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REVIEW ARTICLE OPEN

Interaction between microbiota and immunity in health and

disease
Danping Zheng1,2, Timur Liwinski1,3 and Eran Elinav 1,4

The interplay between the commensal microbiota and the mammalian immune system development and function includes
multifold interactions in homeostasis and disease. The microbiome plays critical roles in the training and development of major
components of the host’s innate and adaptive immune system, while the immune system orchestrates the maintenance of key
features of host-microbe symbiosis. In a genetically susceptible host, imbalances in microbiota-immunity interactions under defined
environmental contexts are believed to contribute to the pathogenesis of a multitude of immune-mediated disorders. Here, we
review features of microbiome-immunity crosstalk and their roles in health and disease, while providing examples of molecular
mechanisms orchestrating these interactions in the intestine and extra-intestinal organs. We highlight aspects of the current
knowledge, challenges and limitations in achieving causal understanding of host immune-microbiome interactions, as well as their
impact on immune-mediated diseases, and discuss how these insights may translate towards future development of microbiome-
targeted therapeutic interventions.
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Cell Research (2020) 30:492–506; https://doi.org/10.1038/s41422-020-0332-7

INTRODUCTION ‘non-communicable’ gastrointestinal diseases including inflamma-

The human body, including the gut, skin and other mucosal tory bowel disease (IBD)8 and celiac diseases,9 as well as extra-
environments, is colonized by a tremendous number of micro- intestinal disorders ranging from rheumatic arthritis,10 metabolic
organisms, collectively termed the microbiome.1 The collective syndrome,11 neurodegenerative disorder12 to malignancy.13 The
genomes of bacteria and other microorganisms in this ecosystem, interactions between the gut microbiota and host immunity are
including fungi, viruses, parasites,2 have been increasingly complex, dynamic and context-dependent. Here, we review and
investigated during the past two decades, facilitated by a rapid exemplify important current knowledge and key concepts linking
development of culture-independent genomic techniques. Recent the microbiome to development and function of the immune
advances in microbiome research revealed that the gut micro- system. We highlight some of the existing mechanistic dissections
biome is not just a passive bystander, but actively impacts of multifaceted microbiome-immunity dialogs in both homeo-
multiple host functions, including circadian rhythmicity, nutritional static and diseased states. Moreover, we discuss the challenges
responses, metabolism and immunity.3,4 and perspectives of microbiome-targeted strategies in study-
The mammalian immune system encompasses a complex ing disease pathogenesis and developing new microbiome-
network of innate and adaptive components in all tissues, and related treatments. As the large body of evidence related to host
plays a vital role in host defense against various potentially immune-microbiome interactions cannot be summarized by a
harmful external agents and endogenous perturbations of home- single review, we aim to provide key concepts and examples of
ostasis. From an ecological perspective, mammals and their such interactions and their potential effects on human health and
commensal microorganisms co-evolved toward mutualism and disease risk, while referring throughout the review to multiple
hemostasis.5 Such intimate relationship requires the proper other recent reviews14–16 focusing on distinct aspects of these
functioning of host immunity to prevent commensals from over- emerging interactions.
exploitation of host resources while maintaining immune toler-
ance to innocuous stimuli.6,7 However, perturbation of the gut
microbiome by environmental incursions (such as antibiotic use, THE ROLE OF THE MICROBIOME IN IMMUNE SYSTEM
diet or changes in geography), impairment of host-microbiome DEVELOPMENT
interfaces, or alterations of the immune system can result in Early-life colonization of the mammalian host’s mucosal surfaces
systemic dissemination of commensal microorganism, suscept- plays a pivotal role in maturation of the host’s immune system.17
ibility to pathogenic invasion, and aberrant immune responses. In Most critical events in education of host immunity may take place
addition to regulation of infection and commensal spread, during the first years of life, in which microbiota composition
microbiome-immune interactions are implicated in a variety of displays the highest intra- and inter-individual variability before

1
Immunology Department, Weizmann Institute of Science, 234 Herzl Street, 7610001 Rehovot, Israel; 2Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen
University, Guangzhou, Guangdong, China; 31st Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany and 4Cancer-Microbiome Division,
Deutsches Krebsforschungszentrum (DKFZ), Neuenheimer Feld 280, 69120 Heidelberg, Germany
Correspondence: Eran Elinav ([email protected])
These authors contributed equally: Danping Zheng, Timur Liwinski

Received: 19 February 2020 Accepted: 20 April 2020

Published online: 20 May 2020

© The Author(s) 2020

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reaching a more stable adult-like configuration at the age of ~3 impact on understanding, prevention and treatment of immune-
years.18–20 However, the 'window of opportunity' thus created, may related disorders.
also render infants more susceptible to environmental incursions to
the microbiota, with potentially long-lasting harmful impacts on
immunity.21 The immaturity of the immune system in newborns INTERACTION BETWEEN MICROBIOTA AND IMMUNE SYSTEM
and infants is highlighted by an increased susceptibility to various IN HOMEOSTASIS
infectious pathogens,22 rendering infectious diseases the leading Host-induced compartmentalization of intestinal microbiota
cause for mortality in children.23 On the other hand, an increased The best-studied interface for host-microbiota interactions is the
propensity towards excessive inflammation is also frequently intestinal mucosa. A remarkable feature of the intestinal immune
encountered in prematurely born infants, as exemplified by the system is its ability to establish immune tolerance towards an
potentially devastating disorder necrotizing enterocolitis.24 Most enormous and constantly changing wealth of harmless micro-
studies to date have not noted a reproducible microbial coloniza- organisms while concomitantly preserving immune responses
tion already occurring in utero,25 and it is generally believed that against pathogenic infection or commensal intrusion into the
the largest share of colonization occurs after birth, mainly sterile body milieu.41 In a healthy state, the host’s immune
originating from the maternal microbiota.26 Multiple modulators response to the intestinal microbiota is strictly compartmentalized
impact this initial colonization, including delivery mode that to the mucosal surface.42 A single layer of epithelium separates
impacts on the composition of the initial microbiota across the intestinal lumen from underlying tissues. Many mechanisms
multiple body habitats.27 It is well established that in neonates are employed to achieve microbiota compartmentalization. A
maternal antibodies delivered via breastmilk offer crucial passive dense mucus layer separates the intestinal epithelium from
protection against pathogens.28 Interestingly, a recent work resident microbes.43 The mucus barrier is organized around the
showed that the commensal microbiota of pregnant mice drives hyperglycosylated mucin MUC2. However, MUC2 not only offers
antibody-mediated protective immunity through breastfeeding.29 protection by static shielding, but also constrains the immuno-
The study of mechanistic causal relationships between com- genicity of intestinal antigens by imprinting enteric dendritic cells
mensal microbiota and host immunity is strongly informed by the (DCs) towards an anti-inflammatory state.44 Tight junctions are a
use of germ-free (GF) animal models. Early studies on GF animals critical structure in restricting trans-epithelial permeability. Micro-
demonstrated that absence of commensal microbes is associated bial signals, e.g., via the metabolite indole, promote fortification of
with profound intestinal defects of lymphoid tissue architecture the epithelial barrier through upregulation of tight junctions and
and immune functions.30 αβ and γδ intra-epithelial lymphocytes associated cytoskeletal proteins.45 In addition, secretory IgA
(IELs) are significantly reduced in GF mice compared to conven- antibodies and antimicrobial peptides (AMPs) maintain the
tional colonized animals, and can be strongly induced upon de mucosal barrier function (see below).32,46 Intestinal DCs are
novo colonization.31 IgA antibodies are a mainstay of protective believed to play a critical role in compartmentalizing enteric
humoral mucosal immunity and show substantial reduction in microbiota, through mechanisms involving sampling of gut
newborns and GF animals, which is rapidly restored by microbial bacteria for antigen presentation.47
colonization.32 Gestational maternal colonization increases intest-
inal group 3 innate lymphoid cells (ILC3s) and F4/80+CD11c+ Crosstalk between the innate immune system and the microbiota
mononuclear cells in the offspring.26 The lamina propria of the Microbiota and innate immunity engage in an extensive bidirec-
small intestine contains a large number of IL-17+CD4+ T (Th17) tional communication (Fig. 1). One of the phylogenetically oldest
cells, which represent a class of potent immunomodulatory effec- systems of innate immunity is represented by AMPs. The majority
tor cells.33 Th17 cells are absent in GF mice and are inducible upon of intestinal AMPs is produced by Paneth cells, which represent
microbial colonization, most notably with segmented filamentous specialized secretory cells of the small intestinal mucosa.48
bacteria (SFB),33,34 but also other commensal bacteria.35 Induction Intestinal AMPs exhibit manifold interactions with the microbiota
of Th17 cells by SFB is enabled by their adhesion to epithelial and are an essential component in shaping its configuration.49
cells.36 A bacterial polysaccharide derived from the ubiquitous Adding to the complexity of intestinal AMPs, antimicrobial
commensal Bacteroides fragilis directs the maturation of the secretion from pancreatic acini seems to be critical for main-
developing immune system in mice, including correction of tenance of intestinal homeostasis, as mice featuring reduced
systemic T cell deficiencies and Th1/Th2 imbalances in lymphoid secretion of pancreas-derived cathelicidin-related AMP secondary
tissues.37 An early B cell lineage in the intestinal mucosa is to lack of the potassium channel Orai1 demonstrate a dramatically
regulated by extracellular signals from commensal microbes that increased mortality due to increased systemic microbial transloca-
influence gut immunoglobulin repertoires.38 Intestinal microbial tion and inflammation.50
diversity during early-life colonization is critical to establish an Pattern recognition receptors (PRRs), such as Toll-like receptors
immunoregulatory network that protects from induction of (TLRs), were initially described to sense microbial signals during
mucosal IgE, which is linked to allergy susceptibility.39 The innate infection to elicit a protective immune response. However, ligands
immune receptor Toll-like receptor 5 (TLR5) serves as a sensor for for PRRs are not exclusive to pathogens and are abundantly
bacterial flagellin. Although in mice TLR5-mediated counter- produced by commensal microbiota during healthy colonization
selection of colonizing flagellated bacteria is constrained to the (reviewed in7). TLRs are involved in host defense against
neonatal period, this critical process shapes gut microbiota pathogens, regulate the abundance of commensal microbes and
composition and thus impacts on immune homeostasis and maintain tissue integrity.51 TLR expression in the intestinal
health in adult life.40 epithelium is characterized by a high diversity in terms of spatial,
To summarize, it is increasingly recognized that critical host cell type-specific, and temporal patterns.52 TLR5 is of particular
immune-microbiota interactions operate during a critical time importance in shaping the gut microbiota,53–56 which might be
window in early life, which may have long-lasting impacts on confined to a critical time window during neonatal life.40
multiple immune arms contributing to immune homeostasis and Polysaccharide A (PSA) produced by the commensal Bacteroides
susceptibility to infectious and inflammatory diseases later in life. fragilis is another well-studied example of a single molecule
However, the mechanisms of these interactions are still relatively promoting symbiosis and host immune system education.57–59
poorly defined, and the long-term impacts of subtler dysbiosis PSA is recognized by the TLR2/TLR1 heterodimer in cooperation
states during the neonatal period on adult immunity and risk of with Dectin-160, a C-type lectin PRR.61 Downstream to TLR1/TLR2
immune-mediated diseases merit future studies in human. More and Dectin-1 signaling, the phosphoinositide 3-kinase (PI3K)
detailed insights into such modulatory effects, if present, may bear pathway is activated leading to inactivation of glycogen synthase

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Fig. 1 Intestinal microbiota-immunity interplay in homeostasis. Selected mechanistically well-characterized microbiota-immune system
interactions are depicted. Microbiome-derived TLR and NOD ligands and metabolites (e.g., SCFA, AhR ligands) act directly on enterocytes and
intestinal immune cells, but can also reach remote tissues via the systemic circulation to modulate immunity. Foxp3+ Treg cells and Tfh/ex-
Th17 cells localize in Peyer’s patches to promote class switch of B cells and production of secretory (s)IgA. These contribute to
compartmentalization of commensal microbiota and regulate homeostatic microbiota composition. Intestinal colonization by SFB and many
other commensals promotes differentiation of CD4+ Th17 cells. Moreover, SFB colonization elicits signaling via the ILC3/IL-22/SAA1/2 axis to
induce IL-17A production by RORγt+ Th17 cells. ILC3-derived IL-22 contributes to containment of specific microbiota members by promoting
IL-17A production by Th17 cells. Furthermore, deletion of ILC3-expressed MHCII activates commensal-specific CD4+ T cells to prevent an
immune response against harmless colonizers. Early-life microbial colonization limits the expansion of iNKT cells, in part via production of
sphingolipids, to prevent potential disease-promoting activity within the intestinal lamina propria and the lungs. Colonization with Bacteroides
fragilis, a prominent member of mammalian intestinal microbiota, is able to promote CD4+ T cell differentiation and to balance Th1 and Th2
populations, an effect that relies on its PSA. PSA is taken up by lamina propria DCs through a TLR2-dependent mechanism and presented to
naïve CD4+ T cells. In the simultaneous presence of activated TGF-β, these cells can differentiate to regulatory T cells (iTreg). IL-10 produced by
these cells promotes immune homeostasis. Contrarily, IL-23 licensed through the same cascade promotes expansion of pro-inflammatory
Th17 cells.

kinase 3β (GSK3β), which in turn induces cAMP response element- induced by the effector molecules interleukin-1 (IL-1) and IL-18
binding protein (CREB)-dependent expression of anti- through their respective receptors.66 Mice deficient in MyD88
inflammatory genes.60 Moreover, Dectin-1 may regulate intestinal display an altered microbiota composition.56 MyD88 controls the
immunity by controlling Treg cell differentiation through mod- epithelial expression of several AMPs, including RegIIIγ, which
ification of microbiota configuration.62 Additional PRRs suggested restricts the number of surface-associated gram-positive bacteria
to shape the gut microbiota composition are NOD-like receptors and limits activation of adaptive immunity.67 Moreover, MyD88
(NLRs). Nucleotide-binding oligomerization domain-containing regulates T cell differentiation, promotes microbiota homeostasis
protein 1 (NOD1) serves as an innate sensor assisting generation through stimulation of IgA and controls the expansion of Th17
of adaptive lymphoid tissues and maintenance of intestinal cells by restricting growth of SFB in mice.68
homeostasis.63 The bacterial sensor NOD2 prevents inflammation Some NLRs assemble into multiprotein complexes abundant in
of the small intestine by restricting the growth of the commensal many different cell types termed inflammasomes, whose pleio-
Bacteroides vulgatus.64 Stimulation of NOD2 by commensal trophic immune functions are reviewed extensively elsewhere.69
bacteria promotes gut epithelial stem cell survival and epithelial Inflammasomes activate inflammatory caspases, which promote
regeneration.65 the maturation of IL-1β and IL-18, and induce a lytic type of cell
MyD88 is an adapter for multiple innate immune receptors that death termed pyroptosis.69 NOD-, LRR (leucine‐rich repeat)- and
recognize microbial signals, and of the signaling pathways pyrin domain-containing 6 (NLRP6) is such protein assembling

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inflammasome in the intestinal mucosa. The NLRP6 inflamma- transcriptome and chromatin state profiling hints towards a much
some has been linked with regulation of microbiome composition more diverse landscape of ILCs.91 ILCs represent a rapidly growing
and maintenance of intestinal homeostasis.70 NLRP6 inflamma- new research area reviewed more comprehensively
some signaling is co-modulated by microbiota-derived metabo- elsewhere.92,93 The phenotypic diversity and functional plasticity
lites, which regulates epithelial IL-18 secretion and AMP of the host’s intestinal ILCs are shaped by integrating signals from
expression profiles.71 Moreover, the NLRP6 inflammasome gov- the microbiome.91 One factor regulating proliferation and function
erns intestinal ‘sentinel’ goblet cell mucus secretion, which offers of group 3 ILCs is the microbial metabolite sensor Ffar2.94
critical protection against pathogens.72,73 Beyond its role with Recently, a dichotomous regulation of group 3 ILCs by a pair of
regard to the bacterial kingdom, NLRP6 regulates intestinal Helicobacter species in mice was identified. These species
antiviral innate immunity.74 Importantly, the impact of NLRP6 on activated ILCs but negatively regulated the proliferation of group
microbiota community structure is dependent on the background 3 RORγt+ ILCs that are crucial for host immunity and inflamma-
microbiota in the vivarium, with dysbiosis occurring in mice tion.95 Type 3 ILCs mediate immune surveillance of microbiota
lacking NLRP6 only in the presence of distinct microbiome configuration to facilitate early colonization resistance through a
configuration containing pathobionts such as Helicobacter spp.75 transcriptional regulator ID2-dependent regulation of IL-22.96
Another notable example of NLR assembling inflammasomes is NCR+ ILC3 cells were demonstrated to be essential for maintaining
NLRP3. Regulation of NRLP3 inflammasome signaling is required cecal homeostasis in mice during Citrobacter rodentium infec-
to maintain intestinal homeostasis. In patients with ulcerative tion.97 A commensal linked with risk for allergic disease in
colitis, a surplus of anti-commensal IgG engages gut-resident children, Ruminococcus gnavus, induces infiltration of the colon
FcγR-expressing macrophages, inducing NLRP3- and reactive and lung parenchyma by eosinophils and mast cells in mice via a
oxygen species-dependent production of the pro-inflammatory cascade implicating type 2 ILCs, hinting at a crucial role of ILCs in
cytokine IL-1β.76 Upon intestinal injury, certain members of the immune tolerance.98
microbiota such as Proteus mirabilis stimulate monocytes to
induce NLRP3-dependent IL-1β release, which elicits intestinal Interactions between the adaptive immune system and the
inflammation.77 Moreover, sensing of intact bacterial peptidogly- microbiota
can and peptidoglycan fragments by the innate immune system In addition to the impacts of host-microbiota interactions on
through numerous PRRs is necessary for proper development of innate immune function, recent research also uncovered mechan-
immune cells and other tissues (reviewed in78). Another crucial isms governing mutualism between the microbiome and the
PRR interacting with the microbiota through inflammasome adaptive immune system (Fig. 1). One example involves B cells,
signaling is the absent in melanoma 2 (AIM2). The AIM2 crucial mediators of gut homeostasis by producing a large array of
inflammasome was described to regulate intestinal homeostasis secretory IgA antibodies responsive to commensals.46 Several
through the IL-18/IL-22/STAT3 pathway.79 Mammalian peptido- grams of IgA are secreted every day in the human intestines.99
glycan recognition proteins (PGRPs) protect the host from colitis Secretory IgA can be produced either in a T cell-independent or a
by promoting balanced microbiota configuration and by prevent- T cell-dependent manner. IgA produced in a T cell-dependent way
ing production of IFNγ by NK cells in response to injury.80 These plays a more important role in shaping gut microbial commu-
protective effects are in part achieved synergistically with NOD2.81 nities.100 The relationship between intestinal IgA and microbiota is
IPAF is an important member of the NOD‐LRR family of proteins. It mutualistic, in that a diversified and selected IgA repertoire con-
recognizes intracellular flagellin and activates inflammasomes, tributes to maintenance of a diversified and balanced microbiome,
stimulates caspase‐1, and promotes IL‐1β production in a TLR5‐ which facilitates the expansion of Foxp3+ regulatory T cells
independent manner in Salmonella-infected macrophages.82 sustaining homeostatic IgA responses in a regulatory loop.101
However, its role in host-commensal interplay is still not clearly Interestingly, intestinal secretory IgA antibodies preferentially coat
defined. Other PRRs potentially implicated in regulating host- colitogenic bacteria, therefore preventing perturbation of enteric
microbiome symbiosis requiring further exploration are RIG-I-Like homeostasis and inflammation.102 In the absence of B cells, or of
Receptors (RLRs)83 and OAS-Like Receptors (OLRs).84 IgA, intestinal epithelia upregulate epithelium-inherent immune
An underappreciated area of microbiota research is represented defense mechanisms mediated by interferon-inducible response
by commensal protists. In an elegant study on transkingdom pathways, which are associated with subsequent changes in
interactions, the authors demonstrate that the murine commensal microbiome composition. Interestingly, the simultaneous repres-
protist Trichomonas musculis protects against enteric bacterial sion of Gata4-related metabolic functions in this scenario results in
infection by activating epithelial inflammasome signaling, and impaired intestinal absorption and metabolic alterations.103
thus promoting DC-driven Th1 and Th17 immunity.85 Recently, a new subset of subepithelial mesenchymal cells
Monocytes and macrophages are crucial innate immune expressing the cytokine RANKL were identified to serve as
effector cells and have vital homeostatic roles.86 Recent research intestinal M cell inducers, thereby fostering IgA production and
started to shed light on the relationships between these gut microbiota diversification.104
monocytes/macrophages and the commensal microbiota. A large Studies conducted during the past decade provided a more
microbiota-derived polysaccharide has been shown to induce an detailed picture of the crosstalk between the gut microbiome and
anti-inflammatory gene signature in murine intestinal macro- CD4+ regulatory T cells. A subset of colonic regulatory CD4+
phages.87 Moreover, butyrate can drive monocyte-to-macrophage T cells lack differentiation in GF mice resulting from the absence of
differentiation through histone deacetylase 3 (HDAC3) inhibition, bacterial consortia capable of fermenting dietary fiber into short-
thereby amplifying antimicrobial host defense.88 Recently, it has chain fatty acids (SCFAs).105–107 Reactivity to intestinal bacteria
been demonstrated that a soluble microbiome-derived metabo- seems to be a 'healthy' property of both intestinal and systemic
lite, trimethylamine N-oxide (TMAO), can drive murine macro- human CD4+ T cells, which may support homeostasis by providing
phage polarization in an NLRP3 inflammasome-dependent a large pool of immune cells protective against pathogens.108 Of
manner.89 these cells, the Th17 subset is intensely studied because of its
Innate lymphoid cells (ILCs) are a more recently discovered ambiguous roles in both host protection and inflammatory
heterogenous innate immune cell population specialized in the disorders.109 The intestine harbors functionally distinct Th17 cell
rapid secretion of polarized cytokines and chemokines to combat populations and their inflammatory propensity is largely deter-
infection and promote mucosal tissue repair.90 ILCs have been mined by distinct bacteria eliciting their differentiation. Th17 cells
categorized into three distinct types based on transcription factors elicited by SFB are non-inflammatory, while Th17 cells induced by
and cytokine signatures. However, an in-depth single-cell Citrobacter are a potent source of inflammatory cytokines.110

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While it is well established that microbiota is involved in Th17 Antibiotic-induced microbiome disturbances
differentiation in the intestine36 and the skin111, oral barrier Th17 Antibiotics are an indispensable treatment against infectious
cell development seems to be largely independent from microbial diseases and their introduction has dramatically changed health-
colonization.112 Another example of microbiome regulation of care and human life expectancy. However, evidence suggests that
adoptive T cell responses involves CD8+ (cytotoxic) T cells, whose antibiotic use during childhood is associated with the develop-
effector functions are paramount in elimination of intracellular ment of a range of immune-mediated diseases, including allergies
pathogens and cancer cells. While these cells require priming by and IBD.21,128 Intake of antibiotics profoundly affects the composi-
professional antigen-presenting cells (APCs) and are amplified by tion and function of the gut microbiota, and may introduce long-
CD4+ T cell signaling113, antigen-activated CD8+ T cells show no lasting adverse effects on the host.129 Different immune cell
transition into memory cells in GF mice, as microbiota-derived subsets and functions can be altered by antibiotic-driven gut
SCFAs are required to promote their memory potential.114 A microbial dysbiosis. In rats, administration of antibiotics inhibits
fraction of primary bile acids secreted into the intestine escape intestinal mucosal mast cell activation and suppresses dietary lipid
into the colon where they are converted into secondary bile acids uptake.130 Broad-spectrum antibiotic-mediated microbial pertur-
by the microbiota, and may have various signaling functions that bation and depletion of microbiota-derived SCFAs causes
are yet to be fully explored. A recent work showed that hyperactivation of intestinal macrophages and expansion of
microbiota-derived secondary bile acids regulate gut RORγ+ proinflammatory T helper cells and increases susceptibility to
regulatory T cell homeostasis.115 infection.131 Furthermore, antibiotic treatment permits over-
Follicular helper T (Tfh) cells are specialized to assist B cells, and growth of enteric fungi, thereby promoting pulmonary M2
are crucial for germinal center formation, affinity maturation, and macrophage polarization, which in turn promotes allergic airway
generation of high-affinity antibody responses and memory B inflammation.132 Microbiota disruption by antibiotics results in
cells.116 Tfh cells are implicated in maintenance of microbiota enhanced pathogen-specific Th1 cell responses and tissue
homeostasis as highlighted by studies showing that impairment of pathology in an CX3CR1+ MNP-dependent manner.133 Signifi-
Tfh cells resulting from lack of expression of co-receptor cantly reduced RORγt+ Tregs in GF or antibiotic-treated mice
programmed cell death 1 (PD-1) or ATP-gated ionotropic P2RX7 promote Th2 type-associated immune responses and inflamma-
receptor can alter gut microbiota composition.117,118 The relation- tion upon helminth infection.134 In humans with pre-existing
ship between Tfh cells and the microbiota is reciprocal, as Tfh cell immune system impairment, microbiome depletion through
differentiation is impaired in GF mice and can be restored by broad-spectrum antibiotics not only results in a diminished
administration of Toll-like receptor 2 (TLR2) agonists that activate T antibody response to seasonal influenza vaccination, but also
cell-intrinsic MyD88 signaling.119 In mice, SFB can induce Tfh cell leads to augmented circulatory inflammatory signatures and
differentiation in Peyer’s patches by limiting the access of IL-2 to altered plasma metabolome profiles.135 The long-term health
CD4+ T cells, thereby amplifying the master regulator Bcl-6 of Tfh consequences of antibiotic-induced microbiome alterations in
cells.120 The microbiota-Tfh axis may also be relevant in auto- humans merit more long-term observational studies and clinical
immune diseases, as in mice SFB-induced Tfh cell differentiation can trials.
boost autoantibody production and thus exacerbate arthritis.120
Additionally, recent studies began to uncover the relationships Diet-induced microbiome alterations
between the microbiota and tissue-resident DCs, which represent Recent studies began to unravel the links between dietary
an important class of APCs shaping immune responses. DCs are microbiota modulation and host immunity. Western style diets
able to send their dendrites outside the epithelium to directly profoundly affect gut microbiome configuration and adversely
capture bacteria.121 Recently, a Syk kinase-coupled signaling impact on host immunity.136 For example, a diet high in saturated
pathway in DCs was described to be critical for microbiota- fats increases the levels of taurocholic acid, a secondary bile acid,
induced production of IL-17 and IL-22 by CD4+ T cells.122 and in turn fosters the expansion of Bilophila wadsworthia. This
Moreover, a noncanonical NF-κB-inducing kinase (NIK) was pathobiont promotes Th1 type immune responses and increases
recently reported to be a crucial mediator of mucosal DC function. susceptibility to colitis in IL10–/– mice.137 High-fat diet can also
In the same study, DC-specific NIK altered enteric IgA secretion aggravate disease severity in chemically induced murine colitis by
and microbiota homeostasis, rendering mice vulnerable to enteric disturbing the homeostasis of intestinal DCs, possibly by reducing
pathogens.123 butyrate and retinoic acid levels.138 Dietary long-chain fatty acids
A relatively unexplored set of immune cells with crucial may exacerbate autoimmunity in the central nervous system (CNS)
relationship to the commensal microbiota is represented by by modulating the gut microbiome and metabolome.139 In mice,
invariant natural killer T cells (iNKTs). The gut microbiota affects intake of dietary carbohydrates,105 certain probiotics,140 artificial
the phenotypes and functions of iNKTs in mice, with iNKTs from sweeteners141 and emulsifiers142 can modulate host immunity and
GF animals showing a less mature phenotype and decreased inflammation, in part mediated by compositional changes of the
activation by antigens.124 Mono-colonization of neonatal GF mice gut microbiome. In humans, individuals with higher fecal
with the commensal Bacteroides fragilis or exposure to a purified abundance of the bacterial genus Dialister and lower levels of
sphingolipid originating from B. fragilis was able to restore iNKT Coriobacteriaceae family members show reduced serum levels of
cell numbers in GF mice and to protect the animals from the pro-inflammatory cytokine IL-6 after short-term consumption
oxazolone-induced colitis.125 of whole grains.143
In addition to dietary quantity and content, the timing of dietary
intake has been recently shown to affect microbiome composition
INFLUENCE OF ENVIRONMENTAL MICROBIOME and in turn immunity. Intermittent fasting ameliorates disease
PERTURBATION ON THE IMMUNE SYSTEM severity in a murine model of autoimmune encephalomyelitis and
The gut microbiome is shaped by a wealth of environmental in patients with multiple sclerosis by microbiota-mediated
factors whose impacts dominate over host genetics.126 These balancing of IL-17-producing and regulatory T cells.144 In a murine
environmental factors, including diet, antibiotic use, westernized colitis model, a fasting-mimicking diet exerted a protective effect
lifestyle, etc., are potential triggers of inflammatory and auto- through modulation of the gut microbiome including an increase
immune diseases.127 Understanding of environmental gut micro- of Lactobacillus.145 In contrast, mistimed dietary intake accelerates
biome modulation and its impact on disease propensity is still in alcohol-associated colonic carcinogenesis by reducing the number
its infancy. Currently, the best-studied environmental sources of of butyrate- and SCFA-producing bacteria, which causes mucosal
microbiome variation are antibiotic treatment and diet. Th17/regulatory T cell imbalance.146

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Fig. 2 Dysregulation of microbiome-immunity interaction in disease. Under the influence of certain environmental factors and host genetic
susceptibility, aberrant interactions between the microbiome and the host’s immune system contribute to the development of various
immune-mediated disorders. In IBD as an example, antibiotic use or dietary changes, in the presence of genetic susceptibility (e.g., NOD2
mutation), may lead to alterations of the gut microbiome configuration, including decreased richness and perturbed taxonomic and
metabolite composition. These microbiome alterations are strongly associated with aberrant mucosal immune responses, including
upregulated Th17, Th1 and Th2 type responses, downregulated T regulatory cells, and dysregulated humoral immunity. This may finally result
in chronic, clinically-overt intestinal inflammation and tissue injury.

Of note, the impact of the microbiome on immunity in gastrointestinal tract, characterized by a growing global preva-
laboratory mice can be vastly divergent from that in humans, lence.148 Multiple lines of evidence point towards central roles
which is in part explained by differences in microbiota between of gut microbiome perturbations in the pathogenesis of IBD.
mice raised in laboratory versus wild environments. Mice with a These include a reduced bacterial diversity and marked shifts in
natural wild microbiota are more resilient to environmental abundance of certain bacterial taxa, including decreased abun-
challenges and show responses to immunotherapy that are more dance of Bacteroides, Firmicutes, Clostridia, Lactobacillus, Rumino-
resemblant of humans.147 Therefore, it is important to study the coccaceae and increased abundance of Gammaproteobacteria and
impact of environmental exposures on the host immune system in Enterobacteriaceae,149,150, coupled with altered microbiome-
a context of such human-like microbiota configuration, which may associated metabolite profiles.151,152 The breakdown of the tightly
promote better understanding of immune system-microbiota regulated intestinal barrier leads to translocation of bacterial
interactions and their translation into clinical applications. symbionts into the mucosal layer, fueling aberrant host immune
responses and tissue injury.153 As such, disruptions of gut barrier
integrity, including the mucus layer, epithelial cell junctions, and
DYSREGULATION OF MICROBIOME-IMMUNITY INTERACTION AMP secretion are all believed to be involved in IBD pathogen-
IN DISEASE esis.154 For example, mice deficient in Muc2 may develop
Aberrant interactions between the microbiome and the host’s spontaneous colitis,155 and mucus layer defects due to Muc2
immune system in genetically susceptible individuals may mutation drive early gut dysbiosis in colitis-prone mice.156
contribute to the development of complex immune-mediated Genome-wide association studies revealed so far more than
diseases (Fig. 2). Among these, the most extensively studied 200 susceptibility loci for IBD, many of which encode proteins
examples include IBD, systemic autoimmune diseases, cardiome- involved in innate and adaptive immune sensing and response to
tabolic diseases and cancer. Additionally, the microbiome- bacterial signals. Among these, mutation in the NOD2 gene was
immunity link has been suggested to modulate other ‘multi- the first to be confirmed to be strongly associated with
factorial’ diseases (e.g., neurodegenerative diseases) but requires susceptibility to CD.157,158 NOD2 is an intracellular PRR capable
further human studies. More importantly, the causal effect of the of recognizing bacterial peptidoglycan-conserved motifs. NOD2
microbiome on immune dysregulation in most human disorders acts as a critical regulator of the intestinal commensal microbiota,
listed above remains to be proven. by controlling the expression and secretion of AMPs159 (see
above) and suppressing the expansion of certain proinflammatory
Inflammatory bowel disease bacterial species such as Bacteroides vulgatus.64 The dysregulated
IBD, mainly encompassing Crohn’s disease (CD) and ulcerative microbiome-immunity interaction in the context of NOD2 muta-
colitis, is a chronic, recurrent inflammatory disorder of the tion is assumed to play important roles in CD pathogenesis.

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Likewise, mutations in autophagy-related 16-like 1 (ATG16L1), Cardiometabolic disease
another CD-associated risk allele, not only result in impaired Chronic low-grade inflammation is considered a hallmark of
exocytosis in Paneth cells,160 but potentiate inflammatory metabolic disorders, including diabetes mellitus, obesity, athero-
responses and necrosis of intestinal epithelial cells through sclerosis and non-alcoholic fatty liver disease (NAFLD). In
modulation of IL-22 signaling.161 The role of inflammasome metabolically highly active organs such as the liver or adipose
signaling in regulating the crosstalk between the microbiome tissue, the crosstalk between immune cells and parenchymal cells
and immunity is likewise implicated in pre-clinical IBD models. For plays a critical role in the pathogenesis of metabolic diseases.178
example, perturbation of the NLRP6 inflammasome pathway Growing evidence shows that gut microbiome-derived metabo-
results in susceptibility to murine colitis through expansion of lites can reach systemic circulation through the gut barrier and
members of the Prevotellaceae family in some vivaria,70 and fuel metabolic inflammation.179 Various TLRs in the liver recognize
promotes intestinal inflammation in IL10–/– mice by enhancing bacterial ligands and trigger downstream inflammatory cascades.
colonization with Akkermansia muciniphila.162 The contribution of Activation of these TLRs can contribute to the development of
adaptive immune responses to the expansion of IBD-associated NAFLD and nonalcoholic steatohepatitis (NASH), with the most
pathobionts, including aberrant roles of effector T cells, regulatory extensively studied pathway being LPS-TLR4 signaling.180 In
T cells and antibody-mediated humoral immunity, has been addition to TLRs, the NLRP6 and NLRP3 inflammasomes may
reviewed extensively elsewhere.153 exert protective effects against NAFLD/NASH through modulation
Notwithstanding all of these data, whether microbiome of the gut microbiota.181 Multiple interactions between the host’s
alterations represent the cause or consequence of intestinal immune system and the gut microbiota were reported to be
inflammation remains unclarified to date. Some emerging involved in type 1 diabetes (T1D). For example, GF non-obese
evidence supports a causal role of gut dysbiosis in IBD, since diabetic mice lacking MyD88 signaling robustly develop T1D,
transfer of disease-associated microbiota triggers CD-like inflam- while microbial colonization of these mice attenuates the
mation in genetically susceptible GF recipient mice.163 Microbiota disease.56 Depletion of Akkermansia muciniphila causes systemic
from IBD patients transplanted to GF mice likewise induces translocation of endotoxin-activated CCR2+ monocytes. These in
imbalances in intestinal Th17 and RORgt+ regulatory T cells.164 turn activate innate pancreatic B1a cells, resulting in increased
More strikingly, one single pathobiont, Mucispirillum schaedleri, insulin resistance.182 Furthermore, the crosstalk between the
was demonstrated to be sufficient to trigger a Th1 cell-driven microbiome and immunity plays a crucial role in obesity. For
intestinal inflammation in mice deficient in both NOD2 and example, microbiome-derived tryptophan metabolites modulate
CYBB.165 Similarly, ectopic colonization of oral Klebsiella spp. white adipose tissue inflammation in obesity, mediated through
derived from IBD patients, induces Th1-type intestinal inflamma- the miR-181 family of microRNAs.183 Recently, the innate immune
tion in IL10–/– mice.166 Furthermore, abnormal T cell and B cell sensor NLRP12 was shown to decrease high fat diet-induced
adaptive immunity can be transmitted to GF mice from infant- obesity in mice by preserving SCFA-producing members of the
harbored microbiome born to IBD-prone mothers.167 Increasing Lachnospiraceae family.184 One of the most perilous common
knowledge on molecular impacts of distinct commensals and their sequelae of cardiometabolic disease is atherosclerosis and its
small-molecule products on the clinical features of IBD may enable complications. The gut microbiota-derived metabolite TMAO has
the development of future targeted interventions. been linked to atherosclerotic heart disease in both mice and
humans.185 Interestingly, TMAO augments arthrosclerosis by
Rheumatoid arthritis upregulating the macrophage scavenger receptors CD36 and
Rheumatoid arthritis (RA) is a systemic autoimmune disorder SR-A1, and by reinforcing cholesterol accumulation in macro-
mainly involving the joints, characterized by synovial inflamma- phages and foam cell formation.186
tion and bone cartilage destruction. The pathogenesis of this
highly debilitating disease is currently unclear. Genetic (e.g., HLA- Cancer
DRB1), microbiome and environmental factors have been Interactions between the gut microbiota and the immune system
implicated in the pathogenesis of RA. An increased abundance are believed to impact on cancer immune surveillance. In the
of Prevotella copri was reported in treatment-naïve new-onset RA context of colon cancer, NK cell killing of tumors is directly
patients168,169 and in individuals at high risk for RA.170 Another inhibited by the presence of Fusobacterium nucleatum in the
study identified a strong link between three rare genera tumor microenvironment. This is in part mediated by binding of
(Collinsella, Eggerthella and Faecalibacterium) and RA, among the bacterium’s Fap2 protein to the human TIGIT receptor.187
which Collinsella is associated with proinflammatory IL-17A Higher amounts of F. nucleatum in human colorectal cancer tissue
production.171 In a Chinese cohort, RA patients displayed an are furthermore associated with a lower density of CD3+ T cells, a
over-representation of Lactobacillus salivarius and reduced levels population associated with a more favorable clinical outcome.188
of Haemophilus spp. in intestinal, dental and saliva specimens.172 In remote tissues such as the liver, the intestinal commensal
Microbiome-derived metabolites, most notably SCFAs, interact Clostridium species utilize bile acids as messengers to enhance the
with a variety of immune pathways implicated in RA.173 antitumoral effect of hepatic CXCR6+ NKT cells, affecting both
Spontaneous development of T cell-mediated autoimmune primary and metastatic liver tumors.189 The microbiome has been
arthritis in IL1rn–/– mice requires the activation of TLR2 and TLR4 recently suggested to also modulate anticancer immunotherapy
by microbial ligands.174 Dysbiotic microbiota from IL1rn–/– mice responses. For example, higher abundances of the commensals
elicits a IL17 response by intestinal lymphocytes.175 Moreover, Bifidobacterium longum, Collinsella aerofaciens, and Enterococcus
genetically susceptible mice colonized with dysbiotic microbiota faecium stimulate a more favorable T cell-mediated response to
from RA patients show an enhanced Th17 type response.169 anti-PD-1 therapy in both preclinical models and patients suffering
Similarly, inoculation of SFB into GF mice is sufficient to induce from metastasized melanoma.190–192 Another study revealed a
Th17 activation and to instigate autoimmune arthritis.176 In positive correlation between fecal Akkermansia muciniphila
addition to the enteric bacteria, the periodontal pathobiont abundance and PD-1 blockade efficacy in patients with epithelial
Porphyromonas gingivalis can induce a TLR2- and IL-1-mediated tumors, potentially dependent on CCR9+CXCR3+CD4+ T lympho-
Th17 response and thereby exacerbate autoimmune arthritis.177 cyte recruitment and IL-12 secretion.193 Immune responses to
Future studies are required to determine the influence of RA other anticancer treatments, including CTLA-4 blockade194 and
treatment on the microbiome and the causal role of microbiome cyclophosphamide,195 were also associated with distinct gut
alterations potentially modulating human RA. microbiome configurations. Unraveling the role of the gut

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Fig. 3 Microbiome-immunity interaction in extra-intestinal organs. The gut microbiome and microbiome-associated metabolites
translocate from the intestinal lumen to various organs (e.g., liver, brain or lung) through the circulatory system, and subsequently induce
tissue-specific local immune responses. In the liver, bacterial LPS is recognized by TLR4 in different cell types, leading to upregulation of
various pro-inflammatory chemokines and adhesion molecules. MAMPs influence the number, function and maturation of Kupffer cells, and
glycolipid antigen-containing probiotics can activate hepatic NKT cells. The gut-resident pathobiont Klebsiella pneumoniae can translocate and
induce Th17 cell responses in the liver. In the CNS, microbiome-derived SCFAs regulate microglial homeostasis, and promote regulatory T cells
to counter-regulate CNS autoimmunity. In the lung, SCFA-induced primed myeloid cells translocate to the lung and shape the pulmonary
immunological landscape. Clostridium orbiscindens-derived product desaminotyrosine modulates type I IFN signaling. In addition, exposure to
different lung-resident microbes (e.g., Pseudomonas, Lactobacillus, pneumotypeSPT) is associated with an enhanced Th17 type response.

microbiome in anticancer immune surveillance and immunother- throughput sequencing-based studies revealed a diversity of site-
apy may hold great promise in optimizing treatment responses in specific but temporally stable microbial communities in the
cancer patients, and has been reviewed elsewhere in greater healthy human skin200,201 featuring inter-individual variability.202
detail.13,196 The skin microbiota induces protective and regulatory immu-
Aside from the gut microbiome, most recent research begins to nity that contributes to host-microbe mutualism. Skin-resident
explore the role of intra-tumor tissue microbiome in regulating commensals not only effectively control the equilibrium of T
cancer immunity. For example, intra-tumor microbiota in pan- effector and regulatory T cells in the tissue, dependent of IL-1 and
creatic adenocarcinoma (PDAC) in mice and humans promotes MyD88 signaling,111 but also regulate components of the
carcinogenesis through induction of a tolerogenic immune cutaneous complement system203 as well as the expression of
program, including suppressive differentiation in monocytes via various cutaneous AMPs.204 Certain aspects of the regulation of
selective TLRs and T cell anergy.197 In addition, the presence of cutaneous innate and adaptive immunity by the skin microbiome
Gammaproteobacteria in murine colon cancer and human PDAC feature strain specificity. One of the most highly abundant skin
contributes to resistance against therapy with gemcitabine.198 commensals, Staphylococcus epidermidis, can specifically induce
Interestingly, the intra-tumor microbiome in long-term survivors homing of CD8+ T cells primed by CD103+ DCs into the epidermis
of PDAC patients exhibits higher microbial diversity, which may and can promote skin antimicrobial responses in an IL17-
induce potent immune infiltration and antitumor immunity.199 dependent manner.205 Furthermore, the S. epidermidis-specific
These studies indicate the potential of tumor tissue-resident CD8+ T cell response is restricted to non-classical MHC class I
microbiota as a therapeutic target, which warrants further molecules, which also promote tissue repair.206 During skin injury,
mechanistic studies. TLR2 recognition of S. epidermidis cell wall component lipoteichoic
acid suppresses skin inflammation and inhibits release of
inflammatory cytokines, thereby promoting wound healing.207 It
CROSSTALK BETWEEN MICROBIOTA AND EXTRA-INTESTINAL should be noted that colonization with skin commensal during the
ORGAN IMMUNITY neonatal period is crucial for establishing immune tolerance
Although most studies in the field to date focused on the interplay through massive accumulation of active T regulatory cells in the
of microbiota and mucosal immunity in the intestine, interactions neonatal skin, collaboratively driven by hair follicle
of both the gut microbiota and extra-intestinal microbiota com- morphogenesis.208,209 Moreover, epidermal keratinocytes also
munities with extra-intestinal organ immunity have been gain- actively participate in cutaneous immune defenses. Microbial
ing increased attention (Fig. 3). Emerging evidence highlights that metabolites, such as SCFAs produced by the commensal skin
the local microbiomes of extra-intestinal mucosal surfaces provide bacterium Propionibacterium acnes, can modulate keratinocyte
niche-specific functions, including modulation of organ-specific inflammatory activity through inhibition of the keratinocytes’
immune responses. histone deacetylases.210 Furthermore, cutaneous commensals
such as coagulase-negative Staphylococcus strains produce anti-
Skin microbials that protect from pathobionts such as Staphylococcus
Alike the intestine, the skin (the body’s largest organ) represents a aureus.211
dynamic and complex ecosystem, harboring and interacting with Skin dysbiosis has been associated with different inflammatory
a plethora of locally-entrenched commensal microorganisms. High skin disorders, including atopic dermatitis212 and psoriasis.213

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Whether skin dysbiosis is the cause or consequence of these associated molecular patterns (MAMPs) from gut bacteria can
disorders is not yet clarified, but it has been proposed that locally directly influence the number, function and maturation of hepatic
amplified immune responses to particular skin microbes, or Kupffer cells (KCs), a critical componentof the hepatic innate
increased microbial load, in the setting of impaired skin barrier immune system.229 Intestinal pathogens may exacerbate immu-
and genetic predisposition, might contribute to pathology.214 For nological hepatic injury by activating DCs and NKT cells in the
example, skin colonization with Staphylococcus aureus promotes liver.230 Similarly, glycolipid antigen-containing probiotics were
skin allergy in a mouse model of atopic dermatitis through δ- reported to stimulate hepatic NKT cells in a strain- and dose-
Toxin-induced mast cell activation.215 Furthermore, epidermal dependent manner.231 Hepatic stellate cells, the main fibrosis-
JunB is critical for immune-microbiota interactions, as mice lacking inducing cell line in the liver, can also be directly stimulated by
JunB expression in skin epithelial cells are characterized by bacterial lipopolysaccharide (LPS), mainly through induction
augmented Th2 and Th17 type immune responses, accompanied of TLR4 signaling. This results in an upregulation of multiple
by increased S. aureus colonization.216 However, many open chemokines and adhesion molecules.232 Innate immune sensing
questions remain to be explored, including the molecular basis of of gut-derived microbial products by different TLRs, including
cutaneous microbiota-immune interactions and mechanisms by TLR4, TLR9, TLR5, and their downstream impacts on liver
which the cutaneous immune system discriminates between inflammation in the context of NAFLD/NASH have been recently
skin commensals and pathogens. reviewed elsewhere.180
Liver inflammation impacted by gut microbiota was also
Lung described in primary sclerosing cholangitis (PSC), a chronic
Emerging evidence highlights an important crosstalk between the inflammatory and cholestatic liver disease. The enteric pathobiont
gut microbiome and the lung (‘gut-lung axis’). Alterations in the Klebsiella pneumonia cultured from PSC patient specimens was
gut microbiome or microbiome-derived metabolites may impact demonstrated to damage the intestinal epithelial barrier,
on lung immunity in the context of pulmonary diseases. Gut thereby inducing bacterial translocation that promotes Th17 cell
commensals regulate antiviral immunity at the respiratory mucosa responses in the murine liver.233 Interestingly, a recent study
through inflammasome activation upon influenza A virus infec- showed alterations of the bile microbiota in PSC patients,
tion.217 Accordingly, GF mice show an impaired pulmonary characterized by reduced biodiversity, higher abundance of the
pathogen clearance.218 Microbiome-derived SCFAs promote bone pathobiont Enterococcus faecalis, and increased levels of the
marrow hematopoiesis, and the primed myeloid cells subse- noxious secondary bile acid taurolithocholic acid.234 However, it
quently migrate to the lung, shaping the lung’s immunological remains unclear whether these alterations are causally involved in
landscape and conferring protection against airway inflamma- PSC or are merely a consequence of biliary disease.
tion.219 Desaminotyrosine, a product derived from the gut Recent studies also demonstrated carcinogenic effects of
commensal Clostridium orbiscindens, exerts distal effects on the microbiome-derived small molecules via regulation of immune
lung to protect against influenza through modulation of type I IFN responses in liver malignancy, including secondary bile acid
signaling.220 mediating upregulation of hepatic NKT cells,189 deoxycholic acid
Additionally, recent evidence points towards a potential of a modulating the inflammatory secretome,235 lipoteichoic acid
locally entrenched lung microbiota possibly impacting pulmonary regulating prostaglandin E2 expression,236 and LPS signaling
immunity.221 In mice, the rapid formation of an airway micro- through TLR4.237
biome within the first 2 postnatal weeks is critical for immune
tolerance to inhaled allergens through PD-L1-related mechan- Central nervous system
isms.222 The human microbiome in the lower respiratory tract The development of a healthy brain and balanced neuro-
forms within the first 2 postnatal months, alongside lung immune immunity relies on integration of numerous endogenous and
maturation.223 Alterations of the lung microbiota has been environmental cues. Among these, molecular signals originating
implicated in exacerbation of chronic pulmonary diseases, from the gut microbiome may play prominent roles in modulating
including chronic obstructive pulmonary disease, asthma and brain cell function.238 Microglia are among the primary innate
cystic fibrosis.224 Notably, exposure to different lung microbes is immune cells in the CNS, and are instrumental in CNS immune
associated with different cellular immune responses. For example, defense and contribute to brain development and homeostasis.239
enrichment of Pseudomonas and Lactobacillus in mouse models of The microbiota contributes to microglia homeostasis, potentially
chronic lung inflammation,225 or pneumotypeSPT derived from mediated by signaling through SCFAs.240 GF mice display marked
a diseased human bronchoalveolar system,226 is related to an defects in microglia structure and function and hence fea-
enhanced Th17 type response. Pathobionts such as members of ture impaired CNS innate immune responses.240,241 Interestingly,
Proteobacteria induce severe TLR2-independent airway inflamma- the maternal microbiome impacts on microglial development
tion and lung immunopathology.227 More recent evidence during prenatal stages, and microglial perturbations associated
suggests that certain lung commensals may instigate the with the absence of microbiota manifest in a sex-dimorphic
development of pulmonary adenocarcinoma by activating γδ manner.242 Both microbial dysbiosis and microglial dysfunction
T cells that produce IL17. This highlights the putative role of a lung have been described in several neurological diseases, including
microbiome-immunity crosstalk in lung cancer.228 However, the behavioral, inflammatory and neurodegenerative disor-
study of the lung microbiome and the interplay between ders.243 Whether microbiota-microglia interactions contribute to
commensal microbial communities and pulmonary immunity is the pathogenesis of these disorders merits further studies.
only in its infancy, with many more mechanistic insights expected Moreover, diet-derived SCFAs were reported to promote
to be revealed in future studies. regulatory T cells to counter-regulate autoimmunity in the
CNS,139 and the intestinal microbiota modulates meningeal IL-
Liver 17+ γδ T cells, which impact on the pathogenesis of ischemic
The liver features direct anatomical connection to the gastro- brain injury.244 Despite tremendous recent advances, the study of
intestinal tract via the portal venous circulation and bile duct the interplay between the microbiome and neuro-immunity in
system, thereby being constantly exposed to bacterial products of health and disease is still in its infancy. Some studies shed light on
gut microbiome origin (‘gut-liver axis’). Intestinal commensals and possible mechanisms driving such putative 'gut-brain axis' in the
their products were repeatedly reported to translocate from the context of neuro-immunity. For example, depletion of gut
intestinal lumen to the liver in certain contexts, in which they may commensal bacteria by antibiotic treatment dampens the
impact hepatic immune responses. For example, microbial- progression of experimental autoimmune encephalomyelitis in

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mice, which is suggested to be mediated by induction of IL-10- microbiome and the immune system interact in a context of
producing regulatory T cells.245 Offsprings of pregnant female environmental triggers and host genetics. Integration of multi-
mice that harbor certain gut bacteria with a propensity to induce T omics data sets, including metagenomics, single-cell transcrip-
helper 17 response are at increased risk of developing neurodeve- tomics, epigenomics, proteomics and metabolomics, will aid in
lopmental disorders.246 Interestingly in a murine maternal elucidating how the gut microbiome and the immune system are
immune activation model, IL-17a-mediated inflammatory cross-regulated in these differing and complex contexts. Impor-
responses were shown to exert beneficial roles in improving tantly in all of these efforts, the microbiome research community
social behaviors in offsprings of adult mice.247 Potential micro- massively uses laboratory mice that harbor a divergent microbiota
biota involvement in these mechanisms merits further stu- from ‘wild’ animals and humans, thereby featuring a limited
dies. Continued research efforts in this direction may hold great translational potential and reproducibility as compared to ‘real-life’
therapeutic promise in uncovering new regulatory pathways settings. The newly created ‘wilding mice’ with low genetic
impacting a variety of inflammatory, developmental and degen- variability but a highly natural and resilient microbiota,147 may
erative neurological diseases. enable better mechanistic dissection of host-microbiome interac-
tions and provide a valuable preclinical tool to phenocopy human
Intra-organ low-biomass microbiomes immune responses. Indeed, a recent study has shown that the gut
There is growing recent interest in utilizing next-genera- microbiota in wild mice can better recapitulate the natural
tion sequencing to characterize sparsely populated low-biomass phenotypes in humans, as laboratory mice receiving wild
microbiomes in seemingly ‘sterile’ organs, such as the skin,206 microbiota exhibit less susceptibility to influenza virus infection
lungs,248 reproductive organs249 and bile ducts.234 However, and colitis-induced tumorigenesis, which is associated with less
caution is required in interpreting such findings, as many studies infiltration of immune cells and enhanced anti-inflammatory
that attempt to investigate low-biomass microbiome samples are responses.262 Future studies should consider incorporating similar
challenged by high false positive signals resulting from contam- approaches to better resemble natural microbiome-immune
ination and sequencing-related challenges and artefacts.250 interplay in order to increase the translational potential of such
Contaminating microbial DNA may originate from multiple studies.
environmental sources, such as laboratory extraction, amplifica- In addition, many studies focusing on microbiome-immunity
tion and library preparation kits.251 Notably, the notion of the interaction have utilized 16S rRNA sequencing to characterize the
existence of a placental microbiome and its link to reproductive microbiome, but this modality is limited by its genus-level and
health was recently challenged by a thorough comparison of purely compositional resolution. Given that strain level resolution
results using different kits, blank controls and complementary and functional insights are better served by shotgun metage-
approaches of microbial detection not exclusively relying on nomic sequencing, the field is expected to increasingly rely on this
sequencing.252,253 In order to avoid fallacious conclusions, more sophisticated methodology (in addition to metatranscrip-
strategies to control contamination must be considered when tomics, metabolomics, metaproteomics and culturomics) in
working with low microbial biomass tissues, including experi- decoding immune-microbiota interactions. Finally, the micro-
mental and computational measures.250,254–256 Although promis- biome configuration and immune responses are both increasingly
ing, these strategies largely still await proof that signals uncovered appreciated to be highly variable among human individuals, with
from low-biomass microbiomes reliably translate into verifiable more variances typically explained by inter-individual variation
mechanistic biological insights. than by disease state. This inherent inter-individual variability and
associated complexity constitutes a major experimental chal-
lenge but also presents an opportunity for microbiome research
CHALLENGES AND PITFALLS IN IMMUNE-MICROBIOME by enabling utilization of artificial intelligence and machine
RESEARCH learning in decoding individualized patterns in the microbiome
Recent research has greatly enhanced our understandings of the impacting on human health. As such, it will be intriguing to
intimate but complicated crosstalk between the microbiome and predict the ‘personalized’ host immune responses based on gut
the immune system. Nevertheless, many unknowns and chal- microbiome profiles, which will ultimately facilitate the develop-
lenges remain, in disentangling microbiome-immunity interac- ment of personalized microbiome-targeted treatments for immu-
tions in homeostasis and disease. nological diseases.
Exploring the roles of the commensal microbiome in impacting
immunity in health and in disease requires more mechanistic
studies. Indeed, current evidence from animal models indicates a PERSPECTIVES
bidirectional relationship to exist between microbiome perturba- A massive effort during the past decade in studying microbiome-
tion and immune dysregulation. As such, distinct microbiota and immune interactions has led to better understanding of
metabolites drive immune activation, and chronic inflammation their molecular basis, while pointing to the importance of these
conversely may shape the dysbiotic configuration and functions of interactions in impacting a variety of human immune-related
microbial communities. However, a direct causal relationship diseases. Such insights are already spurring the development of
between the microbiome and immunity before the onset or microbiome-targeted therapeutic strategies in immune-mediated
during early stages of disease has not been established in most diseases. For example, in an aim to restore a healthy microbiome
medical conditions. Moreover, the role of other previously configuration in patients suffering from dysbiosis linked to
underappreciated microorganisms, including viruses, fungi, para- immune-mediated disease, fecal microbiome transplantation
sites and their impact on the host immunity, emerges as an (FMT), which has so far been widely used in Clostridium difficile
important but challenging subject to be explored in future studies. infections, is considered also as potential treatment in this clinical
As an example, while recent research begins to uncover the role context. However, there is still no general consensus on which
of fungi257,258 and viruses259,260 in IBD pathogenesis, the interplay features constitute a ‘healthy’ microbiome. The efficacy of FMT in
between the mycobiome, virome and microbiome adds a layer of diseases such as IBD, is therefore still under evaluation and many
complexity in mining their impacts on innate and adaptive challenges remain to be overcome, including optimization of fecal
immune responses. Furthermore, many diseases of unknown processing and patient safety. Given that the prophylactic and
etiology, including IBD, autoimmune arthritis and cancer, are therapeutic efficacy of traditional individual probiotics in promot-
influenced by both genetic and environmental factors (e.g., diet, ing human health is limited, the use of ‘next-generation
smoking, etc.).261 It is imperative to investigate how the probiotics’, or rationally defined microbial consortia, potentially

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