Taming the Sentinels: Microbiome-Derived Metabolites and Polarization of T Cells

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: IBD; T cells; T regulatory cells; Th lineage polarization; Th17 helper cells; inflammatory bowel disease; intraepithelial lymphocytes; metabolites; metabolome; microbiome.

Figure 1

Summary of short chain fatty acids (SCFAs) metabolism and functions. (A) Most of the SCFAs are produced in the large intestine upon fermentation of dietary fiber, which is carried out by the host microbiome’s bacterial members. (B) SCFAs can activate cell-intrinsic cascades through the g-protein-coupled receptors (GPCRs) (upper panel) or affect transcription of the genes upon inhibition of histone deacetylases HDAC (lower panel). In the gut, SCFAs, after transport into the colonocytes’ intracellular compartment (mostly through monocarboxylate transporter channels (MTC) and sodium-coupled monocarboxylate transporters (SMCT)), are utilized as an energy substrate (butyrate) or channeled further to the blood circulation through the portal vein. (C) Systemic distribution of SCFAs. (D) Impact of the different SCFAs on T cell lineage polarization. Graphic created with BioRender.

Figure 2

(A) Schematic representation of the endogenous and microbiota-associated pathways engaged in tryptophan breakdown in the gut environment. Highlighted in violet is a putative light-independent synthesis pathway of 6-formylindolo [3,2-b]carbazole (FICZ), an endogenous aryl hydrocarbon receptor (AHR) ligand. (B) The Trp metabolites act as AHR and pregnane X receptor (PXR) ligands. Upon activation, AHR and PXR translocate into the nucleus and activate the transcription of target genes. (C) AHR stimuli play an important role in the development of intraepithelial lymphocytes (IEL) subsets and in control of the Treg–Th17 axis. Graphic created with BioRender.