Immune regulation by microbiome metabolites

Abstract

Commensal microbes and the host immune system have been co-evolved for mutual regulation. Microbes regulate the host immune system, in part, by producing metabolites. A mounting body of evidence indicates that diverse microbial metabolites profoundly regulate the immune system via host receptors and other target molecules. Immune cells express metabolite-specific receptors such as P2X₇ , GPR41, GPR43, GPR109A, aryl hydrocarbon receptor precursor (AhR), pregnane X receptor (PXR), farnesoid X receptor (FXR), TGR5 and other molecular targets. Microbial metabolites and their receptors form an extensive array of signals to respond to changes in nutrition, health and immunological status. As a consequence, microbial metabolite signals contribute to nutrient harvest from diet, and regulate host metabolism and the immune system. Importantly, microbial metabolites bidirectionally function to promote both tolerance and immunity to effectively fight infection without developing inflammatory diseases. In pathogenic conditions, adverse effects of microbial metabolites have been observed as well. Key immune-regulatory functions of the metabolites, generated from carbohydrates, proteins and bile acids, are reviewed in this article.

Keywords: barrier function; bile acids; immunity; indole; inflammation; metabolites; microbiome; short-chain fatty acids.

Figure 1

Production of microbial metabolites and their major receptors in the immune system. The gut microbiota can metabolize a variety of dietary materials, which include carbohydrates, proteins, lipids, plant‐derived molecules, bile acids and environmental contaminants. These materials are metabolized into short‐chain fatty acids (SCFAs), polyamines, ATP, indoles, phytochemical metabolites and bile acid metabolites. SCFAs function as histone deacetylase (HDAC) inhibitors to regulate gene expression and activate G‐protein‐coupled receptors (GPCRs) such as GPR43, GPR41, GPR109A (C4) and Olfr78 (C3). Other metabolites collectively activate nuclear receptors [aryl hydrocarbon receptor precursor (AhR), pregnane X receptor (PXR), VDR, LXR and farnesoid X receptor (FXR)], TGR5 and P2XRs. These receptors are expressed by various cells in the innate and adaptive immune systems to sense the presence of the gut microbial metabolites.

Figure 2

Impacts of microbial metabolites on the immune system. Gut microbial metabolites exert far‐reaching influences on the host. They regulate the immune system through histone deacetylases (HDACs), receptors and/or metabolic integration. Short‐chain fatty acids (SCFAs) fuel and fortify epithelial cells for promoting barrier functions. SCFAs also function as a neutrophil chemotaxin, and regulate macrophages and dendritic cells (DCs) through G‐protein‐coupled receptors (GPCRs) and HDACs. Bile acid metabolites also induce tolerogenic DCs and type 2 macrophages (M2), effects mediated by multiple receptors. Aryl hydrocarbon receptor precursor (AhR) activation by gut microbial metabolites induces regulatory T‐cells that express FoxP3 and IL‐10. Many gut microbial metabolites support the generation of induced Tregs for immune tolerance. SCFAs also fuel B‐cells and promote their differentiation into IgA‐ or IgG‐producing plasma B‐cells, an effect mediated by HDAC inhibition and metabolic regulation by SCFAs. However, during infection, gut microbial metabolites promote the generation of effector T‐cells such as Th1 and Th17 cells to fight pathogens. P2X7 activation by adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide (NAD) exert both positive and negative regulatory roles in the immune system. Both tolerogenic and inflammatory functions of gut microbial metabolites have been reported, indicating that the overall functions of gut microbial metabolites are determined by the immune status of the host.