Regulation of Gastrointestinal Immunity by Metabolites

Abstract

The gastrointestinal tract contains multiple types of immune cells that maintain the balance between tolerance and activation at the first line of host defense facing non-self antigens, including dietary antigens, commensal bacteria, and sometimes unexpected pathogens. The maintenance of homeostasis at the gastrointestinal tract requires stringent regulation of immune responses against various environmental conditions. Dietary components can be converted into gut metabolites with unique functional activities through host as well as microbial enzymatic activities. Accumulating evidence demonstrates that gastrointestinal metabolites have significant impacts on the regulation of intestinal immunity and are further integrated into the immune response of distal mucosal tissue. Metabolites, especially those derived from the microbiota, regulate immune cell functions in various ways, including the recognition and activation of cell surface receptors, the control of gene expression by epigenetic regulation, and the integration of cellular metabolism. These mucosal immune regulations are key to understanding the mechanisms underlying the development of gastrointestinal disorders. Here, we review recent advancements in our understanding of the role of gut metabolites in the regulation of gastrointestinal immunity, highlighting the cellular and molecular regulatory mechanisms by macronutrient-derived metabolites.

Keywords: bile acids; dietary metabolites; intestinal homeostasis; metabolism; microbial metabolites; microbiota; short-chain fatty acids; tryptophan.

Figure 1

Dietary metabolism in the gastrointestinal tract. Dietary components—carbohydrates, lipids, and proteins—are digested into diverse metabolites via complex reactions of enzymes released from host tissues and microbial fermentation in the gut. BCFAs, branched chain fatty acids; CLAs, conjugated linoleic acids; DCA, deoxycholic acid; HYA, 10-hydroxy-cis-12-octadeccenoid acid; hydroxy FA, hydroxy fatty acid; LCA, lithocholic acid; oxoFA, oxo fatty acid; SCFAs, short chain fatty acids.

Figure 2

Immune regulation by carbohydrate metabolites. Lactate and pyruvate induce dendrite protrusion of intestinal CX3CR1⁺ macrophages via GRP31 to enhance the immune response. Lactate also maintains gut homeostasis via Wnt/β-catenin signaling activation to induce intestinal stem cell proliferation. SCFAs act as HDAC inhibitors or stimulators for GPCRs to regulate intestinal immune homeostasis. SCFAs induce Treg cell differentiation, plasma B cell differentiation, and IL-22 production from ILC3 as well as Th1 and Th17 cells. Additionally, SCFAs regulate the activity of certain macrophages and dendritic cells (DCs). AhR, aryl hydrocarbon receptor; ALDH, aldehyde dehydrogenase; AMPs, anti-microbial peptides; GPCRs, G protein coupled receptor; HDAC, histone deacetylase; HIF1α, hypoxia-inducible factor 1-alpha; ISC, intestinal stem cell; PPAR-γ, peroxisome proliferator-activated receptor-γ; RA, retinoic acid.

Figure 3

Immune regulation by metabolites derived from lipids and amino acids. Microbial metabolites produced from lipids and amino acids regulate intestinal homeostasis. HYAs from lipids and tryptophan metabolites induce the expression of TJ proteins on epithelial cells to fortify intestinal barrier integrity. Bile acid metabolites inhibit the differentiation of Th17 cells but promote Treg cell differentiation through the production of mitoROS and induce the conversion of M1 macrophages to M2 macrophages. Also, bile acid metabolites help to maintain gut barrier integrity through accelerating crypt regeneration. Tryptophan metabolites enhance intestinal homeostasis through AhR activation to promote IL-22 production in ILC3 and stimulation of enteroendocrine L cells to produce GLP-1. BA, bile acids; EFG15, epidermal growth factor 15; FoxP3, forkhead box P3; FXR, farnesoid X receptor; GLP-1, glucagon-like peptide-1; GPBAR1, G protein-coupled bile acid receptor 1; HYA, 10-hydroxy-cis-12-octadeccenoid acid; IECs, intestinal epithelial cells; mitoROS, mitochondrial reactive oxygen species; MUC2, mucin 2; PGE2, prostaglandin E2; PXR, pregnane X receptor; RORγt, RAR-related orphan receptor gamma; TJ, tight junction; TNFα, tumor necrosis factor alpha; TRP, tryptophan.