REVIEWS

How the microbiota shapes

rheumatic diseases
Tom Van de Wiele1, Jens T. Van Praet24, Massimo Marzorati1, Michael B. Drennan2,3
and Dirk Elewaut2,3
Abstract | The human gut harbours a tremendously diverse and abundant microbial community
that correlates with, and even modulates, many health-related processes. The mucosal interfaces
are particularly active sites of microorganismhost interplay. Growing insight into the
characteristic composition and functionality of the mucosal microbiota has revealed that the
microbiota is involved in mucosal barrier integrity and immune function. This involvement affects
proinflammatory and anti-inflammatory processes not only at the epithelial level, but also at
remote sites such as the joints. Here, we review the role of the gut microbiota in shaping local
and systemic immune responses and how disturbances in the hostmicroorganism interplay
can potentially affect the development and progression of rheumatic diseases. Increasing our
understanding of how to promote hostmicroorganism homeostasis could therefore reveal
novel strategies for the prevention or alleviation of rheumatic disease.

1
Laboratory of Microbial
Ecology and Technology
(LabMET), Faculty of
Bioscience Engineering,
Ghent University, Coupure
Links 653, Ghent, B-9000,
Belgium.
2
Laboratory for Molecular
Immunology and
Inflammation, Department
of Rheumatology,
Ghent University Hospital,
De Pintelaan 185,
Ghent, B-9000, Belgium.
3
Unit for Molecular
Immunology and
Inflammation,
VIB Inflammation Research
Center, Ghent University,
Fiers-Schell-Van Montagu
building, Technologiepark
927, B-9052 Ghent
(Zwijnaarde), Belgium.
4
Division of Nephrology
and Infectious Diseases,
AZ SintJan Brugge
Oostende AV, Ruddershove 10,
8000 Bruges, Belgium.
Correspondence to D.E.
dirk.elewaut@ugent.be
doi:10.1038/nrrheum.2016.85
Published online 16 Jun 2016
The human body is colonized by an abundant and genet
ically diverse microbial community, the microbiota.
Although the number of our microbial colonizers is one
order of magnitude higher than the number of our cells,
the number of genes encoded by the human microbiome
(the genome of all microbiota) exceeds that encoded by
the human genome by 100fold. The human microbiota
is considered a major player in health-related processes,
either by direct influence or through interaction with
other health determinants, including genetics, diet, life
style, medical practices, hygiene and the exposome (the
totality of environmental factors humans are exposed to
during their lifetime). The rapid rise of several omics
techniques and their application in the context of large
research initiatives, such as the Human Microbiome
Project1 in the USA and MetaHIT2 in Europe, have
revolutionized the field by shedding light on correlations
between health status and microbiome composition,
specific expression of genes, translation into proteins or
production of specific metabolites. The influence of the
human microbiota on health is being increasingly rec
ognized not to be solely confined to the gut region. For
example, whole-genome shotgun data from the Human
Microbiome Project has revealed the microbiome to be
composed of up to 30% of Clostridium clusters IV and
XIVa3, many of which have immune-modulating effects4.
One of the main tasks of the mucosal immune sys
tem is to maintain a balance between protection against
potentially harmful microorganisms and tolerance to
dietary antigens. Organized lymphoid nodules, such as
Peyers patches and cryptopatches (the existence of the
latter being controversial in humans), have therefore
evolved to enable the immune system to differentiate
between protective and tolerogenic responses57. Not
surprisingly, breaching the integrity of the mucosal
surfaces can result in inflammation in the intestine but
also in other body regions. The microbiota contributes
to the systemic immune effects of local inflamma
tion in the mucosa and the resulting pathologies. Gut
inflammation and the microbiota have been associated
with musculoskeletal diseases such as spondyloarthri
tis (SpA, which includes ankylosing spondylitis [AS])
and rheumatoid arthritis (RA), and might also have a
role in other rheumatic diseases such as systemic lupus
erythematosus (SLE).
In this Review, we highlight progress made in the
past few years on the role of the human microbiota in
maintaining immune homeostasis, and how shifts in
microbiome composition can contribute to rheumatic
diseases. We also discuss current strategies to modulate
altered microbiotas and how this modulation could have
therapeutic applications.
The human gut microbiota
The human intestine is colonized by a complex micro
bial ecosystem, which can be considered as a separate
organ within the human host. This human microbiota
has a coding capacity that exceeds that of the liver by a
factor of 150 (see BOX1 for more facts and figures on
the human gut and its microbiota). High-throughput

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Key points tissues20. Thousands of small molecules derived from

Gut microbiota shape immune responses
Both innate and adaptive immunity are influenced by gut microbiota, locally in the
gut as well as systemically
Intestinal dysbiosis is a feature of several inflammatory rheumatic disorders
Development of anticitrullinated protein antibodies is modulated by HLA shared
epitope alleles, smoking and specialized microbiota at mucosal sites
Gut inflammation in spondyloarthritis is linked to a more severe disease course and
risk of developing Crohn disease and is associated with intestinal dysbiosis
Restoring intestinal homeostasis by altered microbiota is an attractive therapeutic
strategy to combat rheumatic diseases
culture-independent sequencing analyses have shown
that microbiota from the gastrointestinal tract (GIT)
are more complex than microbial populations from
other body sites, with more than 1,000 microbial spe
cies identified to date8,9. Most of the phylotypes (approx
imately 90%) identified in the GIT belong to two phyla,
Bacteroidetes and Firmicutes, whereas Actinobacteria,
Proteobacteria and Verrucomicrobia are represented
with a lower abundance10. The complexity of the gut
microbiota is increased by the presence of methanogenic
archaea (such as Methanobrevibacter smithii), yeasts and
viruses (mainly phages)11. Attempts have been made to
identify a core microbiota with a specific composition.
However, although only two phyla are dominant in the
GIT microbiota, significant interpersonal variability
exists, as evidenced by interindividual differences in
the colonization and composition of hundreds of spe
cies within these phyla; differences in life events, age,
geographic origin, diet, disease, lifestyle and/or drug
uptake lie at the basis of this interindividual variability.
The set of genes of each individual can also influence
the composition of the gut microbiota12.
Some species that have a specific function within the
gut ecosystem have been identified in the gut micro
biota, including Faecalibacterium prausnitzii, a socalled
peacekeeper with recognized anti-inflammatory prop
erties13, and Roseburia intestinalis and Ruminococcus
bromii, which are specialist primary degraders of indi
gestible fibres14,15 and providers of butyrate16. These and
similar findings have led to a gradual shift in the focus
of research in this area, from the study of the compo
sition of the microbiota to the study of its functional
activity. Much research on the microbiota has aimed to
identify the core ecological functions of this organ and
its influence on human health13. Turnbaugh etal.17, for
example, showed that a core gut microbiome can exist
at the level of shared functional genes, even though the
composition of the microbial community is as unique
as an individuals fingerprint. Consequently, metatran
scriptomics and metaproteomics have been introduced
as tools to investigate the gene expression levels of intes
tinal bacteria using faecal samples18,19. More recently,
metabolomics approaches have also been successfully
used in the analysis of the microbiota. These approaches
involve the unbiased quantitative and qualitative analysis
of the complete set of small molecules (molecular weight
<1,000 Da) present in cells, organisms, body fluids or
microorganisms present in the gut or from food and
drug intake are expected to be present in humans21,22.
As the functional characterization of individual
microbiotas progresses, growing evidence is showing
that the gut microbiota is involved in key activities
linked to health and disease (BOX2). The human micro
biota comprises up to 100 trillion cells, which are
exposed to the host through a mucus-covered surface
area of 32m2 (REF.23). Therefore, any factor that dis
rupts the hostmicroorganism equilibrium (such as
depletion and/or thinning of the mucus layer; drastic
changes in diet behaviour and/or malnourishment; use
of antibiotics; inflammation; infection with pathogens;
gastrointestinal surgery; etc.) might affect homeostasis
and have a dramatic effect in the modulation of immune
functions of the host by the microbiota2427. The result
ing microbial imbalance, also termed dysbiosis, can lead
to elevated host inflammation and, subsequently, to the
development of intestinal disorders28. Dysbiosis has been
associated with colon discomfort, and with obesity and
related metabolic disorders, such as diabetes, nonalcoholic
steatohepatitis and cardiovascular diseases29.
A critical window in establishing this hostmicrobial
interplay occurs early in life. Early infancy seems to be
a critical period for intestinal colonization, which has
marked effects on the maturation of the immune system.
Modification of this process of colonization by mode of
delivery at birth, breastfeeding or administration of anti
biotics has been linked to long-term health outcomes.
For example, the lack of contact with the mothers vag
inal and perineal microbiota for children born through
caesarian section results in a different faecal microbiota,
the composition of which is determined moreseo by the
maternal skin microbiota and the microorganisms in the
hospital environment than the microbiota of children
born through vaginal delivery29. These differences in
early colonization are still distinguishable after several
years and have been suggested as a possible underlying
factor for the prevalence of type1 diabetes mellitus,
asthma and coeliac disease among individuals born
through caesarian section3032. Breastfeeding lowers the
risk of asthma and coeliac disease later in life33,34, whereas
antibiotic use in the first year of life enhances the risk of
inflammatory bowel disease (IBD) in childhood35.
The gut microbiota and immunity
Immune recognition of gut microorganisms
The mucosal microbiota has great potential to interact
with the host, both in a positive and in a negative man
ner, owing to hostmicroorganism proximity over a
large surface area in the gut. Therefore, the immune sys
tem needs to be vigilant, which is illustrated by the fact
that gut-associated lymphoid tissue (GALT) represents
70% of the bodys immune system, and 80% of all IgA-
producing plasma cells reside in the intestinal lamina
propria36. Both the innate and adaptive immune systems
can respond to microbiota. Constant signalling between
microorganisms and the host exists in the gut epithe
lium37. Intestinal epithelial cells and dendritic cells pro
truding beyond the epithelium are crucial for the initial

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Box 1 | The human gut and its microbiome: facts and figures
The whole digestive tract is ~9m long. The small intestine is the longest part, at ~7m
The mean total mucosal surface of the digestive tract is ~32m2 on average23
The entire microbiota in a person weighs only 0.52kg (wet weight)
The intestinal tract is a nutrient-rich environment containing up to 100 trillion (1014) microorganisms, the vast majority
of which reside in the colon where densities approach 10111012 cells per ml, the highest recorded densities for any
microbial habitat
At birth, the gastrointestinal tract is sterile. Breast milk has a crucial role in shaping the composition of the microbial
community via transmission of the milk microbiota, including species (for example, Bifidobacterium spp.) selected by
milk oligosaccharides, and maternal antibodies to the infant gut183
The activity and composition of the gut microbiota change from infancy to old age in response to the genetic
background, diet, immune system and health status of the host184
The dominant bacterial groups in different parts of the gastrointestinal tract reflect physiological differences along
the length of the gut (such as oxygen availability, presence of antimicrobial peptides, availability of carbon sources
and pH)183. The oral microbiota is frequently dominated by Firmicutes (for example, Streptococcus salivarius) and
Actinobacteria. The healthy human stomach is dominated by Prevotella, Streptococcus, Veillonella, Rothia and
Haemophilus genera. In the small intestine, the Lactobacillaceae and Enterobacteriaceae families dominate, whereas
the colon is mainly characterized by the presence of species from the families Bacteroidaceae, Prevotellaceae,
Rikenellaceae, Lachnospiraceae and Ruminococcaceae. The mucosa is enriched with mucin degraders (for example,
Bacteroides fragilis and Akkermansia muciniphila).
Today, 7.3 billion humans live on Earth. Together, we represent a reservoir of 10231024 gut microbial cells
Each individual has a unique signature gut microbiota as personal as a fingerprint
The total number of bacteria in our gut is ~10 times greater than the total number of our somatic and germ cells
The number of functional genes in gut microorganisms is ~150 times higher than the number of genes in the human
genome
The human microbiome is defined as the collective genomes of the microorganisms (bacteria, bacteriophages, fungi,
protozoa and viruses) that live inside and on the human body

recognition of mucosal and luminal microorganisms
(FIG.1). The important distinction between trustworthy
microorganisms and (opportunistic) pathogens, which
determines whether the immune system is regulated or
activated, is fulfilled by pattern-recognition receptors
(PRRs). PRRs comprise membrane-associated Toll-like
receptors (TLRs), cytosolic nucleotide oligomerization
domain (NOD)-like receptors and secretory collectins.
The role of PRRs involves recognition of microorganism-
associated molecular patterns, which leads to the rapid
engagement of other essential components of the innate
immune system, including those that produce antimi
crobial peptides. Such a response is mostly aspecific, so
damage to the endogenous microbiota often occurs as a
result38. A more specific response is needed for long-term
protection.
In the intestine, microbial antigens can be recognized
by a variety of antigen-presenting cells, including den
dritic cells, macrophages and Bcells. Before recognition
can take place, the antigens need to cross the epithelial
barrier, which can occur either via intestinal epithelial
cells or via other specialized cell types, such as M cells.
Dendritic cells can sample antigens directly in the intesti
nal lumen, after which they typically migrate to the mes
enteric lymph nodes. Here, dendritic cells can modulate
Tcell activation and maturation into specialized func
tional subsets (Thelper (TH) cell subsets such as TH1, TH2
or TH17 cells, or regulatory T (TREG) cells) upon antigen
recognition. The production of IgA by Bcells, which
has a pivotal role in antimicrobial protection within
the intestine, is mainly regulated by follicular helper T
(TFH) cells39. Maturation of Bcells into high-affinity IgA-
secreting plasma cells occurs within Peyers patches in
neonates and assists in maintaining an immune barrier
within the intestine into adulthood. Some low-affinity
IgAs have also been shown to be generated in isolated
lymphoid follicles and in the lamina propria in a Tcell-
independent manner, and require innate lymphoid cells
as well as TLR and/or inflammatory cytokine signalling
for maturation40,41. The role of innate lymphoid cell pop
ulations in the regulation of inflammation has received
much attention in the past few years42.
Microenvironments in the gut mucosa
The gut microbiota cannot be considered as one unique
population, but more as a collection of ecosystems that
colonize different microenvironments in the gut 10.
A longitudinal gradient exists in the composition and
functionality of the microbiota over the length of the
human gut (from the terminal ileum, to the proximal
colon, to the distal colon). Microbiota specifically asso
ciated with nutrient platforms (food-particle-associated
surfaces) also exist in the gut lumen. In addition, a
cross-sectional gradient from the gut lumen to the
mucosal environment is present. The mucus layer has
a particular double structure, with an inner layer, close
to the epithelium, and an outer layer. The inner layer is
rigid because of elevated levels of mucin2; owing to this
rigidity and to the presence of elevated levels of secretory
IgA and antimicrobial peptides, the inner mucus layer
is typically devoid of microorganisms43. Colonization by
mucosal microbiota is more likely to occur in the outer

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In addition to butyrate-producing Clostridia, other

Box 2 | Functions of the human gut microbiota
Digestion and energy harvesting from otherwise indigestible food components, by
modulation of the absorptive capacity of the intestinal epithelium and production of
enzymes that are absent in humans185
Supporting and priming the immune system
Providing nutrients to the gut epithelium (such as short-chain fatty acids), thereby
exerting a trophic function and influencing the differentiation of gut epithelial cells186
Resistance against colonization by potential pathogens by filling in all the available
functional niches (that is, competition with the pathogen for physical space and
nutrients) and maximizing the functional capacity of the entire ecosystem187
Influencing satiety through the production of short-chain fatty acids via fermentation
of fibres, which can affect the release of gastrointestinal satiety hormones, such as
peptide YY and glucagon-like peptide188
Gut bacteria are also thought to influence our state of mind by producing neuroactive
compounds that act on the brain189
Brain:
Gut bacteria produce
neuroactive compounds
typical mucosal microorganisms also have effects on the
intestinal immune function of the host. For example,
Bacteroides fragilis can produce polysaccharide A, which
affects the immune system in the early stages of coloni
zation. The immune system of germ-free mice is typically
skewed towards a TH2cell-controlled humoral immune
response. Mono-association of germ-free mice with PSA-
producing B.fragilis or treatment with polysaccharide A
stimulates the development of TH1cell-mediated immu
nity53, which, in turn, protects against and suppresses
inflammation54. Another example of a pronounced
immune-modulatory function of the microbiota is the
ability of segmented filamentous bacteria (SFB) to direct
the immune system of mice towards increased production
of TH17 cells, thereby protecting the animals from infec
tious agents55. Our research group also showed that SFB
present during the neonatal colonization process in mice
are important microbial components in the development
of systemic autoimmunity in adult life56.

Regulation of systemic immunity

Immune system:
Gastrointestinal tract:
Gut bacteria regulate
immune system
Gut bacteria inuence development and
satiety, digestion and priming
resistance against colonization,
and provide nutrients to
the gut epithelium
mucus layer, which is lessNature Reviews
rigid and | Rheumatology
contains lower levels
of IgA and antimicrobial peptides43. Not unexpectedly,
studies on tissue samples obtained by gut biopsies or
analysis of the entire mucus layer have revealed the
mucosal microbiota to be fundamentally different from
its luminal or faecal counterparts44,45. In addition to the
presence of higher levels of host immune effectors in the
mucosa than in the lumen or faeces46, this difference can
be attributed to the ability of microorganisms to adhere
to mucus47 and/or their ability to degrade mucins48. In
general, the mucosal microbiome is proportionally more
abundant in Firmicutes (especially Clostridium cluster
XIVa) than in Bacteroidetes10,49.
Regulation of intestinal immunity
Certain microbiota, particularly butyrate-producing
Clostridia, can modulate TREGcells. Administration
of butyrate-producing Clostridia such as F.prausnitzii
and Butyricicoccus pullicaecorum to animal models of
inflammation seems to lower the occurrence of macro
scopic lesions to the intestinal mucosa50,51. Observations
in model systems invitro, animal models and healthy
human individuals indicate that F.prausnitzii, in particu
lar, resides preferentially close to the gut epithelium52.
This proximity might enable the delivery of butyrate
close to the epithelium, which could strengthen the gut
barrier. Atarashi etal.4 demonstrated that mono-as
sociation of germ-free mice with butyrate-producing
Clostridia results in upregulation of FOXP3, which is
crucial for the function of TREG cells.
The role of the microbiota in regulating host immune
responses is best emphasized in mice housed under
germ-free conditions. Analysis of the innate and adap
tive immune systems of germ-free mice revealed that a
microbiota-free environment is associated with reduced
production of antimicrobial peptides, which results in
enhanced susceptibility to microbial infections. For
example, the microbiota contributes to the production
of the antimicrobial molecules REG3 and REG3 in
mice57, and impaired production of these molecules is
associated with increased susceptibility to infection with
Listeria monocytogenes and Yersinia pseudotuberculosis,
respectively58,59. The development of innate immune
phagocytes such as neutrophils is also impaired in germ-
free mice, which results in impaired host defence against
Escherichia coli K1 and Klebsiella pneumoniae60. In addi
tion, neonatal exposure to microorganisms limits the
expansion of invariant natural killer Tcells in the lung
and colon of specific-pathogen-free (SPF) mice, which
makes the animals less susceptible to ovalbumin-induced
allergic asthma than germ-free mice61. Observations in
human monozygotic and dizygotic twins have shown
that non-heritable factors such as the microbiota have a
dramatic effect upon the immune system, which suggests
that the gut microbiota might contribute to much of the
immune variation that is seen in humans62.
Beyond the gut: the skin microbiota
The presence of bacteria in the human body is not lim
ited to the gut. In fact, the human skin the bodys
largest organ hosts a high number of commensal bac
teria63. More than 1010 microbial cells cover the human
body and, as occurs for the GIT, different skin microen
vironments with distinct pH, temperature, moisture and
sebum content are also characterized by different micro
bial groups. Metagenomic analyses have identified four
phyla of bacteria in the human skin64, which are mainly
lipophilic bacteria (including Propionibacterium spp.and
Corynebacterium spp.) and commensal staphylococci.

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The long-established link between IBD and SpA

supports the role of the microbiota in human rheu
matic disease. Furthermore, human observational
studies have assessed whether the composition of the
faecal microbiome differs between patients and controls,
using sequencing of 16S ribosomal RNA (rRNA) genes,
whole-microbial genome sequencing and metabolomic
analysis. However, the results of these analyses do not
Pattern recognition reflect the composition of the luminal or mucosal micro
receptors present on System biomes. Also, no studies have addressed the risk of rheu
immune and epithelial cells ic im matic disease with regards to differences in the neonatal
in the gut recognize mu
Intest ni colonization of the gut by mode of delivery, breastfeeding
microbeassociated ina
l im
or antibiotic use in early childhood with the exception of

ty
molecular patterns present Muco
on the gut microbiota sal

m
a recent study which analysed the frequency of breast

un
Imm

ity
m
Gradients of microbiota u feeding in patients with AS versus controls70. Of inter

icr
ne
present in the gut lumen est, breastfeeding was found to be protective against AS

oen
reco ition
and mucosa create distinct Gut
development, further suggesting a potentially important

vironment
micro-environmental microbiota

gn
ecosystems in the gut
Various mucosal microbiota
are known to regulate
intestinal immune function
of the host
Activation of both the
innate and adaptive
immune systems by the gut
microbiota in turn regulates
systemic immune responses
Figure 1 | Relationship between gut microbiota and immune function of the host.
Nature
Microbial ecosystems present within microenvironments Reviews
in the | Rheumatology
gut elicit intestinal
immune responses following recognition of microbial antigens. The development of
intestinal immunity against gut microbiota subsequently shapes systemic immune
responses of the host.
Under normal healthy conditions, the skin microbiota
lives in homeostasis with the highly sophisticated
immune system of the epidermis and the dermis, which
comprises a network of epithelial cells, lymphocytes and
antigen-presenting cells. Changes in this balance and
in the composition of the skin microbiota have been
associated with the pathogenesis of psoriasis6569.
The microbiota in rheumatic disease
Different types of evidence link the microbiota to
rheumatic disease. In some studies of animal models
of rheumatic disease the composition of the micro
biota was compared between diseased animals. These
comparisons have also been made in studies involving
germ-free and gnotobiotic mice, in which animals were
colonised with a defined microflora. Other studies have
assessed the consequences of modulation of the micro
flora through the use of antibiotics. Some of the limi
tations of these animal studies are their limited sample
sizes and the difficulty to mimic the complex multifactorial
pathogenesis of human disease.
role of gut microbiota in the onset of the disease.
Evidence from animal studies
Modulation of experimentally induced arthritis. Studies
in mice with Tcell-activating genetic modifications (such
as SKG7173 and K/BN mice74) and in mice deficient for
the IL1 receptor antagonist (IL1Ra)75 have shown that
arthritis disease activity is diminished under germ-free
or SPF conditions. Similarly, in rat models of adjuvant-
induced and streptococcal-cell-wall-induced arthritis
and in HLAB*27 transgenic rats, the disease pheno
type is modulated by housing7678. Monocolonization of
germ-free IL1Radeficient mice with the gut-residing
commensal bacterium Lactobacillus bifidus resulted in
arthritis with incidence and severity scores compara
ble to those observed in conventionally housed mice75.
Likewise, introduction of SFB in germ-free K/BN
mice resulted in the onset of arthritis74. Furthermore,
the periodontal pathogens Porphyromonas gingivalis
and P.nigrescans markedly aggravate the severity of
arthritis in mice with collagen-induced arthritis (CIA)79.
Treatment with enrofloxacin, an antibiotic that targets
Gram-negative bacteria, exacerbated arthritis in the CIA
model80. Modulation of the gut microbiota with antibiotic
treatment also influenced the development of arthritis in
the K/BN model74. In these mice, antibiotic treatment
disrupted the gut flora, which was associated with dimin
ished numbers of TH17 cells and attenuated arthritic
pathology74. The mechanisms underlying the differences
in the responses to antibiotic treatment in the CIA and
K/BN models are not known, but could be related to
differences in the microorganisms that are involved in
disease pathogenesis in each model.
In the humanized transgenic HLADRB1 mouse
model, the composition of the faecal gut microbiota dif
fered between mice carrying the arthritis susceptibility
genetic variant (DRB1*0401) and genetically resistant
counterparts (HLADRB1*0402)81. This difference was
associated with increased gut permeability and differ
ential transcription of TH17 regulatory network genes
in the jejunum81. Moreover, the faecal microbiome of
HLADRB1*0401 mice did not vary with sex and age,
whereas HLADRB1*0402 mice had a sex-dependent
and age-dependent microbiome. In HLAB*27 transgenic

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rats, presence of the HLAB27 antigen was associated
with an altered microbial composition of the gut82. An
increase in the relative abundance of Prevotella spp.
and Bacteroides vulgatus and a decrease in the relative
abundance of Rikenellaceae was observed in HLAB*27
transgenic animals when compared with controls82.
Hoentjen etal.83 showed that the administration of pre
biotics reduced the severity of colitis and prevented the
development of arthritis in these rats. This effect was
associated with alterations in the composition of the
intestinal microbiota, decreased levels of proinflamma
tory cytokines and increased levels of immunomodu
latory molecules in the cecum and colon, respectively.
These studies suggest that HLA genes can have a role in
the microbial colonization of the gut and that dysbiosis
might be present in genetically susceptible animals.
Some regulatory B (BREG) cell subsets that have a
role in restraining excessive inflammation are depend
ent on the microbiota. Following induction of arthritis,
IL1 and IL6, which directly promote the differentia
tion of BREG cells and the production of IL10 by these
cells, were only produced in conventionally housed
mice, whereas antibiotic-treated mice did not pro
duce these cytokines84. Bcell-specific deletion of the
genes encoding the IL6 receptor (IL6R) or the IL1
receptor 1 (IL1R1) resulted in reduced numbers of
IL10producing Bcells and exacerbated arthritis84. The
gut microbiota was also shown to modulate arthritis in
experimental models of gout in which disease pathogen
esis depends on IL1. Monosodium urate monohydrate
crystals cause gout by activating the NLRP3 inflamma
some, which leads to IL1 production and neutrophil
recruitment. In germ-free mice, the production of short-
chain fatty acids that are necessary for adequate inflam
masome assembly and IL1 production is decreased85.
This effect depends on the metabolite-sensing receptor
free fatty acid receptor 2 (also known as Gprotein cou
pled receptor 43)85. Overall, observations in some exper
imental models of arthritis show that microbial triggers
by commensal bacteria are required to promote disease
in genetically predisposed animals.
diversity of the gut microbiota differ between control
and diseased mice, and modulation of the gut micro
biome by treatment with vitaminA had a variable effect
on lupus symptoms in different organs91. By lowering
the pH of drinking water, Johnson etal.92 found that
(SWRNZB)-F1 (SNF1) mice developed nephritis at
a slower pace and had lower circulating levels of anti
nuclear antibodies (ANAs) than mice that were given
water with a neutral pH. This intervention changed the
composition of the gut microbiota and modulated the
immune response in the gut mucosa92. Overall, these
data suggest that the presence of the microbiota is not
required for disease onset and development in these
models, but modulation of the intestinal flora influences
disease progression.
Our research team identified an unexpected link
between the gut microbiota and development of ANAs56.
Surprisingly, the appearance of ANAs in adult life was
linked to neonatal colonization of the gut with commen
sal flora. The formation of ANAs was found in approx
imately 25% of lymphotoxin-deficient mice lacking
Peyers patches, cryptopatches and isolated lymphoid
follicles, all of which are components of normal GALT.
Neonatal blockade of lymphotoxin, which affects the
formation of isolated lymphoid follicles, resulted in the
occurrence of ANAs with variable specificities, includ
ing antibodies against the U1 ribonucleoprotein complex
(U1RNP), SSA/Ro and DNA topoisomerase I. By con
trast, blockade during fetal or adult life did not result
in autoimmunity. Elimination of gut flora by treatment
with broad-spectrum antibiotics or by blocking lympho
toxin signalling under germ-free conditions reduced
ANA production. Furthermore, the gut microbiota dif
fered between ANA-positive and ANA-negative animals,
with particularly marked differences being observed
for Methylobacterium spp. belonging to the SFB group.
Germ-free lymphotoxin-deficient animals monocolo
nized with SFB produced more ANAs than lymphotoxin-
deficient controls monocolonized with E.coli, which
indicates that SFB can modulate the development of
generalized autoimmunity in adult life.

Modulation of antinuclear antibody formation and Spondyloarthritis

systemic autoimmunity. The course of lupus-like dis
ease and autoantibody production in mouse models of
generalized autoimmunity are not profoundly different
in animals raised under germ-free or under conven
tional housing conditions8689. However, no data on the
effects of elimination of gut microbiota with antibiotics
are available in these models. Of note, these models,
including NZB, MRL/lpr and pristane-induced lupus,
lack essential features of human disease, such as a bias
towards the female sex and stochastic distribution of
the probability of developing the disease. Nevertheless,
indirect data suggest that gut flora might modulate dis
ease in these models. Studies have shown that caloric
restriction or other dietary interventions, such as sup
plementation with vitamins A, D or E, or with polyun
saturated fatty acids, prevented progression of lupus-like
disease in NZB/W mice90. In the MRL/lpr model, the
most widely used of these models, the composition and
Approximately 20% of patients with inflammatory bowel
disease (IBD) develop arthritis in the joints of the lower
and upper limbs or inflammation of the spine, which
are features that characterize SpA93,94. The incidence of
these manifestations of musculoskeletal disease might
be even higher in patients with Crohn disease and indi
viduals with longstanding IBD95,96. AS, the prototypic
form of SpA, occurs in up to 10% of patients with IBD97.
The existence of a pathogenic link between the gut and
joints is also apparent in enterogenic reactive arthritis, a
disease in which an infectious enterocolitis triggers joint
inflammation98.
Importantly, ~50% of patients with SpA have micro
scopic signs of inflammation in the gut that are not
associated with clinical gastrointestinal symptoms. This
inflammation can have the same histological character
istics as acute inflammation of the gut, in which neutro
phils predominate, in a way that resembles the response

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to acute bacterial enterocolitis. However, one-third
of patients with SpA have chronic microscopic inflam
mation that is characterized by a mononuclear inflamma
tory infiltrate and structural remodelling of the intestinal
mucosa, which resembles the histological characteristics
of Crohn disease98. Mucosal inflammation has a pro
found effect on long-term outcomes in patients with
SpA. Most patients with normal histology or acute intes
tinal lesions have transient arthritis. Clinical remission
of joint inflammation is associated with resolution of gut
inflammation, whereas the presence of gut inflamma
tion is associated with persistent joint inflammation99,100.
Chronic inflammatory lesions in the gut are a risk fac
tor for development of Crohn disease; in one study, 20%
of patients with chronic intestinal lesions developed
clinically overt IBD over a 5year period100. Even in the
early stages of SpA, chronic microscopic gut inflam
mation is strongly associated with the extent of spinal
inflammation101,102.
The intestinal microbiota has been extensively stud
ied in patients with IBD. A consistent finding of these
studies has been decreased diversity, that is, lower
richness and evenness of the intestinal microbiota, in
patients with IBD103. Richness refers to the variety of
unique organisms present in a sample, whereas evenness
relates to the likelihood that two sequences chosen at
random represent the same species. One study reported
on changes in the faeces of children with ulcerative colitis
when compared with faeces from healthy control children.
Patients with ulcerative colitis had lower diversity of
microbial species than controls; among the individuals
with ulcerative colitis, those refractory to corticosteroid
therapy had lower species counts than steroid-responsive
patients104. Likewise, a study of children who were
newly diagnosed with Crohn disease or ulcerative coli
tis showed a decreased microbiota diversity in patients
with Crohn disease (but not in patients with ulcerative
colitis) when compared with that in healthy controls105.
Substantial alterations in the taxonomic composition of
the microbiota have also been reported in patients with
IBD. Although the findings of individual studies vary,
common observations include increases in the abun
dance of Proteobacteria and decreased abundance of
Firmicutes, among which F.prausnitzii106. These differ
ences are associated with functional consequences, such
as a decreased production of short-chain fatty acids,
which are essential for the health of enterocytes and also
have a direct anti-inflammatory effect107.
A strong association between bowel inflammation
and all forms of SpA (including AS, juvenile SpA and
psoriatic arthritis (PsA)9195,108) has been recognized for
several decades, as well as the link between gut inflam
mation and disease progression to AS and Crohn dis
ease. However, surprisingly little is currently known
about the complex relationship between the micro
biota, genetics and inflammation in SpA. Few studies
have directly addressed the role of the gut microbiota in
this relationship. A 2002 study evaluated the composi
tion of the faecal microflora of 15 patients with AS and
15 matched controls by denaturing gradient gel electro
phoresis. No specific differences in colonization profiles
were found between patients and controls, but a higher
prevalence of sulfate-reducing bacteria was found in
patients with AS109. More recently, microbiome analy
ses in patients with SpA have been conducted using
high-throughput 16S rRNA gene sequencing. Costello
etal.110 found a higher abundance of Lachnospiraceae,
Veillonellaceae, Prevotellaceae, Porphyromonadaceae
and Bacteroidaceae in the terminal ileum of patients
with AS than in healthy controls. Stoll etal.111 showed
that F.prausnitzii abundance in the stools of patients
with enthesitis-related arthritis, a subtype of juve
nile SpA, is reduced compared with that in controls,
whereas Bacteroides spp. and Akkermansia muciniphila
were identified as disease-associated agents in subsets of
patients. Differences in the humoral responses to these
bacteria have been proposed to contribute to some
degree to the development of disease112.
SpA has also been linked with skin inflammation
through its association with psoriasis. Evidence showed
that 30% of patients with psoriasis develop PsA113,
although the origin of this pathogenic process is not
clear. Microbial and environmental factors could have
a role in this process, but a link between the micro
biota or the environment with PsA has not yet been
established114. A study in patients with PsA or psoriasis
reported lower frequencies of certain beneficial taxa,
particularly Akkermansia spp. and Ruminococcus spp115.
In patients with PsA, the frequency of these taxa was
lower than their frequency in patients with psoriasis.
These observations are similar to earlier findings in
patients with IBD, who also have different microbiome
profiles to those of healthy individuals116. Further studies,
however, are needed to fully understand the biological
implications of these observations.
Rheumatoid arthritis
Susceptibility genes have been shown to have an impor
tant role in the development of RA, but environmental
factors are also likely to be critical in this process, as
inferred by the fairly low concordance rate of RA in
monozygotic twins117. Development of anti-citrullinated
protein antibodies (ACPAs), which are highly specific
for RA, occurs well before disease onset and is linked to
environmental factors such as smoking117. This obser
vation raised the idea that mucosal sites other than the
gut might contribute to the pathogenesis of RA. Over the
past few years, several studies highlighted that changes
in microbiota composition in the oral cavity, gut and
possibly the lung might facilitate the onset of RA.
Several observational studies have found an associ
ation between RA and periodontal disease. Periodontal
disease occurs more frequently and tends to be more
severe in patients with RA versus healthy controls118
and new-onset RA has been linked with the presence
of periodontal disease119. Moreover, treatment of perio
dontal disease decreases the severity of RA120. Much of
the research on the relationship between the oral micro
biome and RA has been focused on P.gingivalis, because
these bacteria have the unique property of harbouring a
gene that encodes peptidyl arginine deiminase (PAD), an
enzyme that catalyses the conversion of arginine residues

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into citrulline121,122. This role is of particular interest Other rheumatic diseases

because citrullination of proteins (such as vimentin,
keratin and enolase) is associated with the production
of ACPAs under certain conditions123126. Therefore,
P.gingivalis could contribute to the induction of ACPAs,
a strong predictor of the onset of RA. This finding was
supported by additional experimental work invitro and
invivo123126. Conversely, treatment of periodontal dis
ease might lower the levels of circulating ACPAs and
antibodies against P.gingivalis127. Finally, DNA of P.gin
givalis and P.nigrescens was found in serum and synovial
fluid of patients with RA128.
In a small study involving low-throughput 16S rRNA
hybridization, Vaahtovuo etal.129 identified dysbiosis
in the faecal microbiota of patients with newly diag
nosed RA, whereas dysbiosis was not present in the
faecal microbiota of control patients with fibromyal
gia. Another study used PCR primers for Lactobacillus
DNA to show that the faecal microbiota of patients with
RA contained increased diversity of Lactobacilli com
pared with the microbiota of healthy controls130. More
recently, 16S rRNA sequencing showed a strong corre
lation between disease and the presence of Prevotella
copri and loss of Bacteroides in the faecal microbiome in
untreated patients with new-onset RA131. Finally, bacte
rial rRNA from naturally occurring commensals such as
Clostridium spp. have been isolated from synovial tissue
of patients with RA but not patients with osteoarthritis
or those with closed traumatic knee injuries132.
The relationship between the respiratory mucosa,
which harbours its own characteristic microbiota133135,
and RA is also receiving increasing attention. This inter
relationship is complicated by the potential influence of
cigarette smoking, which is associated with increased
airway inflammation and, in some studies, has also
been linked to changes in the microbiota in airways,
particularly in the relative abundance of Prevotella and
Porphyromonas136. The literature, however, is not entirely
consistent in this area133,134,136. One key observation that
makes the lung a particularly interesting site to examine
is the strong link between smoking, citrullination and
RA. Cigarette smoking leads to increased expression of
PAD and protein citrullination in the bronchoalveolar
lavage cells of smokers without arthritis137. Additionally,
PAD polymorphisms, such as PADI4, have been shown
to predispose male smokers to developing RA138. ACPAs
and rheumatoid factor have also been found in induced
sputa of patients with early-stage RA139. However, the
relationship between smoking and autoimmunity in
RA might be more complex than previously thought, as
citrullination of vimentin, a major autoantigen in RA,
was found in lungs of both non-smokers and smokers
with chronic obstructive coronary disease (COPD),
which suggests that citrullination in the lungs of smokers
is mainly due to inflammation140. Altogether, available
evidence indicates that the lung might be an early site of
autoimmune-related injury and a site of generation of
RArelated autoimmunity. Thus, generation of RArelated
autoimmunity could be triggered or at least modulated by
the presence of proinflammatory microbiota derived from
periodontal tissue.
Data on the putative link between the microbiota and
systemic autoimmune diseases other than SpA and RA
are limited in humans141,142. Environmental factors are
critical in the pathogenesis of SLE, the prototypic dis
ease for generalized autoimmunity, with development
of autoantibodies preceding onset of clinical disease143.
A 2015 study has pinpointed a potential role for the
microbiota in SLE via an effect of the microbiota in low
ering the threshold for activation of autoreactive Bcells56.
Unidirectional or multidirectional interplay?
How the microbiota, lifestyle and/or environmental
factors, and host-derived factors such as genetics and
immune responses are interrelated is a key problem to
solve. Which factors are causes and which are conse
quences? This chicken-oregg paradigm has not been
solved at present but some general principles have
emerged, especially from the IBD field.
The changes in the microbiota of patients with IBD
do not directly prove these alterations are responsible for
the inflammatory phenotype of these patients, as they
could be secondary to the inflammatory process itself
or caused by therapy. However, even though some med
ications used to treat IBD, particularly antibiotics, are
likely to alter the contents of the microbiota, alterations
in the microbiota were nevertheless identified in newly
diagnosed patients naive to immunosuppressive ther
apy105. A role for an altered microbiota in IBD is further
substantiated by therapeutic responses to interventions
that alter the microbiota. A meta-analysis of 35 stud
ies involving patients with Crohn disease or ulcerative
colitis concluded that addition of probiotics to stand
ard therapy in patients with ulcerative colitis, although
not in those with Crohn disease, resulted in improved
remission rates144. Conversely, antibiotics can improve
remission rates in patients with Crohn disease, but their
role in ulcerative colitis is less clear145.
Given the reciprocity between bowel and joint inflam
mation in SpA, the intestinal microbiota could have a role
in SpA as well. This role could take place either through
a direct mechanism, whereby entire microorganisms or
their fragments traffic to the joints causing inflammation,
or indirectly, whereby bacteria trigger an autoimmune
reaction against self antigens by molecular mimicry or by
lowering the threshold of activation of autoreactive cells.
Alternatively, intestinal bacteria could skew the immune
system toward a proinflammatory state, which would ulti
mately lead to joint inflammation. A proposed mechanism
to explain the link between gut and joint inflammation is
the aberrant trafficking of lymphocytes, macrophages and
innate lymphoid cells primed in the intestinal mucosa to
the joint146. The association of citrullination in the lung
and RA highlights that other mucosal surfaces could also
be important. In addition, the development of autoim
munity in adult life could be a consequence of neonatal
changes in the hostmicroorganism interplay.
We propose two possible models that could explain
the relationship between the microbiota and the host.
In the linear or unidirectional model a primary cause ini
tiates a one-way directional process. For example, disease

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Prenatal immunity Postnatal immunity Autoimmunity

Lumen

Epithelial cell M cell Mucus Goblet cell

Immature
Peyers patch Peyers patch

LT-12 LT-12
LT receptor LT receptor

Lamina Cryptopatch Immature isolated

propria lymphoid follicle
Mature isolated lymphoid follicle

Mesenteric IL-17
lymph node
IL-17
Dendritic cell IgA+ plasma cell
ROR+ LTi cell Commensal bacterium
Antinuclear
B cell SFB antibodies
T cell Dimeric IgA

Figure 2 | Unidirectional hostmicroorganism interplay. An example in which antinuclear antibodies are induced
by lymphotoxin deficiency is shown. In the postnatal phase, the intestinal lumen is colonized by microbiota.
Nature Formation
Reviews | Rheumatology
of secondary lymphoid organs depends on the TNF cytokine lymphotoxin 12 (LT-12) and its interaction with the
lymphotoxin (LT) receptor. In the neonatal phase, LT-12 is indispensable for formation of isolated lymphoid follicles.
Ablation of LT-12 in the neonatal period, but not during fetal or adult life, is associated with absence of formation of
isolated lymphoid follicles and with microbiota shifts characterized by expansion of segmented filamentous bacteria
(SFB). SFB are strong inducers of IL17driven responses that promote spontaneous production of antinuclear antibodies.
Thus, neonatal colonization of the intestine by SFB in the absence of gut-associated lymphoid tissues is a predisposing
factor for production of antinuclear antibodies in adult life. Adapted from Van Praet, J. T. etal. Commensal microbiota
influence systemic autoimmune responses. EMBO J. 34, 466474 (2015) and Knoop, K. A. & Newberry, R. D. Isolated
lymphoid follicles are dynamic reservoirs for the induction of intestinal IgA. Front. Immunol 3, 84 (2012)56,190

could be induced in an individual with a particular
genetic background following an environmental trig
ger (FIG.2). This occurrence would in turn result in
changes in the microbiota, which could influence local
immune responses in the intestinal tract, for example
by modulation of the formation and maturation of
GALT. These events would lead to changes in systemic
immune responses, loss of tolerance and occurrence of
systemic autoimmunity. An example to which such a
model applies is the induction of ANAs, including anti
bodies against U1RNP, SSA/Ro and DNA topoisomerase
I, following neonatal depletion of the TNF superfamily
cytokine lymphotoxin56 (FIG.2). This depletion ablates
formation of isolated lymphoid follicles, along with an
expansion of SFB56. Similarly, the secretion of lympho
toxin by intestinal innate lymphoid cells has been shown
to regulate the production of IgA and microbiota com
position in the gut of adult animals147, as does TLR5 or
NLRP6 deficiency in mice148,149. These findings suggest
that the gut microbiota can be shaped by the genetic
background in a feed-forward manner. Genetics also
seems to have a critical role in shaping the gut micro
biota in humans150. In a large study of twins, many
microbial taxa were influenced by the genetics of the
host, particularly the family Christensenellaceae, which
formed a cooccurrence network with other heritable

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bacteria and with methanogenic archaea. Interestingly,
this network was associated with metabolic phenotypes.
If the linear model is accurate, its unidirectionality could
have important consequences in the ability of therapy to
restore balance in the composition of the microbiota.
An alternative model is the multidirectional model,
in which the interrelationship between genetics, the
microbiota, environment and immune responses is not
unidirectional and is more plastic (FIG.3). Here, the host
microorganism interplay reaches a steady state that is
dependent on an equilibrium achieved between the dif
ferent variables. In some diseases (such as AS) the genetic
component is the major component of disease, yet the
occurrence of clinical onset relies on environmental,
lifestyle (for example, diet, smoking status) or microbial
changes. In other instances (such as reactive arthritis),
the genetic component can be much less prominent, with
the microbial component being the dominating trigger.
In RA, established risk factors, including smoking status
and sex, influence the gut microbiota, with the effect of
smoking on ACPA production being particularly obvi
ous in patients carrying HLADRB1 shared-epitope
alleles137,151155. The principal difference between the
multidirectional and the linear models is the reversibil
ity of the multidirectional model. Lack of equilibrium
between the four main components of the model (genet
ics, microbiota, environment and immune response)
results in onset of disease. Reestablishing homeosta
sis could, from a conceptual viewpoint, be achieved by
targeting either of these components.
Substantial evidence indicates that some of the
observed relationships between the host genetics, the
environment and the microbiota are species-dependent.
Christensenellaceae are highly heritable, whereas the
Bacterioidetes community is mostly shaped by envi
ronmental factors and most of the species in this group
are not heritable. Members of the Bacterioidetes have
been shown to respond to dietary interventions156,157.
Modulation of the composition of the gut microbiota
by food components might also modulate inflamma
tory responses in the gut. Emulsifiers (such as carboxy
methylcellulose and polysorbate80) are detergent-like
molecules that are ubiquitous components of processed
foods. These substances can increase bacterial transport
across epithelia by affecting mucusbacterial inter
actions. Intake of emulsifiers promoted ulcerative colitis
in mice predisposed to this disorder and was associated
with low-grade inflammation and obesity and/or the
metabolic syndrome in wild-type hosts158.
How can homeostasis be restored?
Genetics is the most complex component of the host
microbiota relationship to modulate. Proofofprinciple
application of gene therapy for rheumatic diseases has
been done in animal models, but clinical practice appli
cation is still a long way ahead159. The modulation of
environmental factors, the modulation of the immune
response (an approach our group is currently investi
gating), and targeting of the microbiota are more obvi
ous strategies for influencing the hostmicroorganism
interplay.
Lifestyle changes (such as smoking cessation in RA)
might be useful yet difficult to implement in a large
proportion of patients. Furthermore, although gene
environment interactions are involved in the onset of
disease, evidence suggests that environmental factors
important in rheumatic diseases can have an effect years
before clinical disease becomes apparent160.
Specific emphasis can be placed on the immune-
modulating potential of several gut microorganisms, such
as Bacteroides fragilis strains or members of Clostridium
clusters IV and XIVa, which may modulate PsA. Although
most of the latter organisms (that is, members of
Clostridium clusters IV and XIVa) have butyrate produc
tion as a core function, their immune-modulating effect
can also be derived from compounds in their secretome or
other antigens. This area of research needs further inves
tigation, but administration of these microorganisms to
animal models has already yielded promising results161.
The outcomes of the Human Microbiome Project1
and MetaHIT2 have confirmed that the resident micro
biota has a crucial role in maintaining the health of the
host. Conversely, dysbiosis is associated with potential
health problems. Therefore, biotherapeutic strategies
designed to preserve or restore the human microbiota
might be an interesting approach for the treatment of
rheumatic diseases.
In the past 20years, much research effort has been
focused on the modulation of the colonic microbiota and
related metabolic processes by prebiotics and probiotics
to improve the health of the host162166. The prebiotic
concept has been defined as the selective stimulation of
growth and/or activity(ies) of one or a limited number of
microbial genus(era)/species in the gut microbiota that
confer(s) health benefits to the host (REF.167). The effects
of nutrients with prebiotic properties on gut health have
received particular attention. Interestingly, improvements
in gut function have been associated with systemic effects
on the host physiology. Dietary fructans and arabinoxy
lans have been shown to decrease fat mass, steatosis, lipae
mia, hyperglycaemia, gut permeability, and intestinal and
systemic inflammation24,167169. The concept of prebiotics
was mostly based on the fact that inulin-type fructans
were able to increase the abundance of bifidobacteria in
the gut. However, the relevance of the bifidogenic effect
perse is debatable, as more than 100 bacterial species
are modulated when a prebiotic approach is used and
several species (Roseburia spp., A.muciniphila, F.praus
nitzii, etc.) are associated with improvements in host
health168,169. Although the prebiotic approach is attrac
tive, as it concerns the dietary modulation of indigenous
intestinal microorganisms that are already adapted to the
host170, it has been primarily used so far in a preventive
manner. However, some therapeutic applications for this
approach have been suggested. A severely disrupted gut
microbiota would benefit from either the introduction
of key microbial species, such as Lactobacillus casei 01
in patients with RA171,172, or the introduction of a general
microbiota population, as has been reported for severe
dysbiosis in cases of recurrent C.difficile infection173.
The efficacy and safety of such approaches, however,
need to be confirmed in controlled trials

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Systemic sclerosis

Genetics

In
tis
yli

am
nd Microbiome Immunity

ma
Environmental
spo

tor
factors
ing

y bo
ylos

wel
Ank

Microbiome

disea
Genetics

se
Immunity

Immunity

Microbiome

Immunity

Genetics

Microbiome
Rh
eu
ma
toid
arth
ritis

Figure 3 | Multidirectional model of hostmicroorganism interplay. In this model, the interaction between host
genetics, environmental factors, the microbiota and immunity is plastic. Lack of balance between these factors
contributes to onset of disease, but the relative contribution of each of these four components varies from disease
Nature Reviews | Rheumatology
to disease. For example, the genetic contribution to disease in ankylosing spondylitis is more prominent than that
in rheumatoid arthritis or inflammatory bowel disease.

A systematic review of the data available on the use
of probiotics in a clinical context showed that the pro
biotics with the greatest ability to restore the microbiota
have the strongest clinical efficacy174. As the gut micro
biota is a complex network of species interacting with
the host, such a restoration could be accomplished by
acting on single or multiple nodes of the network, at a
compositional and/or at a functional level175. The sim
plest application of this concept is the faecal material
transplant (FMT), in which faecal microbial slurry is
transferred from a healthy donor to a diseased recipient,
thereby replacing the whole dysbiotic microbiota of the
recipient176. This form of bacteriotherapy has been mostly
used to treat antibiotic-resistant infections (such as
C.difficile-associated diarrhoea [CDAD]). Yet, the poorly
characterized nature of faecal transplants is associated
with risks of transmission of other diseases, which raises
questions over the widespread applicability of FMT in
less acute and/or life-threatening pathologies177. An inter
mediate solution between use of single bacterial strains
and FMT is the use of synthetic (probiotic) consortia
that include the major taxa of gut bacteria or have the
most represented functionalities178. An example of this
approach is the use of a synthetic mixture of micro
organisms, isolated from an individual on the basis of
their culturability, as a therapeutic agent to cure CDAD179.
Another example is the potential use of a 17strain mix
of Clostridia for treatment of inflammatory diseases161.
At the nutritional level, enteral nutrition has been shown
to have similar efficacy in treating juvenile IBD to that
of conventional corticosteroids180. Yet, proof of efficacy
and production of pharmaceutical-grade products will

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require a big effort in the future, starting from the precise
determination of a causative link between changes in
the composition and activity of the microbiota and the
development of a given pathology175.
An even more futuristic approach to favour human
health by managing the metabolic interactions between
the microbiota and the host is the engineering of spe
cific bacterial strains. This approach could be used to
enhance drug therapies, to produce metabolites with
drug-like activities, to rewire smart bacteria to switch
on and off the production of anti-inflammatory mole
cules or to correct abnormalities in signalling pathways
involved in disease pathogenesis181,182.
Conclusions
Increasing evidence shows that the microbiota influ
ences a wide spectrum of rheumatic diseases, including
SpA, PsA and RA. Of interest, the critical sites where
hostmicroorganism interactions modulate inflam
matory responses might not be identical in each of
these diseases. The gut (ileum and colon) is the most
studied site in SpA, whereas the lung and the skin are
of particular interest in RA and in PsA, respectively.
The influence of the microbiota on rheumatic disease is
also time-dependent under certain conditions, for example
during the neonatal period.
At present, management of the microbiota seems
unlikely to become a self-standing solution for therapy
of rheumatic diseases. However, when dealing with a
multifactorial disease, a multifactorial approach to ther
apy could be a useful strategy at certain stages of dis
ease. Among other factors (genetics, immunity and the
environment), the modulation of the microbiota and its
interaction with the host might be a strategy to control
or prevent rheumatic diseases.
Whether changes in lifestyle practices, such as hygiene,
antibiotic use, diet or smoking status, which all influence
various microorganisms in multiple manners, contribute
to the onset or to the severity and evolution of rheumatic
diseases is yet an unexplored question. Research into the
mechanisms whereby therapeutically altered micro
organisms could modulate rheumatic diseases, for example
by activating immune regulatory cells, is still in its infancy,
yet it is an interesting avenue to pursue.

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Author contributions
T.V.d.W., J.T.V.P., M.M., M.B.D. and D.E. researched data for
the article. T.V.d.W., J.v.P and D.E. made substantial contribu-
tions to the discussion of content. All authors contributed to
reviewed/edited the manuscript before submission.
Competing interests statement
The authors declare no competing interests.