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Microbiome-Derived Metabolites and Polarization of T Cells International Journal of Molecular Sciences Review Taming the Sentinels: Microbiome-Derived Metabolites and Polarization of T Cells Lukasz Wojciech 1, Kevin S. W. Tan 2 and Nicholas R. J. Gascoigne 1,* 1 Immunology Programme and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Singapore 117545, Singapore; [email protected] 2 Laboratory of Molecular and Cellular Parasitology, Healthy Longevity Programme and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Singapore 117545, Singapore; [email protected] * Correspondence: [email protected] Received: 3 September 2020; Accepted: 11 October 2020; Published: 19 October 2020 Abstract: A global increase in the prevalence of metabolic syndromes and digestive tract disorders, like food allergy or inflammatory bowel disease (IBD), has become a severe problem in the modern world. Recent decades have brought a growing body of evidence that links the gut microbiome’s complexity with host physiology. Hence, understanding the mechanistic aspects underlying the synergy between the host and its associated gut microbiome are among the most crucial questions. The functionally diversified adaptive immune system plays a central role in maintaining gut and systemic immune homeostasis. The character of the reciprocal interactions between immune components and host-dwelling microbes or microbial consortia determines the outcome of the organisms’ coexistence within the holobiont structure. It has become apparent that metabolic by-products of the microbiome constitute crucial multimodal transmitters within the host–microbiome interactome and, as such, contribute to immune homeostasis by fine-tuning of the adaptive arm of immune system. In this review, we will present recent insights and discoveries regarding the broad landscape of microbiome-derived metabolites, highlighting the role of these small compounds in the context of the balance between pro- and anti-inflammatory mechanisms orchestrated by the host T cell compartment. Keywords: microbiome; metabolites; metabolome; T cells; T regulatory cells; Th17 helper cells; Th lineage polarization; intraepithelial lymphocytes; inflammatory bowel disease; IBD 1. Introduction The innate and adaptive immune systems make up a cooperative set of machinery involved in organismal defense from pathogens and malignant cells, while limiting reactions to self molecules. T cells are a dominant faction of the adaptive arm, for which initial functional diversification occurs in a central organ, the thymus. To some extent, thymic-derived regulatory T cells (tTregs) can maintain immune homeostasis [1,2]. However, it is widely accepted that to fully perpetuate this pro- and anti-inflammatory balance, immune compartments require specialized executors that are reprogrammed in the peripheral organs. T cell receptor (TCR) specificity can play a vital role in those lineages’ polarization [3–5]. However, experiments carried out on mouse models with transgenic T cell receptors and nextgen sequence (NGS) data from T cell repertoires has revealed that, in some circumstances, clones that express a particular TCR exhibit divergent capability in terms of functional specialization in peripheral organs [6,7]. This promiscuity of the TCR in the context of different T cell lineages indicates a huge plasticity within the adaptive compartment and a complex network of interacting components involved in building up niches for specific cell subsets. Int. J. Mol. Sci. 2020, 21, 7740; doi:10.3390/ijms21207740 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 7740 2 of 17 Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 2 of 17 The intestines constitute a unique,unique, very dynamic, environment that harbors complex microorganism consortia composed composed of of prokaryotes, prokaryotes, eukaryotes, eukaryotes, and and viruses. viruses. It Itis isestimated estimated that that a ahealthy healthy human human microbiome microbiome consists consists of 500 of to 500 1000 to 1000different different species species belong belonginging to more to than more 70 than genera 70 genera[8,9]. From [8,9]. the From immune the immune compartment’s compartment’s perspective, perspective, gut tissues gut tissues maintain maintain the most the mostfunctionally functionally and andphenotypically phenotypically diversified diversified T cell T cellcollecti collection.on. The coexistence The coexistence of these of these two twocomplex complex systems, systems, the themicrobiota microbiota and and immune immune compartment, compartment, necessitates necessitates a asophisticated sophisticated network network of of interacting interacting elements to continuously maintain a beneficial beneficial synergy synergy rather rather than than an an antagonistic antagonistic host host–pathogen–pathogen relationship. relationship. ThereThere is is a a growing growing body body of ofevidence evidence that that gut gutdwelling dwelling consortia consortia constitute constitute key orchestrators key orchestrators for many for manyaspects aspects of host of physiology, host physiology, including including metabolic metabolic capacity, capacity, host defense host defense and behavioral and behavioral processes. processes. The Thequantitative quantitative and andqualitative qualitative impoverishment impoverishment of ofthe the T Tcell cell compartment compartment in in germ germ-free-free animals indicates the great importanceimportance ofof commensalcommensal microorganismsmicroorganisms duringduring developmentdevelopment and peripheralperipheral shaping of this cell subset [1010,11,11].]. Representatives of of the the gut gut microbiome microbiome that that exert exert potentially potentially pro-inflammatory pro-inflammatory [3] and [3] anti and- anti-inflammatoryinflammatory [12–14 [12] –effects14] eff ectson the on thehost host immune immune system system have have recently recently been been identified identified [15] [.15 A]. Adysregulated dysregulated immune immune response response that that results results in in intestinal intestinal inflammation inflammation is is associated associated with with an altered intestinal microbiota,microbiota, reflected reflected by aby decreased a decreased diversity diversity of gut-dwelling of gut communities;-dwelling communities; the phenomenon the isphenomenon called dysbiosis is called [16]. Interestingly,dysbiosis [16 some]. Interestingly, of the hallmarks some ofof inflammationthe hallmarks are of transmittable inflammation upon are guttransmittable microbiome upon transfer gut microbiome [17], which transfer indicates [17 a] pro-, which or anti-inflammatory indicates a pro- or imprintanti-inflammatory associated with imprint the distributionassociated with or composition the distribution of the orspecies composition within of gut the consortia species within [16,18 ].gut consortia [16,18]. Physiological processesprocesses maintained maintained by theby microbiomethe microbiome constitute constitute a source a of metabolicsource of byproductsmetabolic (smallbyproducts chemical (small compounds chemical compounds that make upthat a make uniquely up a configureduniquely configured signaling signaling network) network [18,19].) Besides [18,19]. beingBesides essential being essential in ecological in ecological interactions interactions between between microbiota microbiota species, species, these metabolites these metabolites serve as serve crucial as signalingcrucial signaling molecules molecules engaged engaged in reciprocal in reciprocal host–microbiome host–microbiome interplay interplay [16,18]. It [16 has,18 become]. It has apparent become thatapparent metabolites that metabolites produced produced by the microbiota by the microbiota affect many affect physiological many physiological processes, processes including, controlincluding of thecontrol adaptive of the armadaptive of the arm immune of the systemimmune (Figure system1). (Figure 1). Figure 1. Summary of of short chain fatty acids ( (SCFAs)SCFAs) metabolism and functions. ( (AA)). Most of the SCFAs are produced in in the the large large intestine intestine upon upon fermentation fermentation ofof dietary dietary fiber fiber,, which which is carried is carried out out by bythe thehost host microbiome microbiome’s’s bacterial bacterial members members.. (B) (SCFAsB) SCFAs can canactivate activate cell- cell-intrinsicintrinsic cascades cascades through through the theg-protein g-protein-coupled-coupled receptors receptors (GPCRs) (GPCRs) (upper (upper panel) panel) or oraffect affect transcription transcription of of th thee genes genes upon inhibition of histone deacetylases HDAC (lower panel). In In the the gut, SCFAs, after transport into the colonocytes’ intracellularintracellular compartment compartment (mostly (mostly through through monocarboxylate monocarboxylate transporter transporter channels channels (MTC) and(MTC) sodium-coupled and sodium-coupled monocarboxylate monocarboxylate transporters transporters (SMCT)), (SMCT) are utilized), are asutilized an energy as an substrate energy (butyrate)substrate (butyrate) or channeled or channeled further to further the blood to the circulation blood circulation through thethrough portal the vein. portal (C )vein. Systemic (C). distribution of SCFAs. (D) Impact of the different SCFAs on T cell lineage polarization. Graphic created Systemic distribution of SCFAs. (D). Impact of the different SCFAs on T cell lineage polarization.
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