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Review
. 2017 Jul 19;18(8):851-860.
doi: 10.1038/ni.3780.

Regulation of inflammation by microbiota interactions with the host

J Magarian Blander  1   2   3 , Randy S Longman  1   2 , Iliyan D Iliev  1   2 , Gregory F Sonnenberg  1   2   3 , David Artis  1   2   3
Affiliations
Review

Regulation of inflammation by microbiota interactions with the host

J Magarian Blander et al. Nat Immunol. .

Abstract

The study of the intestinal microbiota has begun to shift from cataloging individual members of the commensal community to understanding their contributions to the physiology of the host organism in health and disease. Here, we review the effects of the microbiome on innate and adaptive immunological players from epithelial cells and antigen-presenting cells to innate lymphoid cells and regulatory T cells. We discuss recent studies that have identified diverse microbiota-derived bioactive molecules and their effects on inflammation within the intestine and distally at sites as anatomically remote as the brain. Finally, we highlight new insights into how the microbiome influences the host response to infection, vaccination and cancer, as well as susceptibility to autoimmune and neurodegenerative disorders.

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Conflict of interest statement

COMPETING FINANCIAL INTERESTS

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1
Dietary fiber and SCFAs in intestinal homeostasis. Anaerobic fermentation of dietary fiber by members of the commensal microbiota, particularly by Clostridia spp., serves as a source of SCFAs, which help to maintain Treg cell expansion, immunosuppressive function and overall intestinal homeostasis. Butyrate is the preferred metabolic energy source for colonocytes but is detrimental to stem cells, inhibiting their proliferation and wound-repair functions. The strategic positioning of colonocytes and stem cells within the colon mirrors the concentration gradient of butyrate: colonocytes are positioned at the location of highest concentrations near the lumen, where they consume butyrate, thus decreasing the concentration to which distally located stem cells within the colonic crypts are exposed. Propionate is the end product of fucose metabolism by the microbiota. The host increases fucosylation of epithelial-cell carbohydrates during infection, thereby protecting its gut commensals. Fucose-using B. acidifaciens increase in abundance and elevate their metabolism of fucose, thus leading to propanediol formation. Propanediol dehydratase converts propanediol to propionaldehyde, thereby generating propionic acid, which in turn tempers inflammation and protects host tissues from collateral damage during the immune response to infection.
Figure 2
Figure 2
Examples of mechanisms mediating host–microbiota interactions. A diverse microbiota provides two signals for NLRP6 inflammasome activation in intestinal epithelial cells: signal 1 is in the form of LPS, and signal 2 is in the form of metabolites such as the bile-acid conjugate taurine. Together, these signals activate the NLRP6 inflammasome in intestinal epithelial cells and lead to the production of epithelial IL-18 and downstream antimicrobial peptides (AMP). Under dysbiotic conditions, such as those in mice lacking the inflammasome adaptor ASC, microbiota-derived histamine, putrescine and spermine are increased, thus suppressing NLRP6 inflammasome signaling in intestinal epithelial cells, decreasing production of epithelial IL-18 and AMP in the colon and promoting intestinal inflammation. B. thetaiotamicron induces the transcription factor HIF-1α in intestinal epithelial cells, thereby activating transcription and production of the antimicrobial peptide LL-37 (CRAMP in mice), which in turn promotes resistance to C. albicans colonization52. Gut anaerobic Firmicutes from the class Clostridia, and several clusters in Gram-negative Bacteroides and Desulfovibrio, express nonribosomal peptide synthetase–encoding gene clusters that mediate the synthesis of dipeptide aldehydes. The dipeptide aldehyde Phe-Phe-H is cell permeable and has been shown to inhibit cathepsins in macrophages, an activity that might modulate antigen processing and innate immune function. The generation of the nonproteinogenic amino acid trans-4-hydroxy-L-proline (t4L Hyp) is one of the most common post-translational modifications in eukaryotic cells but is rare in bacteria. Intestinal commensals such as Clostridiales and human pathogens such as C. difficile chemically reverse proline hydroxylation through the activity of the GRE trans-4-hydroxy-L-proline dehydratase, which generates L-proline. Many Clostridiales then use L-proline as an electron acceptor in amino acid fermentation.
Figure 3
Figure 3
Associations between the intestinal microbiota and autoimmune disorders. Infants from Russia have more abundant E. coli species expressing stimulatory hexa-acylated LPS, whereas infants from Finland and Estonia have more abundant Bacteroides spp. expressing the less stimulatory tetra- and penta-acylated LPS. Hexa-acetylated LPS induces greater Immunological stimulation but also endotoxin tolerance thought to dampen the capacity for immunological education in early life. However, the less stimulatory LPS from Bacteroides spp. impairs LPS tolerance, thus increasing susceptibility to immunological disease later in life. Enrichment of adherent-invasive E. coli in the IgA-coated microbiota in patients with Crohn’s disease–associated spondyloarthritis correlates with E. coli seroreactivity and systemic TH17 cell activation.
Figure 4
Figure 4
Links between the intestinal microbiota and neuroinflammation. Multiple members of the microbiota, such as Escherichia, Lactobaccillus, Bifidobacterium, Enterococcus and Truchuris, produce neurotransmitters and neuropeptides including dopamine, acetylcholine, gamma-aminobutyric acid, serotonin and brain-derived neurotrophic factor. Spore-forming bacteria, primarily Clostridium spp., modulate the colonic luminal metabolome, including SCFAs, thus inducing serotonin biosynthesis by enterochromaffin cells—the major producers of serotonin—and thereby affect intestinal motility and platelet function in mice,. In the colon, C. ramosum induces RORγt+ Treg cells but also represses neuronal-specific transcripts, particularly those encoding nociceptive neuropeptides12. Afferent neurons within the enteric nervous system (ENS) can communicate intestinal conditions to intestinal muscularis macrophages via β2-adrenergic receptors and also to the brain via the vagus nerve,. Intestinal colonization by the microbiota increases blood–brain tight junctions and barrier function, although microbiota-derived SCFAs can gain access to the brain and promote microglia differentiation and function,. Microbiota-dependent metabolism of tryptophan into AHR ligands engages AHR on astrocytes, thus leading to an increase in astrocyte expression of the inhibitor protein SOCS2 and consequently inhibiting activation of the transcription factor NF-κB and thereby limiting inflammation
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