Cell Metabolism CelPress Perspective which is particularly relevant for lism pathways in specific immune cell types (Figure 1). inal epith ant actor in hos in nmune resp t is estimated t approx energy m the consumption of hNADH and FADH molecules he gut mic obiota.Early in life,before adaptive immu d by oxidative phosphorylation (OXPHOS)in mito- FA synthesis is required for the biosynthe sis of the cell in an IL-3-and IL-22-depend nembrane acti targe of signaling 22 production leads an abn mal lipid metabolism tion.It leads to the pro ugh the TCA cycle nd oxPHOS o rol is le,B-o and pyruvate dehy several biomole d BA 11). agy is ind rget d thr ough the oxidation of cholesterol.These mo les nn is d th are a goode they are synth but lonocytes )the the bile duct and re enzymes and damp 20- autopnagy h。 atic produce m us and antimicrobial peptides to maintain a are humar IECs (M et a 201) GR5).far r(FXR).and esides their b ing blocks le for se in nalina nat ays and me for the onin (5-HD which ha 0).Glutamine asp artate are see b feed the TCA cycle to producee or be a substrate fo -formin gbacteria metab mecha synthesis.Meta ofother AAs,such as arginine trypto date 2019:M For nin prod ion.can be achie d by SCFAs(b e mo ro ial hi d the 2015 ven if further in ns are needed,thes eads to the p ng the (AhR)agonists that exhibit immunomodulatory eff ng the production of serotonin from a therapeutic from en perspective n the er the influ blish adrectimm nomodulatory factor,with seven re crophages and non-immu Cell Metabolism 32.October 6,2020 515 Glycolysis is a relatively inefficient way to generate energy, as the breakdown of one unit of glucose produces only two ATP molecules (Lunt and Vander Heiden, 2011). However, it is a source of intermediate molecules for other pathways, including the PPP, AA, and FA metabolism pathways, and it can be swiftly activated, which is particularly relevant for proliferating cells such as T cells. The TCA cycle (or Krebs or citric acid cycle), which takes place in mitochondria in eukaryotes, is a crucial engine in energy gen￾eration. Its primary substrate is acetyl-CoA produced either from pyruvate by oxidative decarboxylation at the end of glycolysis or from FAO. It is estimated that the TCA cycle produces approxi￾mately 30 molecules of ATP from one molecule of glucose, including the consumption of the NADH and FADH2 molecules produced by oxidative phosphorylation (OXPHOS) in mito￾chondria. FA synthesis is required for the biosynthesis of the cell membrane, energy storage, and the generation of signaling molecules. This pathway is tightly dependent on mTOR (mammalian target of rapamycin) signaling and principally uses acetyl-CoA and other molecules provided by glycolysis, the TCA cycle, and the PPP. Beta-oxidation is the main meta￾bolic pathway for FA degradation. It leads to the production of acetyl-CoA, NADH, and FADH2 and then to a high amount of energy through the TCA cycle and OXPHOS. Cholesterol is an essential precursor of several biomolecules, including ste￾roid hormones, vitamin D, oxysterols, and BAs. BAs are pro￾duced through the oxidation of cholesterol. These molecules are a good example of co-metabolism, as they are synthesized as primary and conjugated BAs by the liver (Fiorucci et al., 2018); they reach the intestine through the bile duct and are converted by gut microbiota enzymes into unconjugated sec￾ondary BAs. Most of the BAs are reabsorbed in the terminal ileum and go back to the liver, completing their entero-hepatic cycle. Beyond their role in lipid digestion, BAs are signaling molecules impacting many immune cell types through several membranes and nuclear receptors, such as G protein-coupled BA receptor 5 (TGR5), farnesoid X receptor (FXR), and vitamin D receptor (VDR). Besides their building blocks role for proteins, some AAs are also precursors of bioactive molecules that contribute to the maintenance of signaling pathways and metabolism (Liu et al., 2020). Glutamine and aspartate are involved in nucleotide syn￾thesis (Cory and Cory, 2006; Gots, 1971). Glutamine can also feed the TCA cycle to produce energy or be a substrate for FA synthesis. Metabolites of other AAs, such as arginine and trypto￾phan, are involved in cell proliferation and growth processes (Ba￾dawy, 2019; Milner, 1985). For example, tryptophan can be metabolized into a myriad of active molecules through three ma￾jor pathways: the kynurenine pathway, the serotonin pathway, and the indole pathway. While the first two pathways occur in mammalian cells, the last pathway takes place in the gut micro￾biota and leads to the production of aryl hydrocarbon receptor (AhR) agonists that exhibit immunomodulatory effects (Agus et al., 2018). The production of serotonin from enterochromaffin cells in the gut is under the influence of the microbiome. It is well established as a direct immunomodulatory factor, with seven re￾ceptor isoforms expressed on immune and non-immune cell types (Shajib and Khan, 2015). KEY ROLES OF THE MICROBIOTA IN IMMUNE CELL METABOLISM Several recent studies highlighted newly discovered mecha￾nisms by which the gut microbiota manipulates immunometabo￾lism pathways in specific immune cell types (Figure 1). Epithelial Cells The gastrointestinal epithelium is a highly relevant actor in host￾microbiome interactions; it is one of the first players in the immune response, and intestinal epithelial cells (IECs) are now considered immune cells (Allaire et al., 2018). The energy meta￾bolism of IECs, particularly in the colon, is largely dependent on the gut microbiota. Early in life, before adaptive immune system maturation, unidentified microbiota-derived molecules activate intraepithelial lymphocytes (IELs) and ILC3 through STAT3 phos￾phorylation in an IL-23- and IL-22-dependent manner. In the absence of adaptive immunity, the IL-23-ILC3-IL-22-IEC circuit allows control of the gut microbiota, but the overactivated IL- 22 production leads to an abnormal lipid metabolism with reduced expression of key lipid transporters (e.g., CD36, Fabp1/2), and reduction of triglycerides and free FA in serum (Mao et al., 2018). In germ-free mice, colonocytes exhibit an en￾ergy-deprived state with decreased activity of enzymes of the TCA cycle, b-oxidation, and pyruvate dehydrogenase complex (Donohoe et al., 2011). Autophagy is induced by the energetic stress to maintain homeostasis in colonocytes. The SCFA buty￾rate produced by the gut microbiome in the colon is indeed the only source of carbon for colonocytes. After being transformed into butyryl-CoA, it diffuses passively into the mitochondria, un￾dergoes b-oxidation, and feeds the TCA cycle and OXPHOS to produce energy and dampen autophagy activation (Donohoe et al., 2011). IECs are massively exposed to gut microbes and produce mucus and antimicrobial peptides to maintain a safety distance. Butyrate also promotes intestinal homeostasis by downregulating IDO1 expression and the kynurenine pathway in human IECs (Martin-Gallausiaux et al., 2018). The mecha￾nisms involve a reduction in signal transducer and activator of transcription (STAT) 1 expression and HDAC (histone deacety￾lase) inhibition. Among the different IEC types, enterochromaffin (EC) cells are responsible for the production of serotonin (5-HT), which has major effects on immune cells (see below). Serotonin production in the colon is largely modulated by the gut microbiota and particularly spore-forming bacteria metabolites. The mecha￾nisms are not fully elucidated, but it has been shown that upregulation of TpH1 expression, the rate-limiting enzyme in serotonin production, can be achieved by SCFAs (butyrate and propionate) and some secondary BAs, such as deoxycholate produced by microbial biotransformation of cholate (Yano et al., 2015). Even if further investigations are needed, these data suggest that modulating the gut microbiota composition or directly administrating microbial metabolites could allow manipulating the production of serotonin from a therapeutic perspective. Macrophages Macrophages are in the first line during the immune response but also sense and respond to the microbiota to control it without ll Cell Metabolism 32, October 6, 2020 515 Perspective