Human Microbiome Journal 10 (2018) 11–20

Contents lists available at ScienceDirect

Human Microbiome Journal

journal homepage: www.elsevier.com/locate/humic

Microbiome and the immune system: From a healthy steady-state to allergy T

associated disruption
Soraya Mezouara, Yannick Chantranb,c, Justin Micheld,e, Alexandre Fabref,g,
Jean-Christophe Dubusa,h, Marc Leonea,i, Youssouf Seremea, Jean-Louis Mègea,
⁎
Stéphane Ranquej, Benoît Desnuesa, Pascal Chanezk,l, Joana Vittea,
a
Aix-Marseille Univ, IRD, IHU Méditerranée Infection, MEPHI, Marseille, France
b
Sorbonne Universités, UPMC Univ Paris 06, INSERM, Centre de Recherche Saint-Antoine, team “Immune System, Neuroinflammation and Neurodegenerative Diseases”,
Hôpital Saint-Antoine, Paris, France
c
Immunology Department, AP-HP Saint-Antoine Hospital, Paris, France
d
Aix Marseille Univ, CNRS, IUSTI, Marseille, France
e
Aix-Marseille Univ, APHM, La Conception Universitary Hospital, Department of ENT and Head and Neck Surgery, Marseille, France
f
Aix-Marseille Univ, APHM, Hopital de la Timone, Service de Pédiatrie Multidisciplinaire, Marseille, France
g
Aix Marseille Univ, INSERM, MMG, Marseille, France
h
Aix-Marseille Univ, APHM Assistance Publique Hôpitaux de Marseille, Hôpital Timone Enfants, Pneumo-pédiatrie, Centre de Ressources et de Compétences en
Mucoviscidose, Marseille, France
i
Aix Marseille Univ, APHM, Hôpital Nord, Service d’anesthésie et de réanimation, Marseille, France
j
Aix-Marseille Univ, APHM, IRD, IHU Méditerranée Infection, VITROME, Marseille, France
k
Aix-Marseille Univ, APHM, Hôpital Nord, Department of Respiratory Diseases, Marseille, France
l
Aix-Marseille Univ, INSERM UMR 1062, INRA UMR 1260, C2VN, Marseille, France

A R T I C LE I N FO A B S T R A C T

Keywords: Microbiome and the immune system are constantly shaping each other, in a mutual aim to thrive, defining the
Microbiome unstable equilibrium of the healthy individual. Microbiome is growingly involved in dysimmune conditions such
Mycobiome as allergy, asthma, autoimmunity, and primary or acquired immune deficiencies. The current epidemics of al-
Immune system lergic diseases and asthma has long been linked to the microbial environment through the hygiene hypothesis.
Dysbiosis
Progress in the understanding of the microbiome-immune system crosstalk has unraveled a tight connection
Allergy
between microbial communities and the development of allergic diseases and asthma. Disruption of the mi-
Asthma
Atopy crobiome affects the immune response of the host and paves the way for disease pathogenesis. Conversely,
Atopic dermatitis disease and therapeutic interventions affect microbial communities. We aimed at providing the reader with a
Dendritic cell view of the state-of-the art of microbiome – immune system crosstalk, with special focus on the loopholes giving
Macrophage potential grip to the pathogenesis of microbiome-related dysimmunity.
Mast cell
Chronic rhinosinusitis

1. Introduction
The microbiome consists of a complex mixture of microbes in-
cluding Archaea, bacteria, fungi, protozoa, helminths and viruses. The
description and the understanding of the human microbiome is one of
the most active fields of the biomedical research, with more than
15,000 articles published since 2011 [1]. However, although much has
been learned this field is still a frontier and even simple facts like the
number of bacterial cells in the human body have only recently been
established [2]. Moreover, nearly 70% of the microbiome studies have
focused on the gut microbiome [1]. Knowledge of the microbiome al-
lows better identification of the pathophysiological pathways and opens

Abbreviations: AD, atopic dermatitis; BEC, bronchial epithelial cells; COPD, chronic obstructive pulmonary disease; CRS, chronic rhinosinusitis; DC, dendritic cell;
ICU, intensive care unit; Ig, immunoglobulin; IL, interleukin; IS, immune system; LPS, lipopolysaccharide; LTA, lipoteichoic acid; MALT, mucosal-associated lym-
phoid tissue; MC, mast cell; SA, severe asthma; SCFA, short-chain fatty acid; SDD, selective digestive decontamination; TGF-β, Transforming Growth Factor-beta; Th,
helper T cell; TLR, toll-like receptor; Treg, regulatory T cell
⁎
Corresponding author at: IHU Méditerranée Infection, UF Immunologie, 19-21, Boulevard Jean Moulin, 13005 Marseille, France.
E-mail address: jvitte@ap-hm.fr (J. Vitte).

https://doi.org/10.1016/j.humic.2018.10.001

Available online 24 October 2018

2452-2317/ © 2018 Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
S. Mezouar et al.
the field of intervention through immune modulation [3].
Two drivers of the microbiome composition have been identified in
humans: genetic and immunological factors on one side and environ-
mental, notably diet and environmental biodiversity, on the other side.
Their relative importance is variable according to the site of the con-
sidered microbiome. For example, diet and hygiene, a correlate of en-
vironmental biodiversity, seem to shape gut microbiome whereas ge-
netic and immunological factors are more prevalent for urogenital tract
microbiome [4]. From an evolutionary perspective the two main factors
driving microbiome composition in mammals are host phylogeny [dif-
ferential organismal lineage through time] and diet, each acting at a
different temporal scale and on different subsets of bacteria [5]. At a
smaller scale, humans display a substantial loss of gut bacteria in
comparison to chimpanzees and gorillas. This loss is ancient and partly
linked to diet modification, e.g. increase of animal fats and proteins and
anatomical modification (reduction of gut size) [6]. This reduction of
diversity increased with the Neolithic transition and the industrial
transition with the loss of bacterial lineages in Western world [4,7].
Thus, humans seem to undergo a drastic modification of microbiome
following these transition steps. The effect of environmental changes is
also demonstrated by the fact that non-human primates kept in zoos
display altered microbiomes, reminiscent of the shift observed in hu-
mans moving from non-industrialized to westernized environments [8].
Finally, some microbiome components are usually under-evaluated,
like Archaea [9] and either unicellular [10] or multicellular [11] eu-
karyotes. The Archaea are a minor but important component of the gut
microbiome and are often not detected with universal primers. Pre-
liminary results suggest a dramatic decrease of their diversity in the
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Human Microbiome Journal 10 (2018) 11–20
Fig. 1. The microbiota-immune system in-
teractions shape the mucosal homeostasis.
The microbiota provides direct protection
against pathogens through competition for
nutrients, by affecting the physicochemical
conditions of the local microenvironment
(02, pH…), by the production of bacter-
iocins or by down-modulating the expres-
sion of virulence factors (black arrows).
Commensals can also provide indirect, im-
mune mediated protection by sending “out-
side-in” signals (green arrows) that result in
the proper maturation (both cellular and
organizational) of the mucosal-associated
lymphoid tissue, in the maintain of the
physiological inflammation through Tregs
and Th17 generation and in by favoring the
production of IgA by plasmocytes.
Commensals also induces the expression of
mucins by goblet cells and antimicrobial
molecules, such as RegIIIγ or AMP by
Paneth cells. On the other hand, the mucosal
immune system controls its microbiota
through stratification and compartmentali-
zation. Stratification protect the epithelial
cells by keeping the microbiota at a safe
distance (red arrows) while compartmenta-
lization is provided by the unique structure
of the mucosal associated lymphoid tissue
that restrict DC-B and/or T cell interactions
in the mesenteric lymph nodes and avoid
the systemic immune response.
Abbreviations: PSA, polysaccharide A; SFB,
segmented filamentous bacteria; AMP, anti-
microbial peptides. (For interpretation of
the references to colour in this figure legend,
the reader is referred to the web version of
this article.)
human lineage, as opposite to great apes [12]. The presence of En-
tamoeba is strongly correlated with microbiome composition and di-
versity [10]. Thus, microbiome is still being deciphered, its role in
health is paramount, however numerous forces shape it at different
levels.
Although the microbiome has become synonymous for the collec-
tion of bacterial microbiome, the mycobiome, or the fungal community,
is an essential part of the microbiome [13]. Strikingly, to date less than
400 fungal species have been isolated from humans [14–16]. The es-
timated relative mycobiota abundance is heterogeneous, depending on
the human body site; it ranges from less than 0.1% in the gut to ∼10%
on the skin [17]. Yet an average fungal cell is ∼100 times larger than
an average bacterium, which puts into perspective this relatively low
abundance when considering the total fungal biomass. The fungal
biomass constitutes a significant source of bioactive molecules, which
might significantly influence host physiology [18]. In particular, gut
mycobiota has been shown to modulate the human innate immune
system (IS) via the Dectin-1 receptor [19]. Fungal gut dysbiosis has
been associated with gut inflammation; especially colitis exacerbation,
associated with alterations of the fungal gut communities, occurred in
mice treated with antifungal drugs [20]. Shifts in both bacterial and
fungal microbiome compositions have been evidenced in various
chronic diseases, including inflammatory bowel disease [21–23] or in
cystic fibrosis patients’ respiratory tract [24].
Allergic diseases have evolved into a genuine epidemics over the
last half century [25]. Such a rapid evolution is not attributable to
genetics. Environment and lifestyle changes were soon identified as key
drivers [26] through alterations of human microbiome and related
S. Mezouar et al.
immune responses [27,28]. Biodiversity loss and climate change am-
plify the environment-driven aberrancies of the microbiome [29].
Moreover, external exposome players such as air pollutants, in utero
exposure to tobacco, biocontaminants and even diet exert epigenetic
effects which have been associated with the occurrence of allergic
diseases in the offspring [29]. However, general mechanisms might be
involved in the microbiota – allergy axis, as suggested by a recent paper
replicating the association of early-life dysbiosis and later occurrence of
atopic wheeze in an Ecuadorian pediatric cohort [30]. In this review,
we will first outline the major players and mechanisms of the micro-
biome – IS interaction. Then, we will present a state-of-the art summary
of microbiome disruption in atopic/allergic and asthmatic conditions.
2. Microbiome – Immune system interactions (Fig. 1)
Host-microbiome mutualism largely exceeds the sole metabolic and
nutritional aspects and also involves the interaction between the mi-
crobiome and the IS. Mucosal surfaces and more specifically the gas-
trointestinal tract represent the major interface between the IS and the
microorganisms and the ability to discriminate commensals from pa-
thogens can be considered as the driving force of the evolution of the IS.
The commensal microbiome can confer resistance by direct com-
mensal pathogen – interaction through the preferential consumption of
nutrients required for the growth of pathogens. This competition for
nutrients has been exemplified with commensal Escherichia coli com-
peting with enterohemorrhagic strains for amino acids and other or-
ganic acids [31,32]. In addition, commensal bacteria generate small
metabolites such as short chain fatty acids (SCFA) or acetate, thereby
limiting the growth of pathogens [33] or downmodulating the expres-
sion of virulence genes [34,35]. The indigenous microbiome may also
produce bactericidal or bacteriostatic substances, such as bacteriocins.
For example, Lactobacillus salivarius UCC118 produces a bacteriocin in
vivo that can significantly protect mice against Listeria monocytogenes
[36]. Interestingly, protection is also observed against a naturally
bacteriocin-resistant foodborne pathogen, Salmonella typhimurium UK1,
suggesting competitive exclusion, or immunomodulatory mechanism
[36].
Indeed, commensal microbiome can confer immune-mediated in-
direct resistance against pathogens. The role of the microbiome in
shaping the IS throughout life (outside-in signals) arise from numerous
studies comparing axenic (germ-free) and specific-pathogen-free mice.
Axenic mice are characterized by atrophy of Peyer’s patches with few
germinal centers, immature mesenteric lymph nodes, few isolated
lymphoid follicles, decreased levels of antimicrobial peptides and im-
munoglobulin (Ig) A and an overall reduced number of B, T and den-
dritic cells (DCs) [37]. Moreover, villi are longer and narrower, with a
less complex vascular network while crypts are less deep, with fewer
proliferating stem cells. Axenic rats have less goblet cells, and a thinner
mucus layer characterized by increased neutral mucins [37]. In addi-
tion, they display defects in systemic IS, since the structure of the spleen
and lymph nodes are affected with fewer germinal centers, diffuse B-
cell and T-cell zones and reduced levels of circulating IgG [38]. Very
importantly, colonizing axenic mice with commensal bacteria reverses
these defects, allowing the IS of these mice to develop and normalize
within weeks [39]. These data emphasize the major role of the com-
mensal microbiome in the maturation of the mucosal associated lym-
phoid tissue (MALT) as well as the systemic IS. For example, the
polysaccharide A from Bacteroides fragilis restores systemic T cell defi-
ciencies, lymphoid organogenesis and the differentiation of CD4 T cells
into regulatory T cells (Tregs), which in turn favor mucosal im-
munomodulation and TGF-β production [40,41]. Segmented fila-
mentous bacteria induce the maturation of T helper (Th) 17 cells to
coordinate the equilibrium with Tregs [42] and maintain a physiolo-
gical low-grade inflammation. The role played by Th17 cells may vary
as a function of the global context: in a murine experimental model,
microbiota of infants with atopic heredity induced predominant Th-17
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Human Microbiome Journal 10 (2018) 11–20
responses [43].
On the other hand, the IS controls host microbiome (back-outside
signals) through stratification and compartmentalization which sepa-
rate mucosal immune responses both geographically and functionally
from systemic immunity. Stratification or segregation is provided by the
mucus and anti-microbial molecules. In the colon, where the bacterial
density is the highest, microbiome is kept away from the epithelium by
a dense impermeable inner mucus layer composed of O-glycosylated
MUC2 mucin [44] enriched in lectin-like protein such as ZG16 and β-
defensins [45]. This spatial segregation is also observed in the intestine
where the mucus is more heterogeneous, rich in Paneth cell-derived α-
defensins [46], RegIIIγ C-type lectin [47] and secretory IgA [48].
Anatomical stratification of commensal bacteria is also dependent on
the interleukin (IL)-22 produced by the ILC3 that governs immune ex-
clusion by controlling anti-microbial peptide production [49]. In mice
lacking T CD4 cells, cytokine responses such as IL-22 and IL-23 persist
after weaning, leading to microbiota alterations and subsequent meta-
bolic changes [50]. Compartmentalization of the immune response to-
wards commensal bacteria is provided by the unique structure of the
MALT which reduces the exposure of commensal bacteria to the sys-
temic IS. Indeed, commensal bacteria are physiologically taken up by T
cells or directly by DCs from the sub-follicular zone. DCs interact in the
Peyer patch with B and T cells or migrate to the mesenteric lymph
nodes. In the mesenteric lymph nodes, DCs activate B and T cells, which
then leave the mesenteric lymph nodes by the thoracic duct, to reach
the systemic circulation and home to mucosal tissues generalizing the
mucosal response to all the mucosal surfaces of the organism [51].
In summary, extensive IS – microbiome interactions have a sig-
nificant impact on immune homeostasis that can be linked to numerous
multifactorial diseases. However, it is still unclear whether those al-
terations are the cause of such diseases or the consequence of IS
changes related to those diseases.
3. Macrophage polarization and microbiome
Macrophages display a large array of functions from host defense to
host homeostasis. All these functions are impacted by environment
from tissues to mutualistic commensals. This diversity enabled the
emergence of macrophage polarization complex. The polarization refers
to the set-up of a specific phenotype of macrophage depending of the
pathogens or the microenvironment [52,53].”Classical” activation of
the macrophage resulting in enhanced phagocytic and intracellular lysis
ability and type 1 cytokine secretion is termed M1 polarization, while
“alternative” activation with an anti-inflammatory response corre-
sponds to a M2 phenotype. The success of this classification as a
working hypothesis is related to the reminiscence of T cell polarization
and has generated several debates including our contributions [54,55].
M1-type macrophages are considered as protective in infectious dis-
eases and cancer whereas M2-type macrophages are protective in
parasitic infections and repair responses. We described the role of
macrophage polarization in bacterial infectious diseases and identified
situations in which polarization was associated with a given clinical
condition, prognosis or pathophysiological process [56].
Macrophages are abundant in mucosae at the host-environment
interface. They interact with commensal organisms that have developed
mutualistic relationships with the host. Using axenic animals or anti-
biotic-treated hosts, it has been established that microbiome affects
macrophage functions and likely their polarization status. Most reports
have established that the intestinal microbiome maintains a tolerant
environment through the induction of M2-like intestinal macrophages.
Indeed, the macrophages from lamina propria show down-regulated
expression of innate response receptors and inflammatory functions,
but they retain phagocytosis and bactericidal activities [57]. Com-
mensals shape the polarization status of intestinal macrophages via
direct and indirect pathways. B. fragilis and intestinal Clostridia stimu-
late M2 polarization and Tregs [58]. Some endproducts of bacterial
S. Mezouar et al.
anaerobic fermentation, such as SCFA (α-butyrate), inhibit the in-
flammatory response of macrophages via a mechanism based on the
inhibition of histone deacetylase [59]. Helicobacter hepaticus produces a
large soluble polysaccharide that induces IL-10-mediated M2 type po-
larization in intestinal macrophages [60]. In contrast, intestinal com-
mensals such as Enterococcus faecalis polarize colon macrophages to a
M1 phenotype in a murine model in which macrophages are depleted
with clodronate [61]. Recruited intestinal Ly6Chigh monocytes release
IL-1β in response to commensals in an inflammasome-dependent
manner, favoring M1 polarization [62]. M1 polarization enables sur-
vival of oral commensals such as Streptococcus gordoni [63].
The effect of microbiome may explain the therapeutic effect of
probiotics. The probiotic Clostridium butyricum promotes the develop-
ment of IL-10-producing macrophages that prevent inflammatory colitis
[64]. The strain G-101 of Lactobacillus brevis inhibits the inflammatory
response of mice treated by trinitrobenzenesulfonic acid. This anti-in-
flammatory property is related to the ability of these bacteria to prevent
the expression of M1 markers and to favor M2 markers, presumably via
the production of IL-10 [65]. These findings are inconstant. For in-
stance, some authors failed to evidence any effect on the polarization of
RAW 264.7 murine macrophages as a readout [66], while others re-
ported that probiotics bacteria promote an activation profile of the M1
type in the human monocytic cell line THP-1 stimulated with lipopo-
lysaccharide (LPS) [67]. It is noteworthy that all these studies are
limited to in vitro experiments or animal models, and the extrapolation
to humans must be careful.
The breach of intestinal homeostasis due to the presence of patho-
genic bacteria would interfere with the polarization status of intestinal
and systemic macrophages. The infection with Salmonella typhi or
Helicobacter pylori in patients is associated with reprogramming mac-
rophages towards M1 phenotype whereas M2 phenotype is found in
convalescent patients, suggesting the role of commensals in main-
taining M2 macrophages as major regulators of tolerance [68]. Im-
balances in gut microbiome have also been associated with systemic
diseases such as allergy. Recently, Kim et al. [69] reported the induc-
tion of allergen-induced infiltration of inflammatory cells in mice
treated with antibiotics. This treatment alters macrophage functions but
reorients alveolar macrophages and circulating monocytes toward a M2
phenotype. The latter is involved in allergic airway inflammation in-
duced by allergens. Antibiotic treatment facilitates fungal overgrowth
that exacerbates airway inflammation. The prostaglandin E2 produced
by gut fungi is responsible for eosinophil-mediated inflammation and
M2 polarization of macrophages [69].
In conclusion, he diversity of microbiome needs to be addressed
specifically with respect to macrophage polarization since divergent
results have been reported in different experimental settings.
Unraveling the finely tuned macrophage polarization will complement
our understanding of allergic diseases and support therapeutic inter-
vention through probiotics.
4. Mast cells at the crossroads of microbiome and allergy
There is increasing evidence of a relationship between allergic dis-
order and microbiome. Several studies showed that microbiome mod-
ulates allergy by an alteration of the function of antigen presenting cells
or the regulation of the Th1/Th2 balance [70,71]. However, there is
increasing awareness of a direct modulation of mast cells (MCs) re-
sponses by microbiome [72,73]. In addition to their well-documented
role in allergy, MCs possess multifunctional properties. First, they in-
fluence tissue integrity, function and homeostasis [74]. Second, MCs
are involved in innate and adaptive immune responses notably by their
Toll-like receptors (TLRs) and pattern recognition receptors [75].
Emerging data show a relationship between MCs and microbiome, with
microbes altering MCs activation and function. In addition, the position
of MCs as immune sentinels in skin and mucosal surfaces, that contain a
complex composite of non-pathogenic microbes, suggests the existence
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Human Microbiome Journal 10 (2018) 11–20
of a MCs- microbiome crosstalk. Gut and skin microbiomes have re-
ceived most of the research focus. Several reports have shown a re-
lationship between MCs, microbiome and allergy. For example, it has
been suggested that gut microbes interact with TLRs expressed by MCs
to regulate allergic response to food [76]. In mice models, luminal flora
was shown to modulate antigen-specific anaphylactic responses in a
TLR4-dependent manner. Other studies suggested that commensal
bacteria and products from gut lumen play key roles in regulating MCs
activation and secretion. For example, gut bacteria induced the acti-
vation of intestinal MCs leading to the increased of gut permeability
[77]. In contrast, other studies showed that intestinal commensal or
probiotic bacteria could suppress MCs activation, thus linking gut mi-
crobiome and the allergic response [78–80]. Skin microbiome can also
influence intestinal MCs. Indeed, recently Wang et al. reported that skin
microbiome induces keratinocytes to produce stem cell factor (SCF), a
major player in MCs maturation [81]. Using axenic mice, the same team
showed that these mice expressed abnormally low levels of SCF and
contained undifferentiated MCs. The reconstitution of the microbiome
or the injection of lipoteichoic acid (LTA, a component of the bacterial
cell wall) rescued the phenotype of MCs in a TLR2-dependent manner
[82]. These experimental results are reminiscent of findings with in-
flammatory diseases such as psoriasis or atopic dermatitis. For example,
Nakamura et al. reported that Staphylococcus aureus, found on the skin
of 90% of atopic dermatitis (AD) patients, secreted δ-toxin involved in
IgE dependent MCs degranulation [83]. Collectively, these data support
a contribution of MCs as key link between microbiome and allergy.
Better understanding the MCs – microbiome interplay will contribute to
new insights into microbial involvement in allergic disorders and to the
design of novel therapeutic approaches.
5. Allergy and microbiome – B cells and humoral immunity
IgG and IgA might contribute to protection against IgE-mediated
allergic reactions. Allergen-specific IgG4 induction during allergen
immunotherapy parallels tolerance acquisition [84]. Early-life IgG re-
sponses to environmental and food allergens occur at low levels in non-
allergic individuals [85–87]. However, the most prominent antibody
involved in mucosal immunity is IgA. IgA is the most abundant anti-
body in humans, and an important share of its production is targeted to
the gut lumen as secretory IgA [88]. Luminal secretory IgA binding to
selected bacterial antigens is the first step to multiple mechanisms
aimed at maintaining mucosal homeostasis: immune exclusion [89],
modulation of bacterial functions such as translation [90] and growth
[91], and support of gut microbial diversity [88,89,92]. Physiological
or pathological deprivation of mucosal IgA responses may be associated
with inflammatory diseases. IgA production is scarce in the young in-
fant, and compensated by maternal IgA through breastfeeding [90].
Abnormal gut IgA responses in the first year of life have been associated
with allergy and asthma occurrence at the age of 7 years [92]. Ab-
normalities include a lower proportion of IgA bound to fecal bacteria at
12 months of age and altered IgA recognition patterns [92]. Moreover,
in undernourished children, IgA-coated strains from gut microbiota
were able to convey a diet-dependent enteropathy (disruption of the
small intestinal and colonic epithelial barrier, weight loss, and sepsis),
with Enterobacteriaceae playing a major role [89].
At the other end of the lifespan, immunosenescence has been shown
to affect the composition of gut mucosal IgA. Despite a stable amount of
fecal IgA, IgA coating of some bacterial strains, namely Clostridiaceae
and Enterobacteriaceae with potential pathogenicity, was impaired [93].
Many studies have focused on the role of microbiome in shaping the
Th1/Th2 or the Th/Treg balance of adaptive responses to supposedly
unrelated non-microbial allergens. Much less attention has been paid to
the direct interaction between B-lineage cells involved in allergy and
commensal or opportunistic flora. It has been described in mouse and
human that early-life exposure to T independent antigens, such as
bacterial carbohydrates, appears critical for the establishment of certain
S. Mezouar et al.
B-cell clonotype and imprints lastingly the antibody repertoire [94].
Natural antibodies against bacterial glycans produced by these B-cell
lineages are highly specific and confer effective humoral protection
against bacteria bearing those carbohydrate moieties. Interestingly,
some of these antibodies cross-react between bacterial glycans (e.g.
from Streptococcus or Enterobacter cloacae) and allergens (e.g. Aspergillus
fumigatus and house dust mite) bearing similar motifs and appear to be
protective against allergic airway disease in mouse models [95]. The
mechanisms of this protective effect remain elusive, and it is yet unclear
if these results apply in human. Nevertheless, cross-reactivity is a fea-
ture of IgE known for decades. It may occur between several protein or
carbohydrate allergens in sensitized individuals, reflecting similar epi-
topes on homologous molecules present in different species [96]. It
must be stressed that inter-allergen cross-reactive IgE are now believed
to display poor biological activity, and no clinical relevance [97]. If IgE
cross reactivity happens between more or less phylogenetically distant
allergenic species, it should also occur in other species inasmuch as they
share homologous determinants. Indeed, cross-reactivity has been
shown to happen between protein [98–101] and carbohydrate [102]
allergens from insects and parasitic helminths. Similarly to inter-al-
lergen cross-reactive IgE, these IgE are not believed to be associated to
allergic manifestations [102] but could rather explain the negative as-
sociation between chronic helminth infections and skin prick test re-
activity. Antigenic cross-reactivity can be harnessed by the host’s im-
mune response in order to control microbiome components. For
instance, flagellin from various bacterial species displays conserved
motifs which are recognized through TLR-5, leading to the production
of flagellin-specific IgG and IgA that coat and inhibit bacterial
spreading [90]. In another murine model, IgA coating identified in-
flammatory commensals associated with inflammatory intestinal dis-
eases [103].
However, IgA might play redundant roles with other Ig isotypes, as
IgA deficiency does not markedly alter global fecal microbiota [104].
In brief, indirect arguments suggest that early-life exposure to mi-
crobiome determinants would be able to shape later-life B-cell re-
pertoire and antibody response, enhancing production of potentially
protective IgE or non-IgE cross-reactive antibodies.
6. Microbiome and food allergy
Although gut microbiome is both the most abundant and the most
studied, the link between microbiome and food allergy is still elusive. A
relatively low prevalence of food allergy in general population, the
multiplicity and the biochemical complexity of allergy-eliciting foods,
differences between food allergies occurring during childhood or in
adults, the existence of a so-called developmental window for gut mi-
crobiome implementation and marked interindividual variability in
clinical presentations of food allergies might explain why research in
this field is lagging behind. A curious finding is the inconsistent evi-
dence for decreased gut bacterial diversity in food-allergic patients.
Indeed, Azad [105] and Tanaka [106] described low richness of bac-
terial communities in the gut of food-allergic infants, while Fieten
[107] and Savage [108] did not find differences in the diversity of fecal
bacterial signatures in food-allergic children as compared with non-
allergic counterparts, and Fazlollahi [109] reported increased bacterial
diversity in gut microbiome of egg-allergic children. However, quali-
tative bacterial signatures found in food-allergic patients versus non-
allergic controls are consistently different. In egg-allergic children,
Lachnospiraceae (a Firmicutes division) and Streptococcaceae families
were enriched, while Leuconostocaceae were enriched in controls [109].
Leuconostoccaceae have demonstrated protective effects against allergy
development in a mouse model of ovalbumin-induced food allergy,
through mechanisms resulting in a decrease in IgE production and an
increase in interferon-gamma production [110]. A diminished propor-
tion of Leuconostoccaceae has been reported in food-allergic Japanese
infants [106]. In children with AD, concomitant food allergy (any
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Human Microbiome Journal 10 (2018) 11–20
allergen) was associated with a higher proportion of E. coli and Bac-
teroides pseudocatenulatum, and less Bacteroides breve, Bacteroides ado-
lescentis, F. prausnitzii, and Akkermansia muciniphila than counterparts
without food allergy [107]. Enterobacteriaceae and selected Clostridiae
were also enriched in gut microbiome of Japanese food-allergic infants
[106]. A gut microbiome-wide study of infants aged 3–6 months iden-
tified seven individual genera with significant inverse associations with
food sensitization and/or allergy [108]: Dorea (Lachnospiraceae), Ci-
trobacter (Enterobacteriaceae), Lactococcus (Strepotococcaceae), Oscillos-
pira (Ruminococcaceae), Dialister (Veillonellaceae), and Dialister (Pas-
teurellaceae).
7. Skin microbiome and atopic dermatitis
Numerous microorganisms including bacteria, fungi, viruses, and
mites make a living at the surface of human skin. Skin resident bacteria
are influenced by environmental biodiversity, but most of them belong
to Firmicutes, Bacteroidetes, Proteobacteria and Actinobacteria [111].
Together with keratinocyte-derived antimicrobial peptides, skin com-
mensals exert a protective action at the cutaneous level [112,113].
Their disruption paves the way for the growth of pathogenic micro-
organisms and facilitates the attack of allergenic molecules. The mi-
crobiome-host crosstalk at the cutaneous level is established in early life
during a well-defined developmental window, with Langerhans cells
and regulatory T cells (Tregs) setting up a non-allergic, low-level im-
mune response to skin commensals [111,114].
AD can appear at any age but is usually one of the earliest mani-
festations of the atopic march, suggesting a pathophysiologic role for
abnormal microbiome implementation in neonates and infants. AD is a
frequent disease, with a lifetime prevalence of 10% to 20% [115]. The
pathophysiology of AD is multifactorial, including genetic, im-
munological, microbial, and environmental factors [112]. Among bac-
teria, S. aureus has been prominently associated with AD [113]. In AD
skin, colonization with S. aureus is observed in association with a de-
creased diversity of other bacterial species. Moreover, S. aureus-derived
δ-toxin induces skin mast cells to degranulate and produce Th2-related
cytokines, which in turn favor the development and persistence of al-
lergic responses [116,117]. Intrinsic skin defects such as filaggrin or
cathelicidin deficiency are also associated with an increased load of S.
aureus in the skin microbiome [112,115]. Finally, increased S. aureus
numbers in the gut microbiome of infants are predictors of current AD
[118].
Skin microbiome displays two prominent features: high site-de-
pendent variability and richness in fungal components. Among the
latter, the yeast Malassezia is the predominant eukaryotic symbiont of
human skin, and a growing body of evidence supports its implication in
the development of inflammation and exacerbation associated with AD,
particularly the recognition of IgE binding allergens produced by
Malassezia and the selectivity of immune cells response [119]. Indeed,
both topical and systemic antifungal treatments reduce the severity of
skin symptoms in yeast-sensitized AD patients [120] and patients with
AD react more frequently to Malassezia extract or recombinant antigens
than healthy controls [121]. Several Malassezia species have been as-
sociated with AD, with conflicting results among published studies.
However, the association of the species M. sympodialis with AD has been
most frequently pointed out (reviewed in ref. [119]). The major argu-
ment supporting this hypothesis is that M. sympodialis sensitization is
specific for the clinical manifestations of AD and is absent in patients
with other allergic diseases [122]. Interestingly, Malassezia yeast trig-
gers divergent skin conditions where the inflammatory response is ei-
ther upregulated, such as in AD and seborrheic dermatitis, or down-
regulated, such as in pityriasis versicolor [123]. Complex interactions
between Malassezia yeasts and other communities of the skin micro-
biome might contribute to the pathogenesis of Malassezia-related skin
diseases.
S. Mezouar et al.
Fig. 2. Microbiome in asthma. The main pathophysiological events involving microbiome are depicted from the prenatal stage of development to the established
pulmonary disease (asthma).
8. Microbiome and allergic diseases of the airways
8.1. Microbiome in asthma (Fig. 2)
Airway and gut microbiology may play an important role in the
pathobiology of chronic airway diseases such as severe asthma (SA)
[124]. Airway microbiome is certainly important at the inception of
asthma as it was found that early in life, the occurrence of bacteria
species drove the IS towards an asthma susceptible phenotype related to
the promotion of PDL1 harboring cells [125]. T regulatory cells are
finely tuned by an early contact with lung microbiome leading to the
prevention of susceptibility for asthma [125]. Similarly, early farm dust
exposure decreases airway susceptibility to asthma through the reg-
ulation of the ubiquitin A20 which is severely down expressed in
bronchial epithelial cells (BEC) derived from SA patients [126]. Ex-
posure to endotoxin in vitro abrogates the proinflammatory response of
BEC from SA exposed to house dust mites [126].
At steady state, airway microbiome in SA is different from the
bacterial diversity observed in the normal lung and in lungs of mild-to-
moderate asthma patients. Patients with SA were significantly enriched
in Klebsiella spp and Actinobacteria [127]. These findings have been
reproduced using various sampling methods from bronchoalveolar la-
vage to sputum analysis, and from childhood to adulthood [128,129].
Heterogeneity of airway microbiome has been recently related to in-
flammatory phenotypes in SA [130]. Non-eosinophilic SA phenotype
was associated with a relative increase in the abundance of γ-Proteo-
bacteria and a reduced load of Streptococcus, Gemella and Porphyr-
omonas [130]. This is a relevant finding since non-eosinophilic SA is
related to Th17 inflammation and poorly responsive to corticosteroid
therapy. These findings are confirmatory along with the non-response
of airway macrophages derived from SA patients to dexamethasone
inhibition, after an exposure to Haemophilus influenzae in vitro [131]. At
exacerbation, SA microbiome changes and contributes to the severity of
the event. Several reports show the major impact of treatments on lung
microbiome. It was found that antibiotic use affects the lung micro-
biome, leading to an increase of alpha diversity and Proteobacteria and
decrease of Firmicutes. A change in microbiome is induced by corti-
costeroids alone with an increase, at the genus level, of Haemophilus and
Moraxella. The microbiome of patients treated with inhaled corticos-
teroids and bronchodilators was different from that of untreated pa-
tients demonstrating that the microbiome is not only dependent on the
16
Human Microbiome Journal 10 (2018) 11–20
disease but also on the type of medication [132]. Low abundance mi-
crobial pathogens can orchestrate inflammatory disease by remodeling
a normally benign microbiome into a dysbiotic one.
Dysbiosis has also been reported for the respiratory mycobiome of
SA patients. A higher density of genera including Rhodosporidium,
Pneumocystis, Leucosporidium, and Rhodotorula has been show in the
respiratory tract of patients with SA compared with non-asthmatic
patients, in whom Davidiella, Cryptococcus, and Sterigmatomyces were
relatively more abundant [133]. In patients with fungal asthma, corti-
costeroid treatment was associated with an increased fungal burden in
the bronchoalveolar lavage, with the Aspergillus fumigatus complex
being the most prevalent [134].
Overall, the research investigating the relationships between lung
microbiome and asthma is paramount to better understand and treat
patients suffering from these devastating diseases. 8.1.
8.2. Microbiome and asthma in children
Asthma, which has increased in the past few decades, affects one in
ten children in westernized countries. Albeit pediatric asthma is a
multifactorial disease, accumulating evidence suggests that exposure to
a diverse environmental microbiome in early life has a protective effect
against childhood asthma [135,136]. Birth by Caesarean section, for-
mula-feeding, urban environment, lack of sustained contacts with a
diversity of humans and animals, and antibiotic intake are clearly as-
sociated with an increased risk to develop asthma and allergies later in
life. These factors modify the gut fungal and bacterial microbiome
(dysbiosis), particularly during the first 100 days of life which represent
the critical window for acquiring a Th2-lymphocyte profile. Analysis of
gut microbiota in a US cohort showed that distinct groups, character-
ized by distinct relative risks of atopy and asthma at later stages, could
be identified already during the neonatal period [137]. For instance,
the group with the highest risk of multisensitized atopy at age 2 years
and doctor-diagnosed asthma at age 4 years displayed lower relative
abundance of Bifidobacterium, Akkermansia and Faecalibacterium, higher
relative abundance of fungi such as Candida and Rhodotorula and a pro-
inflammatory fecal metabolome [137]. Conversely, pre- and post-natal
exposure to microbiome-loaded farm environment overrides the effect
of risk alleles in chromosome 17q21 which expose to asthma develop-
ment following rhinovirus respiratory infections. Early colonization of
the airways by Streptococci and Moraxella predispose for recurrent
S. Mezouar et al.
Fig. 3. Microbiome-host interplay, main checkpoints and external influences. The host microbiome crosstalk is depicted through its main functional checkpoints
which can be disturbed by external influences or loss of internal homeostasis.
wheezing respiratory episodes and asthma. When asthma is declared,
the airway microbiome differs from that of healthy children, with a
usually higher bacterial density. A higher fungal density has also been
observed in more severe 9-year-old asthmatic children (increased re-
presentation of Bacteroides and Pneumocystis) [133]. Allergy may
modify this tendency as the global bacterial species richness and di-
versity were significantly reduced in 4-year old mites-sensitized asth-
matics in comparison to healthy non-sensitized children, with an
overrepresentation of Moraxella and Leptotrichia [138]. In the future,
acting on the microbiome, for instance with fecal microbiome trans-
plantation, may be of interest to prevent the development of asthma in
children or even to manage their asthma. Another axis of research deals
with antibiotic use during the perinatal window. At least in murine
models [139], not all antibiotics are associated with an increased risk
on allergic disease later in life. In their model, vancomycine (a Gram-
positive targeting antibiotic) but not streptomycine (targeting both
Gram-positive and Gram-negative bacteria)-treated mouse pups were
prone to experimental asthma.
8.3. Microbiome and rhinosinusitis
In the field of oto-rhino-laryngology the microbiome has mainly
been studied in the sinonasal tract. Rhinitis and asthma share key ele-
ments of pathogenesis and have long been noted to co-occur, in support
of the unified airway model: microbial, epithelial, and immune con-
tinuity from one section of the respiratory tract to the others [140]. In
healthy condition rich and diverse bacterial assemblages are present in
the sinonasal cavity [141]. In CRS, molecular analyses revealed a large
amount of interpersonal variation between patients [142]. Analysis of
microbiome in a large cohort revealed that different CRS associated
with asthma or with purulence are characterized by distinct composi-
tions of resident bacterial communities. According to Ramakrishnan
et al. the bacterial diversity and composition are predictors of surgical
outcome [143]. CRS patients show less biodiversity in their microbiome
than healthy subjects [144]. Significant differences exist in the diversity
of bacteria populations during acute exacerbations of CRS and after
17
Human Microbiome Journal 10 (2018) 11–20
antimicrobial treatment. After therapy, the increase in diversity is ac-
companied by a decrease in the total abundance of the bacterial po-
pulation [145]. However, the role of the sinonasal microbiome in
chronic rhinosinusitis (CRS) remains unclear. CRS is a chronic in-
flammatory disease of the mucosae of the upper airways including the
nose and paranasal sinuses, often comorbid with asthma and linked to
increased asthma severity and exacerbation rate [146].
A recent study reported that among 111 CRS cases, 46 (41.4%) had
concurrent physician-diagnosed asthma [147]. Asthmatic patients had
higher rates of allergic rhinitis (60.9% asthmatic vs. 26.2% non-asth-
matic, p < 0.05). In this study, asthmatic CRS had significantly higher
relative abundance (RA) of the Streptococcus genus. Moreover, asthma-
related exacerbations as reflected by emergency department visits were
associated with significant nasal microbiome changes, including higher
RA of Proteobacteria phylum, notably Burkholderia spp [147].
The presence of microbial dysbiosis in CRS is now supported by
many studies but it is still impossible to assess whether this dysbiosis is
a cause or rather an association of the disease process [144]. Although
probiotic therapies showed early promise, larger studies are required to
establish their real role as a treatment for CRS [144].
9. Concluding remarks
We have aimed at providing the reader with an overview of the
current knowledge in the field of microbiome – IS crosstalk, with spe-
cial emphasis on the unsteady balance associated with health. Dysbiosis
is associated with dysimmunity, often characterized as a Th2-excessive,
Treg-deficient state. Allergy and asthma are typically associated with
such immune deviations. The intervention of microbiome during the
development of allergies and asthma is still incompletely described, and
the description of dynamic aspects of microbial communities and their
shaping of the host IS is still in infancy. The perinatal window of op-
portunity has gained momentum as a concept, but general-population
cohorts over long periods of time are lacking in most countries, and
studies combining prenatal and postnatal data are hampered by ethical,
material, and social constraints.
S. Mezouar et al.
The current understanding of pathophysiologic checkpoints is
summarized in Fig. 3. Research in this field is hampered by the multi-
plicity of multifactorial determinants of allergic/atopic diseases and the
patchy knowledge of mechanistic endotypes underlying clinically de-
fined phenotypes. Harnessing the microbiome – IS interaction is cur-
rently limited to pre/probiotic supplementation and environmental
interventions. Large-scale future studies on birth and adult cohorts,
taking advantage of the most recent tools in microbiology, im-
munology, allergology, and statistics are highly needed. Novel ap-
proaches also imply breaking previous categories. For instance, trans-
kingdom analysis has been proposed in order to address the complexity
of antibiotic-induced alterations [148]. We are at the dawn of a new
global perspective of analyzing the complex interactions between the
host’s immune defenses and its resident microbiome and between the
communities within the host’s microbiome. This approach should sig-
nificantly enhance our deciphering of their influence on human health
in general and, particularly, on allergic diseases.
Declaration of interest
None.
Funding
No specific funding was allocated for this paper.
Conflict of interest
None.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.humic.2018.10.001.
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