Cell Metabolism CelPress Perspective dehyrdirogenase butyrate ind d by antibiotics promotes the pro-inflammato T cell acti mainly through RO production (Sena ta TCA intake enzymes. e0Saleectron red activation.ROS act in syn with calciu nflux to elicit IL-2 te Lymphoid Cell types of innate lymphoid cells (ILCs)charac Microbiota-derived SCFAs boost CDa cell effector fun ized by the exp ssion of specr me ane sm (Tromp et ation.ILCs change theirnerg netabolism profo to fit that .20 ell as the mecha d and amino acid n sm.and ILC3 SCFA can diffus glycolysis bl. the cyt and s ects of antibiotics on the transcriptomic C1 As. ularly butyrate,boost th e of ILC t in the e IL-17 and IL-22,and are eg atabolisn tan ine utilization. se and 1 to me (Bachem et) ntenance f the m de in stre amoun of acetate is (ari hydr arbon recepto rnuclear tran like Liah tate uptake memory CD8 cells expands the acetyl-CoA k cycles are key factors in this process,but the gut micro citrate lya tal 2016).also has some impact (Godinho-Silva et a 019 enzyme in glycolysis. The p call ca city CD of systemic lipid m etabolis et al 20170 bed with host tate,they are likely trig ut mi rate mo nct at le g te pro and asthma.The m m termi n mitoc ROS(mROS)prod on and glycolysis b et al.. me ems involve the inhibiti of HDAC onal has hoo ntly sho rectly tue TCA h pent wn as valerate).a subo nt m cific ba eria stimulates the secretion of ll-13 C2.thr anti-inflam matory cytokine L-10 by and IL-5( retaonLc2 for and en cing glycolysi remains to be explored. arding the activation of mTOR by SCFAs T cell metabolic plasticity is necessary to fit the which are inhibitor and activator of AMP-activa dprote une e vely pa and REDOX etal,2019).Effecto (K m et al.,2016;Lu uet a :Zhou eta 2018).The seconc I Tunctions P300/CBP (E1A glycolysis in effectorTcells and by FAOand OXPHOS inme orotein P300/CREB-b ding protein) etylationof t of mTOR.ading to more atin of the Cell Metabolism 32.October 6,2020 517 dehydrogenase) and lipid metabolism (such as lipoprotein lipase) pathways. As an illustration, the impaired production of butyrate induced by antibiotics promotes the pro-inflammatory polarization of the intestinal macrophages, leading to a global dysfunction of the immune response (Scott et al., 2018). This might play a role in the association between antibiotics intake and the emergence of inflammatory and metabolic diseases (Cox et al., 2014; Hviid et al., 2011). Innate Lymphoid Cells There are different types of innate lymphoid cells (ILCs) charac￾terized by the expression of specific membrane markers, transcription factors, and cytokine signatures. During their acti￾vation, ILCs change their energy metabolism profoundly to fit their new functions (Rolot and O’Sullivan, 2020). Transcriptomic analysis suggests that ILC1s use mTOR signaling, ILC2s depend on sphingolipid and amino acid metabolism, and ILC3s rely on glycolysis (Gury-BenAri et al., 2016). The gut microbiota pro￾foundly impacts ILC function as demonstrated by the dramatic effects of antibiotics on the transcriptomic program of ILC1s, ILC2s, and ILC3s (Gury-BenAri et al., 2016). ILC3 is the main type of ILC present in the gastrointestinal tract. These cells ex￾press RORgt, can produce IL-17 and IL-22, and are crucial reg￾ulators of inflammation, infection, microbiota composition, and metabolism (Klose and Artis, 2016). ILC3 functions, such as maintenance of the intestinal epithelium defense, depend on circadian signals mediated by the circadian regulator ARNTL (aryl hydrocarbon receptor nuclear translocator like). Light￾dark cycles are key factors in this process, but the gut micro￾biota, which is known to be an actor in diurnal rhythmicity (Thaiss et al., 2016), also has some impact (Godinho-Silva et al., 2019). This signaling circuit connecting the gut microbiota, ILC3, and the intestinal epithelial clock is also involved in the regulation of the local and systemic lipid metabolism (Wang et al., 2017). Gut microbiota-derived butyrate modulates ILC2 functions, in￾hibiting their uncontrolled activation and, consequently, their negative role in lung inflammation and asthma. The mechanism is not determined. Yet the involvement of intracellular meta￾bolism is supported by the induction of changes in mitochondrial ROS (mROS) production and glycolysis by butyrate (Lewis et al., 2019). Moreover, the preferential use of FAs over glucose by ILC2 to maintain their function in infection or nutritional stress suggests that butyrate might directly fuel the TCA (Wilhelm et al., 2016). Succinate, produced in the gut by protists and spe￾cific bacteria, stimulates the secretion of IL-13 by ILC2, through an indirect action on Tuft cells and IL-25 (Schneider et al., 2018). The role of succinate of other origin and its direct impact on ILC2 remains to be explored. T Cells T cell metabolic plasticity is necessary to fit the permanently dynamic immune environment. The gut microbiota actively par￾ticipates in this programming via ROS, SCFA, and BA production and REDOX signaling modification (Skelly et al., 2019). Effector and memory T cells have very different functions and needs and thus exhibit different metabolism. It is dominated by aerobic glycolysis in effector T cells and by FAO and OXPHOS in memory T cells. Mitochondrial dynamics are evidence of these differ￾ences, with fused mitochondrial networks in memory T cells and punctate mitochondria in effector T cells (Buck et al., 2016). In addition, mitochondria are a critical component of T cell activation, mainly through ROS production (Sena et al., 2013). T cell stimulation via CD3 induces calcium influx that stimulates the function of pyruvate dehydrogenase and TCA enzymes. TCA cycling activates the mitochondrial electron transport chain and leads to the production of ROS, which are required for T cell activation. ROS act in synergy with calcium influx to elicit IL-2 expression, likely in an NF-kB- and AP-1- dependent manner (Kaminski et al., 2010). Microbiota-derived SCFAs boost CD8+ T cell effector func￾tions by modifying their cellular metabolism (Trompette et al., 2018). SCFAs produced by the metabolism of dietary fibers by the gut microbiota stimulate OXPHOS and mitochondrial mass in CD8+ T cells as well as their glycolytic capacity. The mecha￾nisms are not yet fully understood, but a part of these changes depend on GPR41 activation. Besides, SCFAs can diffuse into the cytoplasm and serve as a substrate for FAO, leading to the production of acetyl-CoA that fuel TCA and then OXPHOS. In activated CD8+ T cells, SCFAs, particularly butyrate, boost the uptake and oxidation of FAs, leading to a disconnection of the TCA cycle from glycolytic input and favoring OXPHOS through FA catabolism and glutamine utilization. This butyrate-induced cellular metabolism adaptation is required for the differentiation to memory T cells (Bachem et al., 2019). In stress situations, a massive amount of acetate is released into the extracellular space via hydrolysis from acetyl-CoA. Ace￾tate uptake by memory CD8+ T cells expands the acetyl-CoA pool though TCA cycle and ATP citrate lyase activity and triggers the acetylation of GAPDH (glyceraldehyde 3-phosphate dehy￾drogenase), a key enzyme in glycolysis. The prompt stimulation of glycolysis allows the rapid recall capacity of CD8+ memory T cells (Balmer et al., 2016). Although these phenomena were described with host cell-derived acetate, they are likely trig￾gered, at least in the gut, by the massive amount of acetate pro￾duced by the gut microbiota. SCFAs also exhibit significant effects on CD4+ T cells, notably regarding the generation of T helper (Th) 17, Th1 (Park et al., 2015), and regulatory T cells (Furusawa et al., 2013; Smith et al., 2013). The mechanisms involve the inhibition of HDACs and regulation of the mTOR pathway (a master regulator of cell growth and metabolism). This link has been recently shown with pentanoate (also known as valerate), a subdominant micro￾biota-produced SCFA that can stimulate the production of the anti-inflammatory cytokine IL-10 by providing additional acetyl￾CoA for histone acetyltransferases and enhancing glycolysis and mTOR activity (Luu et al., 2019). Two mechanisms have been suggested regarding the activation of mTOR by SCFAs (Figure 2). Through their action on energy production pathways, SCFAs induce the production of ATP and the depletion of AMP, which are inhibitor and activator of AMP-activated protein kinase (AMPK), respectively. Consequently, the inhibitor activity of AMPK on mTOR is repressed, thus leading to mTOR activation (Kim et al., 2016; Luu et al., 2019; Zhou et al., 2018). The second potential mechanism involves the HDAC inhibition activity of SCFAs. SCFAs, in association with P300/CBP (E1A binding protein p300/CREB-binding protein), promote acetylation of the ribosomal protein S6 kinase beta-1 (S6K1), which is a down￾stream target of mTOR, leading to more robust activation of the ll Cell Metabolism 32, October 6, 2020 517 Perspective