CellPress Cell Metabolism Perspective are modulated by the gut microbiome,as mitochondrial FA severity (Mottawea et al,21).Overall,the net increase in enag0mgncepenoentotanyeiectomco4tTceiseakoe tion pathogenesis CONCLUSION ory B iota in t of the qu el dis. e (RD)has bee st-microhe intera tion al mou s in the on a hos eptor.D pite the role of the s of IEC in th mou the ules resuting in overactivation of the gut imn cts it remain scarce Yet the gut nicrobiota the gut m EC tabolis nal in Nod-like receptor (NLR)family. (nuc irge par of genome with bacteria a,so con on aor ciated N ontainingX1) effects in colitis sti et al. 2018).NLRX cell anc gut microbiota in IECs anisms are not cle nalian meta-o dulat TCA that NI RX1 may support the glutami d by or depends on metabolites fro The impaired glutami meta eads changes AA ava iity for the nmune a o 6 de metabolites are en rep montrategbgtecalmicoootararne any As induce the acti ion of NLRP3(NOD- epto rom the action of the microbiota or epithe air ah l -18ma the the cell types intr sic dive for by antibiotics,favors an M1 esp se int s and to the r inte inal in the idir nact of l,2018 that of the partner in a link he on th and dise The actionable metabolic HB1 several for modulatic n of the gu Mo one possibility.Ho ver.an even more attractive strategy is to eth c host-microbio me y simultaneously on both sides of the interking- dom cros ACKNOWLEDGMENTS t al ochondrial ment in Crohn's fH.S. es is t d in the au AUTHOR CONTRIBUTIONS The amour microbiota 5 C.M.and H.S.wrote the pap 520 Cell Metabolism 32,October6,2020are modulated by the gut microbiome, as mitochondrial FA metabolism and intestinal barrier function can be rapidly restored by the administration of the probiotic Lactobacillus plantarum, independent of any effect on CD4+ T cells (Crakes et al., 2019). Inflammatory Bowel Disease The prominent role of the gut microbiota in the pathogenesis of inflammatory bowel disease (IBD) has been demonstrated by both human and animal studies (Britton et al., 2019; Lavelle and Sokol, 2020). The first actors in the interaction with the gut microbiota in IBD are epithelial cells. Alterations in the meta￾bolism and functions of IECs are involved in IBD and lead to an impaired intestinal barrier and the translocation of microbial mol￾ecules, resulting in overactivation of the gut immune system. Some studies are now linking the gut microbiota to defective IEC metabolism in intestinal inflammation, notably through the Nod-like receptor (NLR) family. NLRX1 (nucleotide-binding oligomerization domain, leucine-rich repeat containing X1) is a mitochondria-associated NLR with potential anti-inflammatory effects in colitis settings (Leber et al., 2018). NLRX1 is required to maintain balanced glutamine metabolism and barrier func￾tions in IECs. The mechanisms are not clearly demonstrated, but it is suggested that NLRX1 may support the glutamine input into the TCA cycle through its metabolism into glutamate and a-ketoglutarate. The impaired glutamine metabolism in IECs leads to changes in AA availability for the gut microbiota, inducing changes in composition. Interestingly, the altered gut microbiota exhibits a pro-inflammatory effect by itself, as demonstrated by fecal microbiota transfer experiments (Leber et al., 2018). NLR-associated inflammasomes are also involved. SCFAs induce the activation of NLRP3 (NOD-like receptor fam￾ily, pyrin domain containing 3) via their receptors GPR43 and GPR109a, inducing ion (K+ and Ca2+) efflux and promoting epithelial repair in colitis setting through IL-18 maturation and release (Macia et al., 2015). The impact of SCFAs on macro￾phage polarization is also relevant in IBD. SCFA depletion, for example, induced by antibiotics, favors an M1 hyperresponsive phenotype leading to an overproduction of pro-inflammatory cytokines and to the promotion of intestinal inflammation (Scott et al., 2018). Previous studies have also shown a link between mitochon￾drial dysfunction and IBD. The expression of prohibitin 1 (PHB1), an inner mitochondrial membrane component, is decreased in colonic biopsies from IBD patients (Hsieh et al., 2006; Theiss et al., 2007). Moreover, mitochondrial dysfunc￾tion in IECs and notably in Paneth cells can induce ileal inflam￾mation in mouse models (Jackson et al., 2020). Interestingly, Paneth cell abnormalities in patients with Crohn’s disease correlate with alterations in both microbiota composition and OXPHOS in ileal tissue (Liu et al., 2016). Mechanistically, mito￾chondrial respiration impairment forces IECs to acquire a dysfunctional Paneth cell phenotype, leading to metabolic imbalance and inflammation (Khaloian et al., 2020). Moreover, mitochondrial impairment in Crohn’s patients also involves a decrease in H2S detoxification, while the relative abundance of H2S-producing microbes is increased in the gut microbiota. The amount of Atopobium parvulum, a keystone microbiota species for H2S production, correlated with Crohn’s disease severity (Mottawea et al., 2016). Overall, the net increase in H2S due to increased microbiota production and decreased mitochondrial detoxification is involved in intestinal inflamma￾tion pathogenesis. CONCLUSION The effects of the gut microbiome on host immune cells are often examined with classical host-microbe interaction con￾cepts, relying on the recognition of conserved microbial motifs by innate immunity sensors, or on the effect of microbial mole￾cules on a host cell receptor. Despite the crucial role of the cellular metabolism in the ability to mount an appropriate immune response, the studies investigating how the gut micro￾biota directly affects it remain scarce. Yet the gut microbiota has a special relationship with metabolism, notably via the mitochondria due to their common origin. Mitochondria share a large part of their genome with bacteria, so communication and regulation can be evoked between these entities, which are only separated by the cell membrane (Lin and Wang, 2017). Host cell and gut microbiota are tightly connected in an inter-kingdom metabolic network that allows the proper functioning of mammalian meta-organisms. Each pathway is modulated by or depends on metabolites from others. It takes the collapse of only one path to compromise the normal oper￾ation. These processes are even more critical for immunome￾tabolism, as immune cells need to react to stimuli rapidly and to reprogram their metabolism to exercise their functions. Gut microbiota-derived metabolites are genuinely represented in immunometabolism, with a particularly important role of SCFAs, BAs, and AA metabolites. Deciphering all the ins and outs resulting from the action of the microbiota on immunome￾tabolism is highly challenging. Part of the complexity lies in the final effects of the microbial products, which can be different depending on the context or the cell types. The intrinsic diver￾sity of the actors within the gut microbiota and the immune sys￾tem brings an additional level of difficulty in the exploration of these interactions. The next step in the understanding of host-microbiota cross￾talk is to decipher more precisely the bidirectional impact of each metabolism on that of the partner in health and disease. This effort is crucial to identify therapeutic targets that will be actionable through metabolic modulation. These innovative treatments may take several forms. The modulation of the gut microbiota to favor beneficial metabolite-producing bacteria is one possibility. However, an even more attractive strategy is to precisely impact host-microbiota metabolism by accurately supplementing a missing metabolite and/or inhibiting an overac￾tivated pathway simultaneously on both sides of the interking￾dom crosstalk. ACKNOWLEDGMENTS H.S. received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Programme (ERC- 2016-StG-71577). We thank Hugo Michaudel for the design of the figures. AUTHOR CONTRIBUTIONS C.M. and H.S. wrote the paper. ll 520 Cell Metabolism 32, October 6, 2020 Perspective