain fatty acids stimulate adipogenesis via GPCR43. Endocrinology 146: 5092-5099.   DOI   ScienceOn
53 Ge, H., X. Li, J. Weiszmann, P. Wang, H. Baribault, J. L. Chen, H. Tian, and Y. Li. 2008. Activation of G protein-coupled receptor 43 in adipocytes leads to inhibition of lipolysis and suppression of plasma free fatty acids. Endocrinology 149: 4519-4526.   DOI   ScienceOn
54 Kimura, I., D. Inoue, T. Maeda, T. Hara, A. Ichimura, S. Miyauchi, M. Kobayashi, A. Hirasawa, and G. Tsujimoto. 2011. Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41). Proc. Natl. Acad. Sci. U. S. A. 108: 8030-8035.   DOI
55 Nancey, S., J. Bienvenu, B. Coffin, F. Andre, L. Descos, and B. Flourie. 2002. Butyrate strongly inhibits in vitro stimulated release of cytokines in blood. Dig. Dis. Sci. 47: 921-928.   DOI   ScienceOn
56 Delgoffe, G. M., T. P. Kole, Y. Zheng, P. E. Zarek, K. L. Matthews, B. Xiao, P. F. Worley, S. C. Kozma, and J. D. Powell. 2009. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 30: 832-844.   DOI
57 Cavaglieri, C. R., A. Nishiyama, L. C. Fernandes, R. Curi, E. A. Miles, and P. C. Calder. 2003. Differential effects of short-chain fatty acids on proliferation and production of pro- and anti-inflammatory cytokines by cultured lymphocytes. Life Sci. 73: 1683-1690.   DOI   ScienceOn
58 Zimmerman, M. A., N. Singh, P. M. Martin, M. Thangaraju, V. Ganapathy, J. L. Waller, H. Shi, K. D. Robertson, D. H. Munn, and K. Liu. 2012. Butyrate suppresses colonic inflammation through HDAC1-dependent Fas upregulation and Fas-mediated apoptosis of T cells. Am. J. Physiol. Gastrointest. Liver Physiol. 302: G1405-G1415.   DOI
59 Dennis, P. B., A. Jaeschke, M. Saitoh, B. Fowler, S. C. Kozma, and G. Thomas. 2001. Mammalian TOR: a homeostatic ATP sensor. Science 294: 1102-1105.   DOI   ScienceOn
60 Chen, S., D. Liu, J. Wu, B. Xu, K. Lu, W. Zhu, and M. Chen. 2014. Effect of inhibiting the signal of mammalian target of rapamycin on memory T cells. Transplant. Proc. 46: 1642-1648.   DOI
61 Hinnebusch, B. F., S. Meng, J. T. Wu, S. Y. Archer, and R. A. Hodin. 2002. The effects of short-chain fatty acids on human colon cancer cell phenotype are associated with histone hyperacetylation. J. Nutr. 132: 1012-1017.   DOI
62 Yu, X., A. M. Shahir, J. Sha, Z. Feng, B. Eapen, S. Nithianantham, B. Das, J. Karn, A. Weinberg, N. F. Bissada, and F. Ye. 2014. Short-chain fatty acids from periodontal pathogens suppress histone deacetylases, EZH2, and SUV39H1 to promote Kaposi's sarcoma-associated herpesvirus replication. J. Virol. 88: 4466-4479.   DOI
63 Fenton, T. R., J. Gwalter, J. Ericsson, and I. T. Gout. 2010. Histone acetyltransferases interact with and acetylate p70 ribosomal S6 kinases in vitro and in vivo. Int. J. Biochem. Cell Biol. 42: 359-366.   DOI
64 Berndt, B. E., M. Zhang, S. Y. Owyang, T. S. Cole, T. W. Wang, J. Luther, N. A. Veniaminova, J. L. Merchant, C. C. Chen, G. B. Huffnagle, and J. Y. Kao. 2012. Butyrate increases IL-23 production by stimulated dendritic cells. Am. J. Physiol. Gastrointest. Liver Physiol. 303: G1384-G1392.   DOI
65 Singh, N., M. Thangaraju, P. D. Prasad, P. M. Martin, N. A. Lambert, T. Boettger, S. Offermanns, and V. Ganapathy. 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: 27601-27608.   DOI
66 Wang, B., A. Morinobu, M. Horiuchi, J. Liu, and S. Kumagai. 2008. Butyrate inhibits functional differentiation of human monocyte-derived dendritic cells. Cell Immunol. 253: 54-58.   DOI
67 Nascimento, C. R., C. G. Freire-de-Lima, O. A. da Silva de, F. D. Rumjanek, and V. M. Rumjanek. 2011. The short chain fatty acid sodium butyrate regulates the induction of CD1a in developing dendritic cells. Immunobiology 216: 275-284.   DOI
68 Frikeche, J., T. Simon, E. Brissot, M. Gregoire, B. Gaugler, and M. Mohty. 2012. Impact of valproic acid on dendritic cells function. Immunobiology 217: 704-710.   DOI
69 Singh, N., A. Gurav, S. Sivaprakasam, E. Brady, R. Padia, H. Shi, M. Thangaraju, P. D. Prasad, S. Manicassamy, D. H. Munn, J. R. Lee, S. Offermanns, and V. Ganapathy. 2014. Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity 40: 128-139.   DOI
70 Ananthakrishnan, A. N., H. Khalili, G. G. Konijeti, L. M. Higuchi, S. P. de, J. R. Korzenik, C. S. Fuchs, W. C. Willett, J. M. Richter, and A. T. Chan. 2013. A prospective study of long-term intake of dietary fiber and risk of Crohn's disease and ulcerative colitis. Gastroenterology 145: 970-977.   DOI   ScienceOn
71 Maslowski, K. M., A. T. Vieira, A. Ng, J. Kranich, F. Sierro, D. Yu, H. C. Schilter, M. S. Rolph, F. Mackay, D. Artis, R. J. Xavier, M. M. Teixeira, and C. R. Mackay. 2009. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 461: 1282-1286.   DOI   ScienceOn
72 Hou, J. K., B. Abraham, and H. El-Serag. 2011. Dietary intake and risk of developing inflammatory bowel disease: a systematic review of the literature. Am. J. Gastroenterol. 106: 563-573.   DOI
73 Vieira, E. L., A. J. Leonel, A. P. Sad, N. R. Beltrao, T. F. Costa, T. M. Ferreira, A. C. Gomes-Santos, A. M. Faria, M. C. Peluzio, D. C. Cara, and J. I. varez-Leite. 2012. Oral administration of sodium butyrate attenuates inflammation and mucosal lesion in experimental acute ulcerative colitis. J. Nutr. Biochem. 23: 430-436.   DOI   ScienceOn
74 Tarrerias, A. L., M. Millecamps, A. Alloui, C. Beaughard, J. L. Kemeny, S. Bourdu, G. Bommelaer, A. Eschalier, M. Dapoigny, and D. Ardid. 2002. Short-chain fatty acid enemas fail to decrease colonic hypersensitivity and inflammation in TNBS-induced colonic inflammation in rats. Pain 100: 91-97.   DOI
75 Masui, R., M. Sasaki, Y. Funaki, N. Ogasawara, M. Mizuno, A. Iida, S. Izawa, Y. Kondo, Y. Ito, Y. Tamura, K. Yanamoto, H. Noda, A. Tanabe, N. Okaniwa, Y. Yamaguchi, T. Iwamoto, and K. Kasugai. 2013. G protein-coupled receptor 43 moderates gut inflammation through cytokine regulation from mononuclear cells. Inflamm. Bowel. Dis. 19: 2848-2856.   DOI
76 Hamer, H. M., D. M. Jonkers, S. A. Vanhoutvin, F. J. Troost, G. Rijkers, B. A. de, A. Bast, K. Venema, and R. J. Brummer. 2010. Effect of butyrate enemas on inflammation and antioxidant status in the colonic mucosa of patients with ulcerative colitis in remission. Clin. Nutr. 29: 738-744.   DOI
77 Scheppach, W., H. Sommer, T. Kirchner, G. M. Paganelli, P. Bartram, S. Christl, F. Richter, G. Dusel, and H. Kasper. 1992. Effect of butyrate enemas on the colonic mucosa in distal ulcerative colitis. Gastroenterology 103: 51-56.   DOI
78 Steinhart, A. H., T. Hiruki, A. Brzezinski, and J. P. Baker. 1996. Treatment of left-sided ulcerative colitis with butyrate enemas: a controlled trial. Aliment. Pharmacol. Ther. 10: 729-736.   DOI
79 Vernia, P., G. Monteleone, G. Grandinetti, G. Villotti, G. E. Di, G. Frieri, A. Marcheggiano, F. Pallone, R. Caprilli, and A. Torsoli. 2000. Combined oral sodium butyrate and mesalazine treatment compared to oral mesalazine alone in ulcerative colitis: randomized, double-blind, placebo-controlled pilot study. Dig. Dis. Sci. 45: 976-981.   DOI
80 Di, S. A., R. Morera, R. Ciccocioppo, P. Cazzola, S. Gotti, F. P. Tinozzi, S. Tinozzi, and G. R. Corazza. 2005. Oral butyrate for mildly to moderately active Crohn's disease. Aliment. Pharmacol. Ther. 22: 789-794.   DOI   ScienceOn
81 Trompette, A., E. S. Gollwitzer, K. Yadava, A. K. Sichelstiel, N. Sprenger, C. Ngom-Bru, C. Blanchard, T. Junt, L. P. Nicod, N. L. Harris, and B. J. Marsland. 2014. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat. Med. 20: 159-166.   DOI
82 Hadjiagapiou, C., L. Schmidt, P. K. Dudeja, T. J. Layden, and K. Ramaswamy. 2000. Mechanism(s) of butyrate transport in Caco-2 cells: role of monocarboxylate transporter 1. Am. J. Physiol. Gastrointest. Liver Physiol. 279: G775-G780.   DOI
83 Alrefai, W. A., S. Tyagi, R. Gill, S. Saksena, C. Hadjiagapiou, F. Mansour, K. Ramaswamy, and P. K. Dudeja. 2004. Regulation of butyrate uptake in Caco-2 cells by phorbol 12-myristate 13-acetate. Am. J. Physiol. Gastrointest. Liver Physiol. 286: G197-G203.   DOI
84 Ritzhaupt, A., A. Ellis, K. B. Hosie, and S. P. Shirazi-Beechey. 1998. The characterization of butyrate transport across pig and human colonic luminal membrane. J. Physiol. 507(Pt 3): 819-830.   DOI
85 Martin, P. M., Y. Dun, B. Mysona, S. Ananth, P. Roon, S. B. Smith, and V. Ganapathy. 2007. Expression of the sodium-coupled monocarboxylate transporters SMCT1 (SLC5A8) and SMCT2 (SLC5A12) in retina. Invest. Ophthalmol. Vis. Sci. 48: 3356-3363.   DOI
86 Gopal, E., Y. J. Fei, S. Miyauchi, L. Zhuang, P. D. Prasad, and V. Ganapathy. 2005. Sodium-coupled and electrogenic transport of B-complex vitamin nicotinic acid by slc5a8, a member of the Na/glucose co-transporter gene family. Biochem. J. 388: 309-316.   DOI
87 Miyauchi, S., E. Gopal, E. Babu, S. R. Srinivas, Y. Kubo, N. S. Umapathy, S. V. Thakkar, V. Ganapathy, and P. D. Prasad. 2010. Sodium-coupled electrogenic transport of pyroglutamate (5-oxoproline) via SLC5A8, a monocarboxylate transporter. Biochim. Biophys. Acta 1798: 1164-1171.   DOI
88 Thangaraju, M., G. Cresci, S. Itagaki, J. Mellinger, D. D. Browning, F. G. Berger, P. D. Prasad, and V. Ganapathy. 2008. Sodium-coupled transport of the short chain fatty acid butyrate by SLC5A8 and its relevance to colon cancer. J. Gastrointest. Surg. 12: 1773-1781.   DOI
89 Martin, P. M., E. Gopal, S. Ananth, L. Zhuang, S. Itagaki, B. M. Prasad, S. B. Smith, P. D. Prasad, and V. Ganapathy. 2006. Identity of SMCT1 (SLC5A8) as a neuron-specific $Na^+$-coupled transporter for active uptake of L-lactate and ketone bodies in the brain. J. Neurochem. 98: 279-288.   DOI
90 Tolhurst, G., H. Heffron, Y. S. Lam, H. E. Parker, A. M. Habib, E. Diakogiannaki, J. Cameron, J. Grosse, F. Reimann, and F. M. Gribble. 2012. Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes 61: 364-371.   DOI   ScienceOn
91 Hong, Y. H., Y. Nishimura, D. Hishikawa, H. Tsuzuki, H. Miyahara, C. Gotoh, K. C. Choi, D. D. Feng, C. Chen, H. G. Lee, K. Katoh, S. G. Roh, and S. Sasaki. 2005. Acetate and propionate short chain fatty acids stimulate adipogenesis via GPCR43. Endocrinology 146: 5092-5099.   DOI   ScienceOn
92 Nilsson, N. E., K. Kotarsky, C. Owman, and B. Olde. 2003. Identification of a free fatty acid receptor, FFA2R, expressed on leukocytes and activated by short-chain fatty acids. Biochem. Biophys. Res. Commun. 303: 1047-1052.   DOI   ScienceOn
93 Heinonen, K. M. and C. Perreault. 2008. Development and functional properties of thymic and extrathymic T lymphocytes. Crit. Rev. Immunol. 28: 441-466.   DOI
94 Bhandoola, A., B. H. von, H. T. Petrie, and J. C. Zuniga-Pflucker. 2007. Commitment and developmental potential of extrathymic and intrathymic T cell precursors: plenty to choose from. Immunity 26: 678-689.   DOI
95 Gapin, L. 2014. Check MAIT. J. Immunol. 192: 4475-4480.   DOI
96 Tang, Y., Y. Chen, H. Jiang, G. T. Robbins, and D. Nie. 2011. G-protein-coupled receptor for short-chain fatty acids suppresses colon cancer. Int. J. Cancer 128: 847-856.   DOI   ScienceOn
97 Karaki, S., R. Mitsui, H. Hayashi, I. Kato, H. Sugiya, T. Iwanaga, J. B. Furness, and A. Kuwahara. 2006. Short-chain fatty acid receptor, GPR43, is expressed by enteroendocrine cells and mucosal mast cells in rat intestine. Cell Tissue Res. 324: 353-360.   DOI   ScienceOn
98 Wanders, D., E. C. Graff, and R. L. Judd. 2012. Effects of high fat diet on GPR109A and GPR81 gene expression. Biochem. Biophys. Res. Commun. 425: 278-283.   DOI
99 Ingersoll, M. A., S. Potteaux, D. Alvarez, S. B. Hutchison, R. N. van, and G. J. Randolph. 2012. Niacin inhibits skin dendritic cell mobilization in a GPR109A independent manner but has no impact on monocyte trafficking in atherosclerosis. Immunobiology 217: 548-557.   DOI
100 Li, X., J. S. Millar, N. Brownell, F. Briand, and D. J. Rader. 2010. Modulation of HDL metabolism by the niacin receptor GPR109A in mouse hepatocytes. Biochem. Pharmacol. 80: 1450-1457.   DOI
101 Bermudez, Y., C. A. Benavente, R. G. Meyer, W. R. Coyle, M. K. Jacobson, and E. L. Jacobson. 2011. Nicotinic acid receptor abnormalities in human skin cancer: implications for a role in epidermal differentiation. PLoS. One 6: e20487.   DOI
102 Xu, L. L., B. G. Stackhouse, K. Florence, W. Zhang, N. Shanmugam, I. A. Sesterhenn, Z. Zou, V. Srikantan, M. Augustus, V. Roschke, K. Carter, D. G. McLeod, J. W. Moul, D. Soppett, and S. Srivastava. 2000. PSGR, a novel prostate-specific gene with homology to a G protein-coupled receptor, is overexpressed in prostate cancer. Cancer Res. 60: 6568-6572.
103 Gratz, I. K., and D. J. Campbell. 2014. Organ-specific and memory treg cells: specificity, development, function, and maintenance. Front Immunol. 5: 333.
104 Rossjohn, J., D. G. Pellicci, O. Patel, L. Gapin, and D. I. Godfrey. 2012. Recognition of CD1d-restricted antigens by natural killer T cells. Nat. Rev. Immunol. 12: 845-857.   DOI
105 Wan, Y. Y. 2010. Multi-tasking of helper T cells. Immunology 130: 166-171.   DOI   ScienceOn
106 Li, P., R. Spolski, W. Liao, and W. J. Leonard. 2014. Complex interactions of transcription factors in mediating cytokine biology in T cells. Immunol. Rev. 261: 141-156.   DOI
107 Liston, A., and D. H. Gray. 2014. Homeostatic control of regulatory T cell diversity. Nat. Rev. Immunol. 14: 154-165.   DOI
108 Atarashi, K., T. Tanoue, K. Oshima, W. Suda, Y. Nagano, H. Nishikawa, S. Fukuda, T. Saito, S. Narushima, K. Hase, S. Kim, J. V. Fritz, P. Wilmes, S. Ueha, K. Matsushima, H. Ohno, B. Olle, S. Sakaguchi, T. Taniguchi, H. Morita, M. Hattori, and K. Honda. 2013. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 500: 232-236.   DOI   ScienceOn
109 Weber, M., U. Pehl, H. Breer, and J. Strotmann. 2002. Olfactory receptor expressed in ganglia of the autonomic nervous system. J. Neurosci. Res. 68: 176-184.   DOI
110 Mace, T. A., S. A. King, Z. Ameen, O. Elnaggar, G. Young, K. M. Riedl, S. J. Schwartz, S. K. Clinton, T. J. Knobloch, C. M. Weghorst, and G. B. Lesinski. 2014. Bioactive compounds or metabolites from black raspberries modulate T lymphocyte proliferation, myeloid cell differentiation and Jak/STAT signaling. Cancer Immunol. Immunother. 63: 889-900.   DOI
111 McCrudden, F. H., and H. L. Fales. 1913. The cause of the excessive calcium excretion through the feces in infantilism. J. Exp. Med. 17: 24-28.   DOI
112 Kara, E. E., I. Comerford, K. A. Fenix, C. R. Bastow, C. E. Gregor, D. R. McKenzie, and S. R. McColl. 2014. Tailored immune responses: novel effector helper T cell subsets in protective immunity. PLoS. Pathog. 10: e1003905.   DOI
113 Benson, M. J., K. Pino-Lagos, M. Rosemblatt, and R. J. Noelle. 2007. All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation. J. Exp. Med. 204: 1765-1774.   DOI   ScienceOn
114 Li, H., L. Myeroff, D. Smiraglia, M. F. Romero, T. P. Pretlow, L. Kasturi, J. Lutterbaugh, R. M. Rerko, G. Casey, J. P. Issa, J. Willis, J. K. Willson, C. Plass, and S. D. Markowitz. 2003. SLC5A8, a sodium transporter, is a tumor suppressor gene silenced by methylation in human colon aberrant crypt foci and cancers. Proc. Natl. Acad. Sci. U. S. A. 100: 8412-8417.   DOI   ScienceOn
115 Xiong, Y., N. Miyamoto, K. Shibata, M. A. Valasek, T. Motoike, R. M. Kedzierski, and M. Yanagisawa. 2004. Short-chain fatty acids stimulate leptin production in adipocytes through the G protein-coupled receptor GPR41. Proc. Natl. Acad. Sci. U. S. A. 101: 1045-1050.   DOI   ScienceOn
116 Brown, A. J., S. M. Goldsworthy, A. A. Barnes, M. M. Eilert, L. Tcheang, D. Daniels, A. I. Muir, M. J. Wigglesworth, I. Kinghorn, N. J. Fraser, N. B. Pike, J. C. Strum, K. M. Steplewski, P. R. Murdock, J. C. Holder, F. H. Marshall, P. G. Szekeres, S. Wilson, D. M. Ignar, S. M. Foord, A. Wise, and S. J. Dowell. 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.   DOI   ScienceOn
117 Tazoe, H., Y. Otomo, S. Karaki, I. Kato, Y. Fukami, M. Terasaki, and A. Kuwahara. 2009. Expression of short-chain fatty acid receptor GPR41 in the human colon. Biomed. Res. 30: 149-156.   DOI
118 Vinolo, M. A., G. J. Ferguson, S. Kulkarni, G. Damoulakis, K. Anderson, Y. Bohlooly, L. Stephens, P. T. Hawkins, and R. Curi. 2011. SCFAs induce mouse neutrophil chemotaxis through the GPR43 receptor. PLoS. One 6: e21205.   DOI
119 Millard, A. L., P. M. Mertes, D. Ittelet, F. Villard, P. Jeannesson, and J. Bernard. 2002. Butyrate affects differentiation, maturation and function of human monocyte-derived dendritic cells and macrophages. Clin. Exp. Immunol. 130: 245-255.   DOI
120 Kurita-Ochiai, T., K. Fukushima, and K. Ochiai. 1995. Volatile fatty acids, metabolic by-products of periodontopathic bacteria, inhibit lymphocyte proliferation and cytokine production. J. Dent. Res. 74: 1367-1373.   DOI   ScienceOn
121 Breuer, R. I., K. H. Soergel, B. A. Lashner, M. L. Christ, S. B. Hanauer, A. Vanagunas, J. M. Harig, A. Keshavarzian, M. Robinson, J. H. Sellin, D. Weinberg, D. E. Vidican, K. L. Flemal, and A. W. Rademaker. 1997. Short chain fatty acid rectal irrigation for left-sided ulcerative colitis: a randomised, placebo controlled trial. Gut 40: 485-491.   DOI
122 Haberland, M., R. L. Montgomery, and E. N. Olson. 2009. The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat. Rev. Genet. 10: 32-42.   DOI   ScienceOn
123 Amre, D. K., S. D'Souza, K. Morgan, G. Seidman, P. Lambrette, G. Grimard, D. Israel, D. Mack, P. Ghadirian, C. Deslandres, V. Chotard, B. Budai, L. Law, E. Levy, and E. G. Seidman. 2007. Imbalances in dietary consumption of fatty acids, vegetables, and fruits are associated with risk for Crohn's disease in children. Am. J. Gastroenterol. 102: 2016-2025.   DOI
124 Vernia, P., A. Marcheggiano, R. Caprilli, G. Frieri, G. Corrao, D. Valpiani, M. C. Di Paolo, P. Paoluzi, and A. Torsoli. 1995. Short-chain fatty acid topical treatment in distal ulcerative colitis. Aliment. Pharmacol. Ther. 9: 309-313.
125 Gopal, E., Y. J. Fei, M. Sugawara, S. Miyauchi, L. Zhuang, P. Martin, S. B. Smith, P. D. Prasad, and V. Ganapathy. 2004. Expression of slc5a8 in kidney and its role in Na(+)-coupled transport of lactate. J. Biol. Chem. 279: 44522-44532.   DOI
126 Dewulf, E. M., Q. Ge, L. B. Bindels, F. M. Sohet, P. D. Cani, S. M. Brichard, and N. M. Delzenne. 2013. Evaluation of the relationship between GPR43 and adiposity in human. Nutr. Metab. (Lond) 10: 11.   DOI
127 Taggart, A. K., J. Kero, X. Gan, T. Q. Cai, K. Cheng, M. Ippolito, N. Ren, R. Kaplan, K. Wu, T. J. Wu, L. Jin, C. Liaw, R. Chen, J. Richman, D. Connolly, S. Offermanns, S. D. Wright, and M. G. Waters. 2005. (D)-beta-Hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor PUMA-G. J. Biol. Chem. 280: 26649-26652.   DOI
128 Furusawa, Y., Y. Obata, S. Fukuda, T. A. Endo, G. Nakato, D. Takahashi, Y. Nakanishi, C. Uetake, K. Kato, T. Kato, M. Takahashi, N. N. Fukuda, S. Murakami, E. Miyauchi, S. Hino, K. Atarashi, S. Onawa, Y. Fujimura, T. Lockett, J. M. Clarke, D. L. Topping, M. Tomita, S. Hori, O. Ohara, T. Morita, H. Koseki, J. Kikuchi, K. Honda, K. Hase, and H. Ohno. 2013. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504: 446-450.   DOI   ScienceOn