CellPress Cell Metabolism Perspective The Gut Microbiota at the Service of Immunometabolism aMhagecaadiaosotaei 3Sorbonne Universite,INSERM,Centre de Recherche Saint-Antoine,CRSA,AP-HP,Saint Antoine Hospital,Gastroenterology Department, 75012 Paris,France SUMMARY The gut microbiota is implicated in immune system functions.Regulation of the metabolic processes occur- ring in immune cells is crucial for the maintenance of homeostasis and immunopathogenesis.Emerging data demonstrate that the gut microbiota is an actor in immunometabolism,notably through the effect of metab- olites such as short-chain fatty acids,bile acids,and tryptophan metabolites.In this Perspective,we discuss the impact of the gut microbiota on the intracellular metabolism of the different subtypes of immune cells, hi cell Besides the effectson heath,we discus the potentiaons nflammatory bowel diseases INTRODUCTION molecules,either produced or transformed by microorgan- isms.are maior actors in the dialog with immune cells Metabolism involves cellular mechanisms to sustain life during (Backhed et al.,2004;Cavallari et al.,2020;Lavelle and Sokol, physiological or pathological processes.More generally,it is 2020).Given the key role of the gut microbiome in physiolog- about eneray:the utilization of metabolic substrates.notably ical processes,any alteration in its composition or function glucose,fatty acids(FAs),and amino acids(AAs);and the bal could induce or participate in a disease(Pigneur and Sokol. ance between catabolism and anabolism that maintain cellular 2016).The alobal role of the aut microbiota in immunity has homeostasis.Metabolism is impacted by lifestyles and dietary been extensively reviewed (Honda and Littman,2016:Rooks habits,as illustrated by the increased rate of infection in and Garrett 2016)H clly discuss malnourished populations (Blanton et al.2016:Hashimoto of tha et al..2012)and the metabolic syndrome-related disease and pre verfed the ntial of immune cells,in 1n2002,im ations living in de elopedco with the glycolysis ENERGY ARCHITECTURE TO of immune c on met tabolism and,conversely,the meta Immune system development/activation typically involves needs of immune cells during homeostasis and pathological changes in the expression of large numbers of genes and results settings. in the acquisition of new functions,such as high production of The microbiome is a maior contributor to health.contrib cytokines.lipid mediators.and tissue-remodeling enzymes uting to several development processes,homeostatic states, and the ability to migrate through tissues and/or undergo cellular and responses to pathogenic situations.Although the human division.Immune cells use the same pathways as other cell types microbiome is composed of several microbiotas colonizing eray and ensure their effective functionina the different niches (e.g.,lung,skin,mouth,and vagina),the main metabolic pathways involved in immunometabolism are glycolysis,the tricarboxylic acid(TCA)cycle,the pentose phos- ate athw /(PPP).FA oxi (FAO),FA 201)and15.0m(arin 100 trillion mic synthesis,and th s im- 91 (Pasolli et al,2019) cting the e mete olism of The gut micr ia fu -chain protists (lliev a nardi,2017:Ri tryptophan etabolism,lipid meta We presen ill discuss s and refer the with its reader to recent extensive reviews on this topic for more details host.The gut microbiome plays a role in the modulation of (Bantug et al,2018;Goodpaster and Sparks,2017;O'Neill both metabolism and immunity.Indeed,microbiome-derived etal.2016). 514 Cell Metabolism 32,October 6,20202020 Elsevier Inc ®Perspective The Gut Microbiota at the Service of Immunometabolism Chloe´ Michaudel1,2 and Harry Sokol1,2,3, * 1INRA, UMR1319 Micalis and AgroParisTech, Jouy en Josas, France 2Paris Center for Microbiome Medicine (PaCeMM) FHU, Paris, France 3Sorbonne Universite´ , INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Saint Antoine Hospital, Gastroenterology Department, 75012 Paris, France *Correspondence: harry.sokol@aphp.fr https://doi.org/10.1016/j.cmet.2020.09.004 SUMMARY The gut microbiota is implicated in immune system functions. Regulation of the metabolic processes occur￾ring in immune cells is crucial for the maintenance of homeostasis and immunopathogenesis. Emerging data demonstrate that the gut microbiota is an actor in immunometabolism, notably through the effect of metab￾olites such as short-chain fatty acids, bile acids, and tryptophan metabolites. In this Perspective, we discuss the impact of the gut microbiota on the intracellular metabolism of the different subtypes of immune cells, including intestinal epithelial cells. Besides the effects on health, we discuss the potential consequences in infection context and inflammatory bowel diseases. INTRODUCTION Metabolism involves cellular mechanisms to sustain life during physiological or pathological processes. More generally, it is about energy; the utilization of metabolic substrates, notably glucose, fatty acids (FAs), and amino acids (AAs); and the bal￾ance between catabolism and anabolism that maintain cellular homeostasis. Metabolism is impacted by lifestyles and dietary habits, as illustrated by the increased rate of infection in malnourished populations (Blanton et al., 2016; Hashimoto et al., 2012) and the metabolic syndrome-related disease outbreak in overfed populations living in developed countries. In 2002, immunometabolism, a new branch of metabolism, was brought to light with the discovery of the link between CD28 activation and glycolysis in T cells (Frauwirth et al., 2002, p. 2). This field notably aims to understand the impact of immune cells on metabolism and, conversely, the metabolic needs of immune cells during homeostasis and pathological settings. The microbiome is a major contributor to health, contrib￾uting to several development processes, homeostatic states, and responses to pathogenic situations. Although the human microbiome is composed of several microbiotas colonizing different niches (e.g., lung, skin, mouth, and vagina), the most studied is that in the gastrointestinal tract. It is composed of diverse microbial communities, approximately 100 trillion microorganisms (Sarin et al., 2019; Sender et al., 2016) and 150,000 microbial genomes (Pasolli et al., 2019). The gut microbiome is composed of bacteria, fungi, viruses, and protists (Iliev and Leonardi, 2017; Richard and Sokol, 2019; Shkoporov and Hill, 2019), and following millions of years of concomitant evolution, it is in symbiosis with its host. The gut microbiome plays a role in the modulation of both metabolism and immunity. Indeed, microbiome-derived molecules, either produced or transformed by microorgan￾isms, are major actors in the dialog with immune cells (Backhed et al., 2004 € ; Cavallari et al., 2020; Lavelle and Sokol, 2020). Given the key role of the gut microbiome in physiolog￾ical processes, any alteration in its composition or function could induce or participate in a disease (Pigneur and Sokol, 2016). The global role of the gut microbiota in immunity has been extensively reviewed (Honda and Littman, 2016; Rooks and Garrett, 2016). Here, we specifically discuss the effects of the gut microbiota on immunometabolism, and more pre￾cisely, on the intracellular metabolism of immune cells, in health and the potential consequences in diseases. IMMUNOMETABOLISM: ENERGY ARCHITECTURE TO PROMOTE IMMUNITY Immune system development/activation typically involves changes in the expression of large numbers of genes and results in the acquisition of new functions, such as high production of cytokines, lipid mediators, and tissue-remodeling enzymes, and the ability to migrate through tissues and/or undergo cellular division. Immune cells use the same pathways as other cell types to generate energy and ensure their effective functioning. The main metabolic pathways involved in immunometabolism are glycolysis, the tricarboxylic acid (TCA) cycle, the pentose phos￾phate pathway (PPP), FA oxidation (FAO), FA synthesis, and AA metabolism. Among the microbiome metabolism pathways im￾pacting the metabolism of the immune cells, we will notably discuss short-chain fatty acid (SCFA) production, tryptophan metabolism, lipid metabolism, and bile acid (BA) transformation. We present here the main actors we will discuss and refer the reader to recent extensive reviews on this topic for more details (Bantug et al., 2018; Goodpaster and Sparks, 2017; O’Neill et al., 2016). ll 514 Cell Metabolism 32, October 6, 2020 ª 2020 Elsevier Inc