ArticlePDF Available

Germs and joints: The contribution of the human microbiome to rheumatoid arthritis



Rheumatoid arthritis (RA) is a debilitating autoimmune disorder, the etiology of which is poorly understood. A new study reveals dysbiosis in gut and oral microbiomes of affected individuals, potentially providing a basis for patient stratification and clues to pathophysiological mechanisms of RA onset and progression.
news and views
nature medicine volume 21 | number 8
AuGuST 2015 839
represented MLGs revealed substantial micro-
biome divergence between RA patients and
healthy controls, not only in feces but also in
salivary and dental samples. Further, analysis
revealed common elements to the dysbiosis
seen at each site, including the depletion in
Haemophilus species and an overrepresenta-
tion of Lactobacillus salivarius, which were
most marked in severe cases
Fecal samples from RA patients were found
to be enriched in Gram-positive bacteria and
depleted in Gram-negative when compared
with control individuals, including some
Proteobacteria and Gram-negative Firmicutes.
Notably, P. c o p r i in RA-affected individuals
showed a trend of increasing relative abundance
in the first year, consistent with its reported
expansion in NORA patients
. Owing to its
ability to generate citrullinated neoantigens, the
presence of oral Porphyromonas gingivalis has
previously been proposed to be a factor under-
pinning the association of periodontal disease
with RA
. However, the reported enrichment of
P. gingivalis in control oral samples is in keep-
ing with a number of recent studies refuting
this hypothetical link
. Across sites, a number
of MLGs that were enriched in the healthy
samples correlated negatively with markers of
acute inflammation (C-reactive protein) and
RA-specific autoantibodies (anti-cyclic cit-
rullinated peptide (CCP) and/or rheumatoid
factor), whereas some MLGs enriched in RA
individuals showed positive correlations with
anti-CCP, rheumatoid factor, IgG and IgA.
These findings suggest potential utility for
MLGs as markers for RA pathophysiology.
The dysbiosis that was observed at each
of the three sample sites was accompanied
by shifts in the relative abundance of genes
encoding specific functional traits
. In fecal
samples from control individuals, modules
RA is a common debilitating autoimmune
disorder associated with progressive disabil-
ity, systemic complications, and early death.
Although its etiology remains elusive, recent
studies have highlighted the potential influence
of the mucosal microbiome on RA onset and
. In this issue of Nature Medicine,
Zhang et al.
report a case-control metage-
nome-wide association study (MGWAS) of
the fecal, dental and salivary microbiome in a
large cohort of treatment-naïve and treated RA
patients. They reveal the RA-associated micro-
biome to deviate substantially from healthy con-
trols in all sites; they show that these imbalances
can be partially redressed by disease-modifying
antirheumatic drugs (DMARDs).
The development of RA is associated with
the dysregulation of normal immune func-
tion, involving an increased production of both
self-reactive antibodies and pro-inflammatory
T lymphocytes. Genome-wide association
studies (GWASs) have identified a number
of susceptibility alleles, including those pre-
disposing T cell repertoire selection, antigen
presentation, or alteration in peptide affinity
However, genetic predisposition is not sufficient
for RA development, as the genetic heritability
is estimated to be approximately 60%, based on
concordance in monozygotic twins
. It is likely
that an environmental trigger is necessary
for disease onset in genetically predisposed
individuals. An intriguing possibility is that
such a trigger might be provided by abnormali-
ties in the bidirectional cross-talk between the
host and the resident microbiome (Fig. 1).
The concept that bacterial populations,
particularly those in the gut, could contribute
to the development of autoimmune arthritis
is more than a century old and is supported
by a large body of research in both humans
and animal models. Notably, multiple studies
using arthritis-prone animals have shown
that bacterial colonization is a requirement
for the emergence of disease
. Only recently,
however, sequencing and computational capa-
bilities have allowed the complex relationships
between the microbiome, immune modula-
tion, and pathogenesis to be investigated.
The potential of a MGWAS approach was high-
lighted by a recent study comparing the intestinal
microbiome in RA-affected individuals and
controls that showed an overrepresentation
of Prevotella species (particularly P. c o p r i ) in
the feces of new-onset rheumatoid arthritis
(NORA) patients, and a concurrent reduction
in Bacteroides species
Whereas the mucosal surface of the gut offers
arguably the greatest potential for host-microbe
interactions, almost all mucosae have resident
microbiota and respond dynamically to their
presence through immune modulation. In this
study Zhang et al.
therefore aimed to assess
whether the dysbiosis reported in the gut of
RA patients was also evident in the mouth—a
highly plausible hypothesis given the frequent
co-occurrence of RA and periodontal disease,
and the shared pathogenic mechanisms and
immunologic pathways of these conditions
By comparing the differential representation
of metagenomic linkage groups (MLGs are
groups of genetic material in a metagenome
that are probably physically linked; MLG is a
term used in lieu of species’) constructed from
shotgun sequence data, the authors were able to
identify bacterial markers that were enriched
in each sample site
. Analysis of differentially
Germs and joints: the contribution of the human
microbiome to rheumatoid arthritis
Geraint B Rogers
Rheumatoid arthritis (RA) is a debilitating autoimmune disorder, the etiology of which is poorly understood. A new
study reveals dysbiosis in gut and oral microbiomes of affected individuals, potentially providing a basis for patient
stratification and clues to pathophysiological mechanisms of RA onset and progression.
Geraint B. Rogers is in the Infection & Immunity
Theme of the South Australian Health and Medical
Research Institute, and is based at the School of
Medicine, Flinders University, Adelaide, Australia.
© 2015 Nature America, Inc. All rights reserved.
news and views
840 volume 21 | number 8
AuGuST 2015 nature medicine
zinc-dependent matrix metalloproteinases
(MMPs), although the paths by which these could
contribute to cartilage destruction at remote
sites of inflammation remains unclear. Finally,
the relative distribution of MLGs is also infor-
mative with respect to the molecular mimicry
hypothesis, in which the microbial production
of cross-reactive epitopes results in an immune
response against self-antigens
. The potential for
this phenomenon to contribute to RA is sup-
ported by the enrichment of both gut and oral
RA microbiomes with sequences that mimic
key motifs in the RA-related human antigens.
Interestingly, Zhang et al.
found that
MLG distribution changed significantly with
DMARD treatment (methotrexate and/or
Tripterygium wilfordii glycosides), with an
increase in the abundance of control-associated
microbiome markers. These changes were
responsible for lipopolysaccharide biosynthesis
and transport, and type II, III, and IV secretion
systems were enriched, in accordance with the
relative depletion of Gram-negative bacteria in
RA. To some extent, such differences in gene
relative abundance represent indirect mark-
ers of bacterial taxon distribution. However,
they also provide insight into potential drivers
of dysbiosis. L. salivarius, for example, is toler-
ant of the high reactive oxygen species (ROS)
concentrations found at sites of inflammation.
The high relative abundance of this species in
RA-affected individuals may therefore reflect an
elevated immune response at the sites sampled.
In addition, the distribution of functional traits
provides clues to possible bacterial contribu-
tions to pathogenesis. The enrichment of zinc
transport systems genes in RA oral samples
could, for example, influence the activity of
most marked in patients who showed the
greatest clinical improvement. Such findings
highlight the likely bidirectional relationship
between the microbiome and RA, and they
underline the need for caution when assign-
ing causality based on microbial association.
Perhaps most importantly, models based on
gut, dental or salivary MLGs were predictive
of treatment response, with disease classifiers
constructed from sequence data comparable or
superior to existing RA serum markers
The potential for members of the gut or
oral microbiota to contribute to pathogenesis
or to beneficially modulate immune response
in RA raises the possibility of microbiome
manipulation for therapeutic benefit. Probiotic
administration of immunomodulatory spe-
cies has shown some promise in autoimmune
. However, the complexity of the
Gut dysbiosis
Clostridium asparagiforme,
Gordonibacter pamelaeae,
Eggerthella lenta, Lachnospiraceae
bacterium, Bifidobacterium dentium,
Lactobacillus, Ruminococcus lactaris
Veillonella, Haemophilus, Klebsiella
pneumoniae, Bifidobacterium bifidum,
Sutterella wadsworthensis,
Megamonas hypermegale
e.g., HLA-DR4/1,
e.g., autoimmune antibodies,
dysregulation of B and
T cell populations
e.g., TNF-α, IL-1, IL-8,
Cardiovascular disease,
liver and metabolic
function, periodontitis
Microbiome of
RA-affected individual
Oral dysbiosis
Veillonella, Atopium,
Lactobacillus salivarius,
Cryptobacterium curtum,
Selenomonas flueggei
Haemophilus, Aggregibacter,
Cardiobacterium, Eikenella,
Kingella, Neisseria, Leptotrichia,
Porphyromonas gingivalis,
Rothia aeria, Capnocytophaga
Molecular mimcry
Collagen XI, HLA-DR4/1
Reduction of tolerogenic species
Increases in pro-inflammatory
Altered mucosal environment
e.g., high levels of ROS, altered redox
Production of
immunomodulatory molecules
e.g., hydrogen sulfide, homocysteine,
altered SCFA production
Figure 1 The potential influence of the human microbiome on rheumatoid arthritis. Zhang et al.
find that in rheumatoid arthritis there is disruption
to normal microbiome composition (dysbiosis) in the gut and mouth. This can contribute to immune dysregulation, both through molecular mimicry
(the microbial production of epitopes cross-reactive with self antigens, resulting in an immune response against self-antigens) and through changes
in the relative abundance of tolerogenic and pro-inflammatory bacterial species. Dysbiosis may also contribute to disease onset through differences in
the functional characteristics of the constituent species, including the ability to produce metabolites that are pro-inflammatory (for example, hydrogen
sulfide, homocysteine) or immunomodulatory (for example, short-chain fatty acids (SCFAs)). The ability of inflammation to shape the microbiome is
reflected in compositional shifts identified by Zhang et al.
in patients receiving DMARDs. Proposed environmental risk factors may also act, in part,
by contributing to dysbiosis, as might genetic predisposition. These may also lead to comorbidities. CRP, C-reactive protein; HLA-DR, human leukocyte
antigen death receptor; IL, interleukin; PADI4, peptidyl arginine deiminase, type IV; TNF-α, tumor necrosis factor.
© 2015 Nature America, Inc. All rights reserved.
news and views
nature medicine volume 21
number 8
AuGuST 2015 841
similar environmental drivers, translated
according to genetic predisposition. Such a
model could explain common bidirectional
RA comorbidities with underlying inflam-
matory components, most notably, heart
disease and depression
. The development
of the case-control MGWAS now offers an
exciting opportunity to identify common-
alities in microbiome characteristics across
these conditions, and to extend analysis of
relationships between dysbiosis and inflam-
matory dysregulation to other body sites. The
extension of shotgun sequencing approaches
to metatranscriptomic analysis, allowing
characterization of not only bacterial func-
tional potential but also differential gene
expression (both microbial and human), may
provide yet-greater insight and represent a
logical next step.
relationship between the microbiome and
immune regulation suggests that a more sophis-
ticated approach may be apposite. The capacity
to engineer a complete artificial microbiome for
introduction to a specific body site, or to use
synthetic biology to incorporate inducible ther-
apeutic traits in the microbiome, are intriguing
The work by Zhang et al.
has importance
beyond RA. Aberrant immune regulation
resulting from disruption of the healthy
microbiome may be a common underlying
feature of many of the idiopathic inflam-
matory disorders, including metabolic syn-
drome, type 2 diabetes, atherosclerosis
inflammatory bowel disease
. It is interest-
ing to consider whether these conditions
might be manifestations of a common dys-
biotic phenomenon, perhaps resulting from
Competing finanCial interests
The author declares no competing financial interests.
1. Brusca, S.B., Abramson, S.B. & Scher, J.U. Curr. Opin.
Rheumatol. 26, 101–107 (2014).
2. Scher, J.U. et al. eLife 2, e01202 (2013).
3. Zhang, X. et al. Nat. Med. 21, 895–905 (2015).
4. Wellcome Trust Case Control Consortium. Nature 447,
661–678 (2007).
5. MacGregor, A.J. et al. Arthritis Rheum. 43, 30–37
6. Rosenstein, E.D., Greenwald, R.A., Kushner, L.J. &
Weissmann, G. Inflamm. 28, 311–318 (2004).
7. Konig, M.F., Paracha, A.S., Moni, M., Bingham,
C.O. III & Andrade, F. Ann. Rheum. Dis. doi:10.1136/
annrheumdis-2014205385 (26 May 2014).
8. Kamphuis, S. et al. Lancet 366, 50–56 (2005).
9. Kverka, M. & Tlaskalova-Hogenova, H. APMIS 121,
403–421 (2013).
10. Sonnenburg, J.L. Nature 518, S10 (2015).
11. Devaraj, S., Hemarajata, P. & Versalovic, J. Clin. Chem.
59, 617–628 (2013).
12. Hedin, C. et al. Gut doi:10.1136/gutjnl-2014308896
(8 April 2015).
13. Halaris, A. Curr. Psychiatry Rep. 15, 400 (2013).
Supporting itch: a new role for astrocytes in chronic itch
Dustin Green & Xinzhong Dong
A new study shows that astrocytes are involved in the development of chronic itch in a mouse model. This is
dependent on upregulation of lipocalin 2 (LCN2) by the transcription factor STAT-3 and astrogliosis.
Dustin Green is in the Solomon H. Snyder
Department of Neuroscience, Department
of Neurosurgery, Department of Dermatology
and Center for Sensory Biology, Johns Hopkins
University, School of Medicine, Baltimore,
Maryland, USA. Xinzhong Dong is in the
Solomon H. Snyder Department of Neuroscience,
Department of Neurosurgery, Department of
Dermatology, Center for Sensory Biology and
the Howard Hughes Medical Institute,
Johns Hopkins University, School of Medicine,
Johns Hopkins University School of Medicine,
Baltimore, Maryland, USA.
e-mail: or
Acute itch, or pruritus, serves as a biological
warning that protects against parasites,
disease-carrying insects and poisonous plants.
The past decade has provided new insights
into the molecular mechanisms that under-
lie the transmission of itch, identifying new
receptors and neural circuits
. Although
acute itch is protective, chronic itch can be a
devastating illness. Pruritus that lasts longer
than 6 weeks is deemed chronic and is accom-
panied by a host of co-morbidities includ-
ing depression, sleep and anxiety disorders
Millions of people suffer from chronic itch, and
it is associated with a wide variety of diseases,
ranging from diabetes and cancer to kidney
. Up until now, our understanding
of how acute itch transitions into a state of
chronic itch has not been well understood.
Here Shiratori-Hayashi and colleagues pres-
ent exciting work that links astrocytes to the
maintenance of chronic itch
Previous studies of itch have focused on the
peripheral afferent and spinal neural circuits
and molecular pathways. Characterizing pruri-
tus has been no easy task, with studies showing
multiple receptors responsible for mediating
differing itch-inducing substances such as
histamine or the malarial drug chloroquine
Moreover, itch neurons seem to be a hetero-
geneous population with subtypes that share
only certain commonalities. However, the con-
sensus at present is that these peripheral itch
neurons project signals to the dorsal horn, an
area of the spinal cord that receives and pro-
cesses sensory information. Shiratori-Hayashi
and colleagues
took a different approach to
study chronic itch by investigating the role of
glia—specifically astrocytes—a type of support
cell in the central nervous system.
To explore the role of non-neuronal cells in
maintaining itch, the authors used a mouse
model of atopic dermatitis. These mice, when
removed from a pathogen-free environment,
developed the hallmarks of human chronic
itch, including repetitive spontaneous scratch-
ing and skin lesions. Using this animal model,
Shiratori-Hayashi et al.
then examined how
the morphology of astrocytes in the spinal cord
had changed. When the spinal cord was fluores-
cently labeled and examined using a confocal
microscope, the astrocytes displayed enlarged
cell bodies and overly arborized processes char-
acteristic of astrogliosis, a type of change in glia
that occurs only after injury or infection (Fig. 1).
Compared to what they observed in healthy
mice, the authors also saw increased levels of
the astrocyte marker GFAP in segments of the
spinal cord that signal to areas of the body that
the animal scratched
. This phenotype could
also be recapitulated by injecting wild-type
mice with diphenylcyclopropenone (DCP), an
immunotherapy drug known to produce pruri-
tus as a side effect. However, glia from segments
of the spinal cord that did not show itch behav-
ior were normal. Up until now, astrogliosis has
primarily been thought of as a feature found
in nerve-injury models of chronic pain; how-
ever, the findings here also point to it being an
important marker for chronic itch.
To study the possible role that scratching
has in producing astrogliosis, the investiga-
tors ablated a subset of itch-sensing nerve
fibers expressing the ion channel TRPV1,
using high concentrations of the potent plant
toxin resiniferatoxin. Mice whose TRPV1
fibers were abolished showed both reduced
GFAP expression and scratching behavior.
These results provide a possible link between
© 2015 Nature America, Inc. All rights reserved.
... All rights reserved antibodies (anti-cyclic citrullinated peptide (anti-CCP) and/or rheumatoid factor). 207,208 In contrast, some MLGs enriched in RA individuals showed positive correlations with anti-CCP, rheumatoid factor, IgG and IgA. 207,208 Atopic dermatitis (AD) and psoriasis AD is a chronic, multifactorial inflammatory skin condition that severely impacts quality of life, especially in early childhood. ...
... 207,208 In contrast, some MLGs enriched in RA individuals showed positive correlations with anti-CCP, rheumatoid factor, IgG and IgA. 207,208 Atopic dermatitis (AD) and psoriasis AD is a chronic, multifactorial inflammatory skin condition that severely impacts quality of life, especially in early childhood. 209 Gut microbiota have a higher proportion of Clostridia, Clostridium difficile, E. coli and Staphylococcus aureus (which contribute to inflammatory responses) and reduced Bifidobacteria, Bacteroidetes and Bacteroides in AD patients compared to healthy controls. ...
Full-text available
The prevalence of chronic immune and metabolic disorders is increasing rapidly. In particular, inflammatory bowel diseases, obesity, diabetes, asthma and chronic obstructive pulmonary disease have become major healthcare and economic burdens worldwide. Recent advances in microbiome research have led to significant discoveries of associative links between alterations in the microbiome and health, as well as these chronic supposedly non‐communicable, immune/metabolic disorders. Importantly, the interplay between diet, microbiome, and the mucous barrier in these diseases has gained significant attention. Diet modulates the mucous barrier via alterations in gut microbiota, resulting in either disease onset/exacerbation due to a ‘poor’ diet or protection against disease with a ‘healthy’ diet. In addition, many mucosa‐associated disorders possess a specific gut microbiome fingerprint associated with the composition of the mucous barrier, which is further influenced by host‐microbiome and inter‐microbial interactions, dietary choices, microbe immigration and antimicrobials. Our review focuses on the interactions of diet (macronutrients and micronutrients), gut microbiota and mucous barriers (gastrointestinal and respiratory tract), and their importance in the onset and/or progression of major immune/metabolic disorders. We also highlight the key mechanisms that could be targeted therapeutically to prevent and/or treat these disorders.
... Dysbiosis and its association with the pathophysiology of rheumatoid arthritis. The molecular mimicry phenomenon, as well as the increase in the number of bacteria associated with inflammation, lead to de-regulation of the immune system[127]. Credit: Original figure by I.A. Charitos. ...
Full-text available
The use of innovative approaches to elucidate the pathophysiological mechanisms of autoimmune diseases, as well as to further study of the factors which can have either a positive or negative effect on the course of the disease, is essential. In this line, the development of new molecular techniques and the creation of the Human Genome Program have allowed access to many more solutions to the difficulties that exist in the identification and characterization of the microbiome, as well as changes due to various factors. Such innovative technologies can rekindle older hypotheses, such as molecular mimicry, allowing us to move from hypothesis to theory and from correlation to causality, particularly regarding autoimmune diseases and dysbiosis of the microbiota. For example, Prevotella copri appears to have a strong association with rheumatoid arthritis; it is expected that this will be confirmed by several scientists, which, in turn, will make it possible to identify other mechanisms that may contribute to the pathophysiology of the disease. This article seeks to identify new clues regarding similar correlations between autoimmune activity and the human microbiota, particularly in relation to qualitative and quantitative microbial variations therein.
... NCDs provoke, in fact, more than 44 million deaths per year [36] [37] and it is estimated that RA, amongst the others, affects around 1% of the world population [38]. RA's incidence and representativeness make it an interesting case study to explore the relevance of the results offered by the recommender system also being its aetiology complex and not fully elucidated, since it includes both genetic and environmental factors [39], [40]. ...
Full-text available
Drug repurposing is a highly active research area, aiming at finding novel uses for drugs that have been previously developed for other therapeutic purposes. Despite the flourishing of methodologies, success is still partial, and different approaches offer, each, peculiar advantages. In this composite landscape, we present a novel methodology focusing on an efficient mathematical procedure based on gene similarity scores and biased random walks which rely on robust drug-gene-disease association data sets. The recommendation mechanism is further unveiled by means of the Markov chain underlying the random walk process, hence providing explainability about how findings are suggested. Performances evaluation and the analysis of a case study on rheumatoid arthritis show that our approach is accurate in providing useful recommendations and is computationally efficient, compared to the state of the art of drug repurposing approaches.
... Another prominent issue related to the use of NGS is the fact that bacterial DNA can be detected in noninfected (virgin) joints, especially in the presence of inflammatory arthritis [109,110]. In recent years, there has been an explosion in understanding the relevance of microbiome and also recognizing that a distinct microbiome also exists in our joints [111]. The existence of organisms as part of this microbiome compels us to make a distinction between "normal" organism in a native joint and those that are pathogens. ...
Identification of the causative organism(s) in periprosthetic joint infection (PJI) is a challenging task. The shortcomings of traditional cultures have been emphasized in recent literature, culminating in a clinical entity known as ‘culture-negative PJI’. Amidst the growing burden of biofilm infections that are inherently difficult to culture, the field of clinical microbiology has seen a paradigm shift from culture-based to molecular-based methods. These novel techniques hold much promise in the demystification of culture-negative PJI and revolutionization of the microbiology laboratory. This article outlines the clinical implications of culture-negative PJI, common causes of this diagnostic conundrum, established strategies to improve culture yield, and newer molecular techniques to detect infectious organisms.
... It is hypothesized that the gastrointestinal microbiota also contributes to the clinical outcome. Dysbiosis of the gastrointestinal microbiota is associated with many communicable and non-communicable as well as chronic and acute diseases, and therefore, it is likely that it could also be involved in gastric cancer and peptic ulcer (Hsiao et al., 2014;Forslund et al., 2015;Rogers, 2015;Zhang X. et al., 2015;Bratburd et al., 2018;Saus et al., 2019). It is also not unlikely that a beneficial microbe in the gastrointestinal microbiota is involved in protecting certain individuals from H. pylori-mediated pathogenesis. ...
Full-text available
Helicobacter pylori infection in stomach leads to gastric cancer, gastric ulcer, and duodenal ulcer. More than 1 million people die each year due to these diseases, but why most H. pylori -infected individuals remain asymptomatic while a certain proportion develops such severe gastric diseases remained an enigma. Several studies indicated that gastric and intestinal microbiota may play a critical role in the development of the H. pylori -associated diseases. However, no specific microbe in the gastric or intestinal microbiota has been clearly linked to H. pylori infection and related gastric diseases. Here, we studied H. pylori infection, its virulence genes, the intestinal microbiota, and the clinical status of Trivandrum residents ( N = 375) in southwestern India by standard H. pylori culture, PCR genotype, Sanger sequencing, and microbiome analyses using Illumina Miseq and Nanopore GridION. Our analyses revealed that gastric colonization by virulent H. pylori strains ( vacAs1i1m1cagA +) is necessary but not sufficient for developing these diseases. Conversely, distinct microbial pools exist in the lower gut of the H. pylori -infected vs. H. pylori -non-infected individuals. Bifidobacterium (belonging to the phylum Actinobacteria) and Bacteroides (belonging to the phylum Bacteroidetes) were present in lower relative abundance for the H. pylori + group than the H. pylori - group ( p < 0.05). On the contrary, for the H. pylori + group, genus Dialister (bacteria belonging to the phylum Firmicutes) and genus Prevotella (bacteria belonging to the phylum Bacteroidetes) were present in higher abundance compared to the H. pylori- group ( p < 0.05). Notably, those who carried H. pylori in the stomach and had developed aggressive gastric diseases also had extremely low relative abundance ( p < 0.05) of several Bifidobacterium species (e.g., B. adolescentis , B. longum ) in the lower gut suggesting a protective role of Bifidobacterium . Our results show the link between lower gastrointestinal microbes and upper gastrointestinal diseases. Moreover, the results are important for developing effective probiotic and early prognosis of severe gastric diseases.
... Consequently, the establishment of well-balanced intestinal microbial communities in young individuals is essential for the development of healthy immune systems in adults and critical for the prevention of many diseases [2]. Severe imbalance in the equilibrium of intestinal microbial communities may increase the risk of rheumatoid arthritis [3,4], type 1 diabetes [5,6], gastrointestinal disorders [7,8], certain cancers [9,10], and neurodegenerative disorders such as multiple sclerosis, Parkinson's disease, and Alzheimer's disease [11,12]. Indeed, at least 105 diseases and disorders are associated with imbalance in human intestinal microbial communities [13]. ...
Full-text available
We tested two hypotheses concerning the dynamics of intestinal microbial communities of young mice following antibiotic-induced disturbance. The first is that disturbance of the bacterial community causes disturbance of the fungal community. Our results were consistent with that hypothesis. Antibiotics significantly altered bacterial community structure. Antibiotics also altered fungal community structure, significantly increasing the relative abundance of Candida lusitaniae, a known pathogen, while simultaneously significantly decreasing the relative abundances of several other common fungal species. The result was a temporary decrease in fungal diversity. Moreover, bacterial load was negatively correlated with the relative abundances of Candida lusitaniae and Candida parapsilosis, while it was positively correlated with the relative abundances of many other fungal species. Our second hypothesis is that control mice serve as a source of probiotics capable of invading intestines of mice with disturbed microbial communities and restoring pre-antibiotic bacterial and fungal communities. However, we found that control mice did not restore disturbed microbial communities. Instead, mice with disturbed microbial communities induced disturbance in control mice, consistent with the hypothesis that antibiotic-induced disturbance represents an alternate stable state that is easier to achieve than to correct. Our results indicate the occurrence of significant interactions among intestinal bacteria and fungi and suggest that the stimulation of certain bacterial groups may potentially be useful in countering the dominance of fungal pathogens such as Candida spp. However, the stability of disturbed microbial communities could complicate recovery.
Rheumatoid arthritis is an aggressive and severely debilitating disorder that is characterized by joint pain and cartilage damage. It restricts mobility in patients, leaving them unable to carry out simple tasks. RA presents itself with severe lasting pain, swelling and stiffness in the joints and may cause permanent disability in patients. Treatment regimens currently employed for rheumatoid arthritis revolve around keeping clinical symptoms like joint pain, inflammation, swelling and stiffness at bay. The current therapeutic interventions in rheumatoid arthritis involve the use of non-steroidal anti-inflammatory drugs, glucocorticoids, disease-modifying anti-rheumatic drugs and newer biological drugs that are engineered for inhibiting the expression of pro-inflammatory mediators. These conventional drugs are plagued with severe adverse effects because of their higher systemic distribution, lack of specificity and higher doses. Oral, intra-articular, and intravenous routes are routinely used for drug delivery which is associated with decreased patient compliance, high cost, poor bioavailability and rapid systemic clearance. All these drawbacks have enticed researchers to create novel strategies for drug delivery, the main approach being nanocarrier-based systems. In this article, we aim to consolidate the remarkable contributions of polymeric carrier systems including microneedle technology and smart trigger-responsive polymeric carriers in the management of rheumatoid arthritis along with its detailed pathophysiology. This review also briefly describes the safety and regulatory aspects of polymer therapeutics.
Heavy metals exposure has been widely recognized as a risk factor for human health. However, limited information is available about the impacts of heavy metals on rheumatoid arthritis (RA). Herein, we estimated the associations of 3 blood and 11 urinary metals with the risk of RA among 49830 U.S. adults from the National Health and Nutrition Examination Survey (NHANES), 1999–2018. In the single-exposure model, blood cadmium (Cd) and lead (Pb), urinary Cd, Pb, antimony (Sb), tungsten (Tu), and uranium (Ur) were identified to be positively associated with RA risk. Furthermore, weighted quantile sum (WQS) regression, quantile-based g computation (qgcomp), and Bayesian kernel machine regression (BKMR) analyses consistently showed that both blood and urinary metals-mixed exposure were positively correlated with the risk of RA, and highlighted that Cd and Pb were responsible for the outcomes. Such associations were more evident in the young and middle-aged population. These findings indicated that exposure to heavy metals increased RA risk, and advanced the identification of risk factors for RA.
Background : Studies have demonstrated that the gut microbiota of patients with rheumatoid arthritis (RA) is different from that of healthy individuals and could influence inflammation and oxidative stress. Objective : to evaluate the effects of a mixture of probiotics supplementation in cytokine plasma levels, inflammatory biomarkers, oxidative/nitrosativo stress profile and Disease Activity Score 28 (DAS-28) in RA patients. Subjects and Methods : A randomized and double-blind placebo-controlled study was carried out with 42 patients with RA divided into two groups: 1) probiotic group (n=21) who were supplemented, during 60 days, with a daily ingestion of probiotics in a sachet containing (109 CFU/g), of each five freeze-dried strains: Lactobacillus acidophilus LA-14, Lactobacillus casei LC-11, Lactococcus lactis LL-23, Bifidobacterium lactis BL-04 and Bifidobacterium bifidum BB-06; 2) placebo group (n=21) who had, during 60 days, a daily ingestion of maltodextrin. Results : The probiotic group showed a significant reduction in white blood cell counts (p=0.012), tumor necrosis factor alpha (TNF-α, p=0.004), and interleukin 6 (IL-6) plasma levels (p=0.039). However, no differences were observed in the IL-10, adiponectin, C reactive protein, erythrocyte sedimentation rate, ferritin, and DAS-28 between the study groups. Regarding the oxidative/nitrosative stress biomarkers, the probiotic group showed lower nitric oxide metabolites (p=0.004), and higher sulfhydryl group (p=0.028) and total radical-trapping antioxidant parameter (p=0.019) than the placebo group. However, the lipid hydroperoxideand protein carbonyl did not differ between the study groups(p>0.05). Conclusion : The mixture of probiotics reduced the inflammatory biomarkers and improved the oxidative/nitrosative profile in patients with RA.
As a gigantic community in the human body, the microbiota exerts pleiotropic roles in human health and disease ranging from digestion and absorption of nutrients from food, defense against infection of pathogens, to regulation of immune system development and immune homeostasis. Recent advances in “omics” studies and bioinformatics analyses have broadened our insights of the microbiota composition of the inner and other surfaces of the body and their interactions with the host. Apart from the direct contact of microbes at the mucosal barrier, metabolites produced or metabolized by the gut microbes can serve as important immune regulators or initiators in a wide variety of diseases, including gastrointestinal diseases, metabolic disorders and systemic rheumatic diseases. This review focuses on the most recent understanding of how the microbiota and metabolites shape rheumatic diseases. Studies that explore the mechanistic interplay between microbes, metabolites and the host could thereby provide clues for novel methods in the diagnosis, therapy, and prevention of rheumatic diseases.
Full-text available
We carried out metagenomic shotgun sequencing and a metagenome-wide association study (MGWAS) of fecal, dental and salivary samples from a cohort of individuals with rheumatoid arthritis (RA) and healthy controls. Concordance was observed between the gut and oral microbiomes, suggesting overlap in the abundance and function of species at different body sites. Dysbiosis was detected in the gut and oral microbiomes of RA patients, but it was partially resolved after RA treatment. Alterations in the gut, dental or saliva microbiome distinguished individuals with RA from healthy controls, were correlated with clinical measures and could be used to stratify individuals on the basis of their response to therapy. In particular, Haemophilus spp. were depleted in individuals with RA at all three sites and negatively correlated with levels of serum autoantibodies, whereas Lactobacillus salivarius was over-represented in individuals with RA at all three sites and was present in increased amounts in cases of very active RA. Functionally, the redox environment, transport and metabolism of iron, sulfur, zinc and arginine were altered in the microbiota of individuals with RA. Molecular mimicry of human antigens related to RA was also detectable. Our results establish specific alterations in the gut and oral microbiomes in individuals with RA and suggest potential ways of using microbiome composition for prognosis and diagnosis.
Full-text available
To determine the existence of mucosal dysbiosis in siblings of patients with Crohn's disease (CD) using 454 pyrosequencing and to comprehensively characterise and determine the influence of genotypical and phenotypical factors, on that dysbiosis. Siblings of patients with CD have elevated risk of developing CD and display aspects of disease phenotype, including faecal dysbiosis. Whether the mucosal microbiota is disrupted in these at-risk individuals is unknown. Rectal biopsy DNA was extracted from 21 patients with quiescent CD, 17 of their healthy siblings and 19 unrelated healthy controls. Mucosal microbiota was analysed by 16S rRNA gene pyrosequencing and were classified into core and rare species. Genotypical risk was determined using Illumina Immuno BeadChip, faecal calprotectin by ELISA and blood T-cell phenotype by flow cytometry. Core microbiota of both patients with CD and healthy siblings was significantly less diverse than controls. Metacommunity profiling (Bray-Curtis (SBC) index) showed the sibling core microbial composition to be more similar to CD (SBC=0.70) than to healthy controls, whereas the sibling rare microbiota was more similar to healthy controls (SBC=0.42). Faecalibacterium prausnitzii contributed most to core metacommunity dissimilarity both between siblings and controls, and between patients and controls. Phenotype/genotype markers of CD risk significantly influenced microbiota variation between and within groups, of which genotype had the largest effect. Individuals with elevated CD-risk display mucosal dysbiosis characterised by reduced diversity of core microbiota and lower abundance of F. prausnitzii. This dysbiosis in healthy people at risk of CD implicates microbiological processes in CD pathogenesis. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to
Full-text available
Background Antibodies to citrullinated proteins are a hallmark of rheumatoid arthritis (RA). Porphyromonas gingivalis peptidylarginine deiminase (PPAD) has been implicated in the initiation of RA by generating citrullinated neoantigens and due to its ability to autocitrullinate. Objectives To define the citrullination status and biology of PPAD in P gingivalis and to characterise the anti-PPAD antibody response in RA and associated periodontal disease (PD). Methods PPAD in P gingivalis cells and culture supernatant were analysed by immunoblotting and mass spectrometry to detect citrullination. Recombinant PPAD (rPPAD), inactive mutant PPAD (rPPADC351S), and N-terminal truncated PPAD (rPPADNtx) were cloned and expressed in Escherichia coli. Patients with RA and healthy controls were assayed for IgG antibodies to citrullinated rPPAD and unmodified rPPADC351S by ELISA. Anti-PPAD antibodies were correlated with anti-cyclic citrullinated peptide (third-generation) antibody levels, RA disease activity and PD status. Results PPAD from P gingivalis is truncated at the N-terminal and C-terminal domains and not citrullinated. Only when artificially expressed in E coli, full-length rPPAD, but not truncated (fully active) rPPADNtx, is autocitrullinated. Anti-PPAD antibodies show no heightened reactivity to citrullinated rPPAD, but are exclusively directed against the unmodified enzyme. Antibodies against PPAD do not correlate with anti-cyclic citrullinated peptide levels and disease activity in RA. By contrast, anti-PPAD antibody levels are significantly decreased in RA patients with PD. Conclusions PPAD autocitrullination is not the underlying mechanism linking PD and RA. N-terminal processing protects PPAD from autocitrullination and enhances enzyme activity. Anti-PPAD antibodies may have a protective role for the development of PD in patients with RA.
Full-text available
Morbidity and mortality of cardiovascular disease is exceedingly high worldwide. Depressive illness afflicts a significant portion of the population worldwide. Epidemiological studies have confirmed the high co-morbidity between these two entities and the co-morbidity is bidirectional. Systems that contribute to this co-morbidity include the central and autonomic nervous systems, the neuroendocrine, immune, vascular and hematologic systems. Specific pathophysiologic factors include imbalance between the sympathetic and the parasympathetic systems, sympathoadrenal activation, hypothalamic-pituitary-adrenal axis activation, immune system dysregulation with release of pro-inflammatory cytokines and chemokines, platelet activation and hypercoaguability. Inflammation occurs in cardiac and cardiovascular pathology independent of the presence or absence of depression and in depression. Inflammation is closely associated with endothelial dysfunction which is a preamble to atherosclerosis and atherothrombosis. A likely common instigator underlying this co-morbidity is mental stress leading to sustained sympathetic overdrive and diminished vagal tone. Diminished vagal tone contributes to a pro-inflammatory status which affects neurotransmitter regulation, specifically serotonergic transmission. Stress hormones and certain pro-inflammatory substances released by macrophages and microglia upregulate the rate-limiting enzymes in the metabolic pathway of tryptophan. This results in a shunt in tryprophan metabolism away from serotonin formation and down the kynurenine pathway with resulting formation of neurotoxic metabolites.
Full-text available
Background: Obesity, metabolic syndrome, and type 2 diabetes are major public health challenges. Recently, interest has surged regarding the possible role of the intestinal microbiota as potential novel contributors to the increased prevalence of these 3 disorders. Content: Recent advances in microbial DNA sequencing technologies have resulted in the widespread application of whole-genome sequencing technologies for metagenomic DNA analysis of complex ecosystems such as the human gut. Current evidence suggests that the gut microbiota affect nutrient acquisition, energy harvest, and a myriad of host metabolic pathways. Conclusion: Advances in the Human Microbiome Project and human metagenomics research will lead the way toward a greater understanding of the importance and role of the gut microbiome in metabolic disorders such as obesity, metabolic syndrome, and diabetes.
Full-text available
There is increasing evidence that genome-wide association (GWA) studies represent a powerful approach to the identification of genes involved in common human diseases. We describe a joint GWA study (using the Affymetrix GeneChip 500K Mapping Array Set) undertaken in the British population, which has examined 2,000 individuals for each of 7 major diseases and a shared set of 3,000 controls. Case-control comparisons identified 24 independent association signals at P < 5 10-7: 1 in bipolar disorder, 1 in coronary artery disease, 9 in Crohn's disease, 3 in rheumatoid arthritis, 7 in type 1 diabetes and 3 in type 2 diabetes. On the basis of prior findings and replication studies thus-far completed, almost all of these signals reflect genuine susceptibility effects. We observed association at many previously identified loci, and found compelling evidence that some loci confer risk for more than one of the diseases studied. Across all diseases, we identified a large number of further signals (including 58 loci with single-point P values between 10-5 and 5 10-7) likely to yield additional susceptibility loci. The importance of appropriately large samples was confirmed by the modest effect sizes observed at most loci identified. This study thus represents a thorough validation of the GWA approach. It has also demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; has generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in the British population is generally modest. Our findings offer new avenues for exploring the pathophysiology of these important disorders. We anticipate that our data, results and software, which will be widely available to other investigators, will provide a powerful resource for human genetics research.
Synthetic biology may lead to the creation of smart microbes that can detect and treat disease
Despite the progress toward understanding the molecular pathogenesis of rheumatoid arthritis (RA), its cause remains elusive. Genes are important but rather insufficient to explain the majority of RA cases. This review describes the novel data supporting the microbiome and its interactions with the human host as potential en('in')vironmental factors in RA pathogenesis. Animal models of inflammatory arthritis have shown that the presence of bacteria in mucosal surfaces is sufficient to alter local and systemic host immune responses and elicit joint inflammation. Human RA studies have focused on three mucosal sites: the gut, the gingival, and the respiratory tree. The oral microbiome, and specifically Porphyromonas gingivalis, has long been implicated. Novel sequencing technologies have allowed investigations into the role of the gut microbiome in the development of autoimmune arthritis. Most recently, the pulmonary parenchyma has also been described as yet another possible mucosal site of initiation of autoimmunity in RA. Emerging data implicate the microbiome in RA pathogenesis. Mucosal sites exposed to a high load of bacterial antigens - such as the periodontium, lung, and gut - may represent the initial site of autoimmune generation. If validated, these findings could lead to the discovery of potential biomarkers and therapeutic approaches in the preclinical and clinical phases of RA.
A massive genetic study turns up the complex roots of major diseases
The prevalence of chronic autoimmune and inflammatory diseases, such as inflammatory bowel disease, allergies, or rheumatic diseases, is steadily increasing in developed countries. This increase is probably accelerated by environmental factors, such as decrease in infectious burden or changes in food processing. These lifestyle changes then strongly influence the strongest stimulus for the immune system - commensal microbiota. Despite the differences in the affected organ, the immune-mediated diseases have one or more factors in common - microbe either as a trigger or as a protector, mucosal barrier dysfunction, and dysregulation of the immune system. The core questions, which microbes are involved and how these diseases can be cured or even prevented still remain unsolved. Powered by the recent progress in technology, by new insights into the function of immune system, by advances in microbiome research, and extended use of gnotobiological techniques, these mechanisms are now being unravelled and new therapeutic possibilities are emerging. To secure their niche, the microbes devised many ingenious ways, how to dampen the inflammation. Nonpathogenic microorganisms or microbial components isolated from probiotic, commensal or even pathogenic microbes could be, therefore, used to interfere with the pathogenetic mechanisms of immune-mediated diseases.