Blander-2017-Regulation of inflammation by mic.pdf

Regulation of inflammation by microbiota interactions with the hostJ Magarian Blander1,2,3,Randy S Longman1,2,Iliyan D Iliev1,2,Gregory F Sonnenberg1,2,3,and David Artis1,2,31Jill Roberts Institute for Research in Inflammatory Bowel Disease,Joan and Sanford I.Weill Department of Medicine,Weill Cornell Medicine,Cornell University,New York,New York,USA2Department of Microbiology and Immunology,Weill Cornell Medicine,Cornell University,New York,New York,USA3Sandra and Edward Meyer Cancer Center,Weill Cornell Medicine,Cornell University,New York,New York,USAAbstractThe 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.An astounding number and diversity of microorganisms coexist with mammalian organisms1.Recent years have seen an increase in understanding of the complexity and sophistication of the hostmicrobiota relationship and its effects on human health24.Several technological advances have bolstered the study of mammalian microbiomes.Sequencing of 16S-rRNA-encoding genes has identified the constituent bacterial species of the human intestinal microbiota as belonging predominantly to the Bacteroidetes and Firmicutes phyla.Deep sequencing of the internal-transcribed-spacer regions ITS1 and ITS2 of the fungal ribosomal DNA and improved downstream analyses5,6 have unveiled the presence of rich fungal communities,dubbed the mycobiome,within the mammalian intestinal tract7.Sequencing of total DNA,the metagenome,from fecal specimens has enabled systematic studies on the virome and has yielded valuable information about the complex interaction of Reprints and permissions information is available online at http:/ should be addressed to J.M.B.(jmblandermed.cornell.edu).COMPETING FINANCIAL INTERESTSThe authors declare no competing financial interests.Publishers note:Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.HHS Public AccessAuthor manuscriptNat Immunol.Author manuscript;available in PMC 2018 July 19.Published in final edited form as:Nat Immunol.2017 July 19;18(8):851860.doi:10.1038/ni.3780.Author ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor Manuscriptthese commensals with their host.Large-scale endeavors have been launched to characterize the human microbiome:the US National Institutes of Health(NIH)-funded Human Microbiome Project(HMP)and the European Metagenomics of the Human Intestinal Tract(MetaHIT)8,9.Concurrently,gnotobiotic resources and treatment of mice with antibiotics have shown how specific compositions of the mouse or human gut microbiota contribute to disease development and have enabled mechanistic dissection of hostmicrobiota interactions.Targeted phenotypic culturing by subjecting fecal samples to selection for a desired phenotype and subsequent whole-genome sequencing and phylogenetic analysis has revealed that almost 75%of the intestinal microbiota is culturable10.Selection for sporulation has indicated that 5060%of intestinal bacterial genera produce resilient spores adapted for survival and dispersal10,thus potentially explaining why,in humans,the intestinal microbiota of family members with close contact have Ruminococcaceae and Lachnospiraceae spore-forming bacteria in common11.Ex vivo organ cultures of the mouse intestine have allowed for the introduction of molecules and microbes into the gut lumen in a setting that recapitulates luminal flow and features spontaneous peristaltic-like contractions and an intact tissue architecture and cellular network12.Microbiome-wide studies have revealed important correlations between specific microbes and a range of diseases including inflammatory bowel disease(IBD),autoimmune disease13,cancer14 and metabolic4 and neurodegenerative disorders15.Chronic inflammation is a driver of many of these conditions.Here,we focus on the most recent insights into the molecular underpinnings of hostmicrobiota interactions that influence inflammation within the intestine and distal organs.We consider the properties of the microbiota that most critically affect the immune response,including its biogeography,metagenome and metabolome,and how the microbiome modulates the host response to infection,autoimmunity,neuroinflammation,vaccination and tumor immunotherapy.Toward identification of an immune-modulatory microbiotaPhysical and biochemical barriers anatomically segregate the microbiota from mammalian immune cells in the intestine3,16.This demilitarized zone is essential to limit inappropriate immune activation16.On the host side of this zone lies the intestinal epithelium17,which comprises a single layer of intestinal epithelial cells whose frequent cycles of apoptosis and renewal18 maintain cellular fitness and orchestrate intestinal immune homeostasis19.The demilitarized zone is not impermeable,and certain commensals,such as segmented filamentous bacteria(SFB),Acinetobacter spp.,Bacteroides fragilis and Proteobacteria,can associate with the intestinal epithelium20.Proximity to the epithelium evokes the strongest effects on the host.For example,the capsular polysaccharide A of the human commensal B.fragilis stimulates production of the anti-inflammatory cytokine IL-10 by Foxp3+regulatory CD4+T(Treg)cells,thus facilitating colonization while promoting beneficial immunosuppression in the intestine20.Outer-membrane vesicles produced by B.fragilis activate noncanonical autophagy(involving the autophagy-related protein ATG16L1 and the receptor Nod2),thereby inducing Treg cells and suppressing mucosal inflammation21.Intestinal SFB colonization induces a response by IL-17-producing helper T(TH17)cells positive for the transcription factor RORt,thus protecting mice from infection with the Blander et al.Page 2Nat Immunol.Author manuscript;available in PMC 2018 July 19.Author ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor Manuscriptenteric rodent pathogen Citrobacter rodentium3.Similarly,Clostridium spp.and the human symbiont Clostridium ramosum are potent inducers of colonic Treg cells3,12.T celldependent immunoglobulin A(IgA)production is activated by epithelium-associated commensal bacteria,such as Mucispirillum and SFB22.These observations highlight the importance of defining the immunologically relevant microbiome,especially because many of the mucosal responses regulated by the microbiota are critical for intestinal homeostasis and are disrupted in IBD.The mouse circadian clock is synchronized according to diurnal oscillations in the composition and activities of the microbiota2325.The numbers and species of epithelial-associated commensals in mice fluctuate almost tenfold in the dark phase compared with the light phase,and diurnal oscillations in species such as Mucispirillum schae-dleri,Lactobacillus reuteri and Bacteroides acidifaciens are associated with the feeding cycle24.Bacterial adherence to the epithelium controls reprogramming of transcriptional oscillations not only in the colon but also at distant sites,such as the liver,through rhythmic chromatin remodeling and the activity of promoter and enhancer regions24.The diurnal detoxification of acetaminophen,regulated by circadian liver functions,is disrupted by changes in the microbiota24.The aforementioned immunologically relevant microbiome includes several keystone pathosymbionts identified through sorting and sequencing of IgA-coated microbiota(a technique termed IgA-seq or Bug-FACS)22,26,27.During the first two years of life in humans and gnotobiotic mice,age-specific bacterial taxa define distinct temporal patterns of mucosal IgA responses28.IgA can cross-link bacteria in the mammalian intestine,thereby inhibiting bacterial pathogenesis or the genetic spread of antimicrobial resistance29.Fecal IgA varies independently of bacterial phylogeny and can be perturbed during disease30.Enrichment of Enterobacteriaceae and Lachnospiraceae in IgA-coated and IgA-negative microbiota,respectively,in both Crohns diseaseassociated spondyloarthritis31 and malnutrition26,suggest that a potential core IgA response may exist in various inflammatory conditions.Keystone pathosymbionts may similarly affect mucosal T cell responses.Human-derived adherent-invasive Escherichia coli and Bifidobacteria adolescentis induce both mucosal and systemic inflammatory TH17 cells31,32.Although both of these pathosymbionts recapitulate the close epithelial adherence that has been observed for SFB,B.adolescentis triggers an epithelial transcriptional response distinct from that of SFB,thus suggesting the potential for shared and distinct pathways in microbial induction of TH17 cells.Whereas cluster IV,cluster XIVa and cluster XVIII Clostridium support Treg induction33,nearly one-quarter of the 53 species recently profiled similarly induce colonic Treg cells.This potential redundancy by a diverse group of bacteria may serve to ensure consistency in mucosal homeostasis.However,the immunomodulatory properties of different bacterial species do not necessarily cluster by phylum or genus,thus highlighting the importance of considering strain-specific traits when assessing immunological phenotypes.The subset of microbes that colonize lymphoid tissues are known as lymphoid-tissue-resident commensal(LRC)bacteria and include alpha-and betaproteobacteria,such as Alcaligenes,Achromobacter,Bordetella and Ochrobactrum species3437.LRC bacteria Blander et al.Page 3Nat Immunol.Author manuscript;available in PMC 2018 July 19.Author ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor Manuscriptselectively colonize the Peyers patches,isolated lymphoid follicles and mesenteric lymph nodes in healthy humans,nonhuman primates and mice,and their entry to these tissues depends in part on M cells,IgA and the cytokine IL-22(refs.34,36,38).LRC bacteria colonize dendritic cells and uniquely modulate cytokines that promote responses by local TH17 cells and group 3 innate lymphoid cells(ILC3)34.Innate lymphoid cells are ubiquitously distributed in humans and mice but are enriched at mucosal surfaces and rapidly respond to cytokine milieus after colonization with microbes37.Among subsets of innate lymphoid cells,ILC3 are most heterogeneous,uniquely express RORt and broadly comprise two subsets on the basis of expression of the chemokine receptor CCR6 or the transcription factor T-bet.CCR6+ILC3 lymphoid-tissue-inducer-like cells persist after birth in secondary lymphoid tissues,cryptopatches and isolated lymphoid follicles.CCR6+ILC3 promote gut-associated lymphoid-tissue maturation and IgA production,and contribute to the innate host defense to enteric pathogens37.CCR6+ILC3 are also antigen-presenting cells that regulate homeostasis with beneficial microbes by limiting the development of microbiota-specific CD4+T celleffector responses in the intestine37.In contrast,T-bet+ILC3 are localized diffusely in the intestinal lamina propria,require the aryl hydrocarbon receptor(AHR)and expand after microbiota colonization37,39.AHR protects mucosal sites from pathogenic infection and inflammation40.T-bet+ILC3 are responsive to microbial sensing by mononuclear phagocytes positive for the chemokine receptor CX3CR1,and subsequent ILC3 production of IL-22 has been linked to intestinal-tissue repair and barrier function by acting directly on intestinal epithelial stem cells37,41.IL-22 production by ILC3 also regulates epithelial fucosylation and supports diverse microbiota colonization37.LRC bacteria also induce IL-10 production by dendritic cells and provide tissue-protective functions in the context of intestinal-barrier damage34.ILC3 promote anatomical containment of LRC bacteria,because ILC3 depletion results in systemic bacterial dissemination and chronic immunological activation37.Additional research is required to define the mechanisms by which LRC bacteria colonize dendritic cells and mammalian lymphoid tissue,as well as to interrogate the functional potential and compositional changes of LRC bacteria in the context of chronic inflammatory diseases.Interaction with symbiotic fungi,protozoa,worms and virusesRich and diverse fungal communities(mycobiota)colonize the mammalian barrier surfaces.Mycobiota diversity increases in the lower gastrointestinal tract,and several genera such as Candida,Saccharomyces,Aspergillus,Cryptococcus,Malassezia,Cladosporium,Galactomyces and Trichosporon have the potential to colonize the intestines7,4244.Fungal-community changes with outgrowth of Candida spp.have been documented in people with IBD43,4547.Deficiencies in the receptor Dectin-1(also known as CLEC7A)and the downstream adaptor protein CARD9 lead to susceptibility to more severe experimental colitis as well as fungal and bacterial dysbiosis6,7,48.Clec7a/mice colonized with Candida tropicalis show aggravated experimental colitis,whereas the absence of Candida leads to less severe disease6,49.Fungi and bacteria share similar niches in the intestine,and these communities influence each other.Antibiotic treatment promotes gut Candida col-onization7,50,which can have immunological outcomes at distant sites such as the lung7,51.Bacteria affect fungal colonization both directly and indirectly.Bacteroidetes Blander et al.Page 4Nat Immunol.Author manuscript;available in PMC 2018 July 19.Author ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor Manuscriptthetaiotamicron,which induces the production of the antimicrobial peptide CRAMP by the transcription factor HIF-1,prevents Candida albicans gut colonization52.In addition to fungi,the common mouse protozoan Tritrichomonas musculis is a transmissible microorganism in mice that increases susceptibility to T celldependent intestinal inflammation while providing protection from intestinal infections through inflammasome activation and production of the cytokine IL-18 by intestinal epithelial cells53,54.The mammalian gastrointestinal tract is also colonized with eukaryotic viruses,which may substantially affect intestinal health and disease.Colonization with common murine norovirus is able to compensate for several,but not all,functional and immunological defects in germ-free or antibiotic-exposed mice55.In the presence of a diverse microbiota,several enteric eukaryotic viruses interact with the commensal microbiota and consequently induce immu