CelPress Cell Metabolism Perspective ho metaboes ,ta201.a oetMsn8SmCf82.uhgwhyoursetmnateymphodce microblota.metabolites and hos cvtonCel Metap1. Hg89oo0tm呼 10. ShikoporovAand Hll CBactenophge of me t,M.R..Panikov.N..Michaud.M..Gatni.CA Bohlooly-' e'h0eetaboieaheratonsasociaedwhagninedeficien osstalk in n's dis te out ROR·requlatory T ce 2oe,296e紫ommrone tA66a登eoRhKim, M., Qie, Y., Park, J., and Kim, C.H. (2016). Gut microbial metabolites fuel host antibody responses. Cell Host Microbe 20, 202–214. Klose, C.S.N., and Artis, D. (2016). Innate lymphoid cells as regulators of im￾munity, inflammation and tissue homeostasis. Nat. Immunol. 17, 765–774. Lampropoulou, V., Sergushichev, A., Bambouskova, M., Nair, S., Vincent, E.E., Loginicheva, E., Cervantes-Barragan, L., Ma, X., Huang, S.C.-C., Griss, T., et al. (2016). Itaconate links inhibition of succinate dehydrogenase with macrophage metabolic remodeling and regulation of inflammation. Cell Metab. 24, 158–166. Lavelle, A., and Sokol, H. (2020). Gut microbiota-derived metabolites as key actors in inflammatory bowel disease. Nat. Rev. Gastroenterol. Hepatol. 17, 223–237. Leber, A., Hontecillas, R., Tubau-Juni, N., Zoccoli-Rodriguez, V., Abedi, V., and Bassaganya-Riera, J. (2018). NLRX1 modulates immunometabolic mech￾anisms controlling the host-gut microbiota interactions during inflammatory bowel disease. Front. Immunol. 9, 363. Lewis, G., Wang, B., Shafiei Jahani, P., Hurrell, B.P., Banie, H., Aleman Muench, G.R., Maazi, H., Helou, D.G., Howard, E., Galle-Treger, L., et al. (2019). Dietary fiber-induced microbial short chain fatty acids suppress ILC2-dependent airway inflammation. Front. Immunol. 10, 2051. Lin, C.J., and Wang, M.C. (2017). Microbial metabolites regulate host lipid metabolism through NR5A-Hedgehog signalling. Nat. Cell Biol. 19, 550–557. Liu, T.-C., Gurram, B., Baldridge, M.T., Head, R., Lam, V., Luo, C., Cao, Y., Simpson, P., Hayward, M., Holtz, M.L., et al. (2016). Paneth cell defects in Crohn’s disease patients promote dysbiosis. JCI Insight 1, e86907. Liu, Y., Hou, Y., Wang, G., Zheng, X., and Hao, H. (2020). Gut microbial metab￾olites of aromatic amino acids as signals in host-microbe interplay. Trends Endocrinol. Metab. Published online April 10, 2020. https://doi.org/10.1016/ j.tem.2020.02.012. Lunt, S.Y., and Vander Heiden, M.G. (2011). Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. Annu. Rev. Cell Dev. Biol. 27, 441–464. Luu, M., Pautz, S., Kohl, V., Singh, R., Romero, R., Lucas, S., Hofmann, J., Rai￾fer, H., Vachharajani, N., Carrascosa, L.C., et al. (2019). The short-chain fatty acid pentanoate suppresses autoimmunity by modulating the metabolic￾epigenetic crosstalk in lymphocytes. Nat. Commun. 10, 760. Macia, L., Tan, J., Vieira, A.T., Leach, K., Stanley, D., Luong, S., Maruya, M., Ian McKenzie, C., Hijikata, A., Wong, C., et al. (2015). Metabolite-sensing re￾ceptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome. Nat. Commun. 6, 6734. Mao, K., Baptista, A.P., Tamoutounour, S., Zhuang, L., Bouladoux, N., Martins, A.J., Huang, Y., Gerner, M.Y., Belkaid, Y., and Germain, R.N. (2018). Innate and adaptive lymphocytes sequentially shape the gut microbiota and lipid metabolism. Nature 554, 255–259. Martin-Gallausiaux, C., Larraufie, P., Jarry, A., Be´ guet-Crespel, F., Marinelli, L., Ledue, F., Reimann, F., Blottie`re, H.M., and Lapaque, N. (2018). Butyrate produced by commensal bacteria down-regulates Indolamine 2,3-Dioxyge￾nase 1 (IDO-1) expression via a dual mechanism in human intestinal epithelial cells. Front. Immunol. 9, 2838. Mills, E.L., Kelly, B., Logan, A., Costa, A.S.H., Varma, M., Bryant, C.E., Tourlo￾mousis, P., Dabritz, J.H.M., Gottlieb, E., Latorre, I., et al. (2016). Succinate € dehydrogenase supports metabolic repurposing of mitochondria to drive in- flammatory macrophages. Cell 167, 457–470.e13. Milner, J.A. (1985). Metabolic aberrations associated with arginine deficiency. J. Nutr. 115, 516–523. Mottawea, W., Chiang, C.-K., Muhlbauer, M., Starr, A.E., Butcher, J., Abuja- € mel, T., Deeke, S.A., Brandel, A., Zhou, H., Shokralla, S., et al. (2016). Altered intestinal microbiota-host mitochondria crosstalk in new onset Crohn’s dis￾ease. Nat. Commun. 7, 13419. O’Neill, L.A.J., Kishton, R.J., and Rathmell, J. (2016). A guide to immunome￾tabolism for immunologists. Nat. Rev. Immunol. 16, 553–565. Omenetti, S., Bussi, C., Metidji, A., Iseppon, A., Lee, S., Tolaini, M., Li, Y., Kelly, G., Chakravarty, P., Shoaie, S., et al. (2019). The intestine harbors functionally distinct homeostatic tissue-resident and inflammatory Th17 cells. Immunity 51, 77–89.e6. Park, J., Kim, M., Kang, S.G., Jannasch, A.H., Cooper, B., Patterson, J., and Kim, C.H. (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. Pasolli, E., Asnicar, F., Manara, S., Zolfo, M., Karcher, N., Armanini, F., Beghini, F., Manghi, P., Tett, A., Ghensi, P., et al. (2019). Extensive unexplored human microbiome diversity revealed by over 150,000 genomes from metagenomes spanning age, geography, and lifestyle. Cell 176, 649–662.e20. Pigneur, B., and Sokol, H. (2016). Fecal microbiota transplantation in inflam￾matory bowel disease: the quest for the holy grail. Mucosal Immunol. 9, 1360–1365. Richard, M.L., and Sokol, H. (2019). The gut mycobiota: insights into analysis, environmental interactions and role in gastrointestinal diseases. Nat. Rev. Gastroenterol. Hepatol. 16, 331–345. Rodrı´guez-Prados, J.-C., Trave´ s, P.G., Cuenca, J., Rico, D., Aragone´ s, J., Martı´n-Sanz, P., Cascante, M., and Bosca´ , L. (2010). Substrate fate in acti￾vated macrophages: a comparison between innate, classic, and alternative activation. J. Immunol. 185, 605–614. Rolot, M., and O’Sullivan, T.E. (2020). Living with yourself: innate lymphoid cell immunometabolism. Cells 9, E334. Rooks, M.G., and Garrett, W.S. (2016). Gut microbiota, metabolites and host immunity. Nat. Rev. Immunol. 16, 341–352. Rosser, E.C., Piper, C.J.M., Matei, D.E., Blair, P.A., Rendeiro, A.F., Orford, M., Alber, D.G., Krausgruber, T., Catalan, D., Klein, N., et al. (2020). Microbiota￾derived metabolites suppress arthritis by amplifying aryl-hydrocarbon recep￾tor activation in regulatory B cells. Cell Metab. 31, 837–851.e10. Sarin, S.K., Pande, A., and Schnabl, B. (2019). Microbiome as a therapeutic target in alcohol-related liver disease. J. Hepatol. 70, 260–272. Schneider, C., O’Leary, C.E., von Moltke, J., Liang, H.-E., Ang, Q.Y., Turn￾baugh, P.J., Radhakrishnan, S., Pellizzon, M., Ma, A., and Locksley, R.M. (2018). A metabolite-triggered tuft cell-ILC2 circuit drives small intestinal re￾modeling. Cell 174, 271–284.e14. Scott, N.A., Andrusaite, A., Andersen, P., Lawson, M., Alcon-Giner, C., Lec￾laire, C., Caim, S., Le Gall, G., Shaw, T., Connolly, J.P.R., et al. (2018). Antibi￾otics induce sustained dysregulation of intestinal T cell immunity by perturbing macrophage homeostasis. Sci. Transl. Med. 10, eaao4755. Sena, L.A., Li, S., Jairaman, A., Prakriya, M., Ezponda, T., Hildeman, D.A., Wang, C.-R., Schumacker, P.T., Licht, J.D., Perlman, H., et al. (2013). Mito￾chondria are required for antigen-specific T cell activation through reactive oxygen species signaling. Immunity 38, 225–236. Sender, R., Fuchs, S., and Milo, R. (2016). Are we really vastly outnumbered? Revisiting the ratio of bacterial to host cells in humans. Cell 164, 337–340. Shajib, M.S., and Khan, W.I. (2015). The role of serotonin and its receptors in activation of immune responses and inflammation. Acta Physiol. (Oxf.) 213, 561–574. Shkoporov, A.N., and Hill, C. (2019). Bacteriophages of the human gut: the ‘‘known unknown’’ of the microbiome. Cell Host Microbe 25, 195–209. Skelly, A.N., Sato, Y., Kearney, S., and Honda, K. (2019). Mining the microbiota for microbial and metabolite-based immunotherapies. Nat. Rev. Immunol. 19, 305–323. Smith, P.M., Howitt, M.R., Panikov, N., Michaud, M., Gallini, C.A., Bohlooly-Y, M., Glickman, J.N., and Garrett, W.S. (2013). The microbial metabolites, short￾chain fatty acids, regulate colonic Treg cell homeostasis. Science 341, 569–573. Song, X., Sun, X., Oh, S.F., Wu, M., Zhang, Y., Zheng, W., Geva-Zatorsky, N., Jupp, R., Mathis, D., Benoist, C., and Kasper, D.L. (2020). Microbial bile acid metabolites modulate gut RORg+ regulatory T cell homeostasis. Nature 577, 410–415. Tannahill, G.M., Curtis, A.M., Adamik, J., Palsson-McDermott, E.M., McGet￾trick, A.F., Goel, G., Frezza, C., Bernard, N.J., Kelly, B., Foley, N.H., et al. (2013). Succinate is an inflammatory signal that induces IL-1b through HIF-1a. Nature 496, 238–242. Thaiss, C.A., Levy, M., Korem, T., Dohnalova´ , L., Shapiro, H., Jaitin, D.A., Da￾vid, E., Winter, D.R., Gury-BenAri, M., Tatirovsky, E., et al. (2016). Microbiota ll 522 Cell Metabolism 32, October 6, 2020 Perspective