Commensal bacteria at the interface of host metabolism and the immune system

Abstract

The mammalian gastrointestinal tract, the site of digestion and nutrient absorption, harbors trillions of beneficial commensal microbes from all three domains of life. Commensal bacteria, in particular, are key participants in the digestion of food, and are responsible for the extraction and synthesis of nutrients and other metabolites that are essential for the maintenance of mammalian health. Many of these nutrients and metabolites derived from commensal bacteria have been implicated in the development, homeostasis and function of the immune system, suggesting that commensal bacteria may influence host immunity via nutrient- and metabolite-dependent mechanisms. Here we review the current knowledge of how commensal bacteria regulate the production and bioavailability of immunomodulatory, diet-dependent nutrients and metabolites and discuss how these commensal bacteria-derived products may regulate the development and function of the mammalian immune system.

Figure 1

Commensal bacteria at the interface of host metabolism and immunity. (a) Commensal bacteria regulate digestion by mediating bile acid synthesis, lipid absorption, amino acid metabolism, vitamin synthesis and SCFA production. (b) Commensal bacteria participate in digestion and regulate host metabolic homeostasis, and commensal bacteria–derived nutrients regulate the immune system. This commensal bacteria–metabolite–immune system axis (orange arrows) exists in a complex network of interactions among commensal bacteria, host digestion and the immune system (orange and black arrows).

Figure 2

Regulation of bile acid metabolism by commensal bacteria and effects of bile acids on immune cells. (a) Roles of commensal bacteria in synthesis of bile acids. Bile acids are synthesized in the liver from cholesterol-derived precursor molecules and are emptied into the small intestine. There, commensal bacteria deconjugate bile acids and convert primary into secondary bile acids. Bile acids are reabsorbed in the ileum and transported to the liver to complete enterohepatic circulation. Some bile acids gain access to systemic circulation. Molecular structure of bile acid is representative of some but not all bile acids. (b) Bile acid signaling in macrophages and monocytes via GPBAR1 and NR1H4. Both pathways lead to inhibition of NF-κB, albeit by different mechanisms. GPBAR1 signaling involves cAMP-PKA-mediated inhibition of STAT1 and NF-κB, and NR1H4 signaling leads to NR1H4-NCoR1–mediated repression of NF-κB–responsive elements (NRE). Bile acid stimulation of both pathways leads to less NF-κB–dependent gene expression. (c) Bile acid signaling in NKT cells. This cell type expresses NR1H4, and bile acid engagement of this nuclear receptor represses osteopontin expression. This molecule has many functions, including promoting neutrophil activation and chemotaxis as well as NKT cell activation in an autocrine or paracrine manner. (d) Pathogens and diseases associated with immune responses regulated by bile acids. NAFLD, non-alcoholic fatty liver disease.

Figure 3

Synthesis of SCFAs by commensal bacteria, and regulation of immunity by SCFAs. (a) Commensal bacteria ferment nondigestible polysaccharides ingested in the diet (for example, cellulose) to produce SCFAs. Various SCFAs and their molecular structures are shown. C1–C6 refers to the number of carbons. Isoforms of these SCFAs are not shown. (b) Known molecular pathways through which SCFA regulate populations of immune cells. SCFAs bind the G protein–coupled receptor GPR43, which leads to a decrease in cAMP levels, calcium influx and ERK1/2 activation. SCFAs also inhibit histone deacetylases (HDACs), which are transcriptional repressor proteins. (c) SCFA regulation of neutrophils, macrophages/monocytes (MΦ), dendritic cells (DCs), CD4⁺ T cells and intestinal epithelial cells (IEC). ROS, reactive oxygen species; MHCII, major histocompatibility class II.