Whole metagenomic and metatranscriptomic sequencing endeavours are defining the functional potential and real-time activity of microbiomes and revealing interactions between microbial metabolism and host development.
Gut microorganisms produce a diverse metabolite repertoire from the anaerobic fermentation of undigested dietary components that reach the colon, as well as from endogenous compounds that are generated by the microorganisms themselves and their hosts.
Complex carbohydrates are abundant substrates for bacterial fermentation in the colon, and their major metabolic end-products are short-chain fatty acids (SCFAs). SCFAs inhibit histone deacetylases (HDACs) and are ligands for G protein-coupled receptors; therefore, they act as signalling molecules that influence the expansion and function of haematopoietic and non-haematopoietic cell lineages. SCFA-driven HDAC inhibition tends to promote a tolerogenic, anti-inflammatory cell phenotype that is crucial for maintaining immune homeostasis and supports the concept that the microbiota can function as an epigenetic regulator of host physiology.
D-glycero-β-D-manno-heptose-1,7-bisphosphate (HBP), an intermediate in the lipopolysaccharide biosynthetic pathway of Gram-negative bacteria, initiates a novel innate immune signalling axis without first requiring bacterial lysis — a phenomenon that is so far unique to Neisseria gonorrhoeae.
Meta-omics and evolving computational frameworks are leading to the prediction and discovery of more microbial metabolites and components that are relevant to immune system function. It is also important to probe how well-known microbial metabolites (such as SCFAs) and co-metabolites (such as polyamines and aryl hydrocarbon receptor ligands) influence immune cell subsets and their functions.
The microbiota — the collection of microorganisms that live within and on all mammals — provides crucial signals for the development and function of the immune system. Increased availability of technologies that profile microbial communities is facilitating the entry of many immunologists into the evolving field of host–microbiota studies. The microbial communities, their metabolites and components are not only necessary for immune homeostasis, they also influence the susceptibility of the host to many immune-mediated diseases and disorders. In this Review, we discuss technological and computational approaches for investigating the microbiome, as well as recent advances in our understanding of host immunity and microbial mutualism with a focus on specific microbial metabolites, bacterial components and the immune system.
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The authors thank the members of the Garrett laboratory for their helpful discussions. The work relevant to this Review is supported by the grants R01 CA154426 and R01 GM099531, a Burroughs Wellcome Career in Medical Sciences Award and a Searle Scholars Award to W.S.G.
The authors declare no competing financial interests.
An imbalance in the composition or function of the microbial species that are normally found in mammalian hosts. It is associated with alterations in immune function and susceptibility to inflammatory diseases, allergies and metabolic conditions.
- Gnotobiotic mouse models
Experimental models in which germ-free mice are selectively colonized by defined microorganisms and kept in isolators to control their microbial colonization status.
- Bone marrow–liver–thymus humanized mice
(BLT humanized mice). Immunodeficient mice that are engrafted with human fetal liver and thymus under the renal capsule. Three weeks later, mice are irradiated and then injected with a suspension of CD34+ cells from the same human fetal liver sample. These fetal liver cells seed to the mouse bone marrow.
- Humanized mouse models
Experimental models in which mice carry functioning human genes, cells, tissues (including faecal material) or organs that are introduced by transgenesis, injection or transplantation. For example, an immunodeficient mouse transgenically expressing susceptibility genes for type 1 diabetes and reconstituted with T cells from a patient with type 1 diabetes and human islets of Langerhans can be used to study relevant autoimmune processes.
- Fluorescence in situ hybridization
(FISH). A technique in which fluorescent probes are used to visually label specific DNA sequences in the nuclei of cells.
- Metabolic oligosaccharide engineering
(MOE). A technology in which synthetic sugar analogues are exogenously supplied to living cells and biosynthetically incorporated into cell surface polysaccharides. An advantage of this technology is that it can be used for prokaryotic and eukaryotic cells that are grown under aerobic or anaerobic conditions.
- Bio-orthogonal click chemistry
(BCC). A chemical reaction in a living cell that allows a labelled synthetic probe to be covalently linked to targeted cellular substrates without disrupting any native functions of the cell. This method can be used to tag and visualize biomolecules within cells of interest.
- Anaerobic fermentation
The process of extracting energy from carbohydrates. Some bacteria are facultative anaerobes, meaning they can switch between aerobic respiration and anaerobic pathways, depending on the availability of oxygen or other electron acceptors. Other bacteria are obligate anaerobes, meaning they completely rely on anaerobic fermentation and can only survive in the absence of oxygen.
- Histone deacetylases
(HDACs). Enzymes that remove the acetyl groups from lysine residues that are located at the amino termini of histones. In general, decreased levels of histone acetylation are associated with the repression of gene expression. The balance of histone acetylation is maintained by the interplay between HDACs and histone acetyltransferases.
- Dextran sodium sulfate-induced injury model
(DSS-induced injury model). A commonly used experimental model of colonic injury and mucosal inflammation induced in mice by ingestion of the sulfated polysaccharide DSS. This model causes acute colonic epithelial damage and inflammation.
- T cell transfer colitis model
A well-characterized model of chronic colitis that is induced by the transfer of CD4+CD45RBhi (naive) T cells from healthy wild-type mice into immunodeficient syngeneic recipients.
Compounds inclusive of drugs, food components and pollutants.
- Innate lymphoid cell
(ILC). A lymphoid cell that is derived from the common lymphoid progenitor and does not express a recombined antigen receptor. ILCs have important roles in innate immune responses to infectious microorganisms, in epithelial homeostasis and in lymphoid tissue formation.
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Rooks, M., Garrett, W. Gut microbiota, metabolites and host immunity. Nat Rev Immunol 16, 341–352 (2016). https://doi.org/10.1038/nri.2016.42
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BMC Biology (2023)
Host metabolome and faecal microbiome shows potential interactions impacted by age and weaning times in calves
Animal Microbiome (2023)
A 90-day oral exposure to food-grade gold at relevant human doses impacts the gut microbiota and the local immune system in a sex-dependent manner in mice
Particle and Fibre Toxicology (2023)
Comparative analysis of intestinal microbiota composition and transcriptome in diploid and triploid Carassius auratus
BMC Microbiology (2023)