TYPE Mini Review

PUBLISHED 08 September 2022

DOI 10.3389/fimmu.2022.1007165

Gut microbiota and rheumatoid

OPEN ACCESS arthritis: From pathogenesis to
EDITED BY
Ying Yang,
Yunnan University, China
novel therapeutic opportunities
REVIEWED BY
Xinchang Wang, Ting Zhao 1,2†, Yuanyuan Wei 1†, Youyang Zhu 3†, Zhaohu Xie 1,
Zhejiang Chinese Medical University,
China Qingshan Hai 1*, Zhaofu Li 1* and Dongdong Qin 1*
*CORRESPONDENCE 1
School of Basic Medical Sciences, Yunnan University of Chinese Medicine, Kunming, China,
Dongdong Qin 2
The First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming, China,
qindong108@163.com 3
The Third Affiliated Hospital, Yunnan University of Chinese Medicine, Kunming, China
Qingshan Hai
haiqingshan@163.com
Zhaofu Li
lzf0817@126.com
†
These authors have contributed
Rheumatoid arthritis (RA) is a chronic autoimmune disease that primarily affects
equally to this work the joints. Microbial infection is considered a crucial inducer of RA. Alterations
SPECIALTY SECTION
in the composition of intestinal bacteria in individuals with preclinical and
This article was submitted to established RA suggest a vital role of the gut microbiota in immune dysfunction
Nutritional Immunology, characteristic of RA. However, the mechanisms by which gut dysbiosis
a section of the journal
Frontiers in Immunology contributes to RA are not fully understood. Furthermore, multiple therapies
RECEIVED 30 July 2022
commonly used to treat RA may alter gut microbiota diversity, suggesting that
ACCEPTED 17 August 2022 modulating the gut microbiota may help prevent or treat RA. Hence, a better
PUBLISHED 08 September 2022 understanding of the changes in the gut microbiota that accompany RA should
CITATION aid the development of novel therapeutic approaches. This mini-review
Zhao T, Wei Y, Zhu Y, Xie Z, Hai Q, Li Z discusses the impact of gut dysbiosis in the pathogenesis of RA, the selection
and Qin D (2022) Gut microbiota and
rheumatoid arthritis: From of gut microbiota-related biomarkers for diagnosing RA, and provides
pathogenesis to novel examples of cross-modulation between the gut microbiota and some drugs
therapeutic opportunities.
commonly used to treat RA. Some suggestions and outlooks are also raised,
Front. Immunol. 13:1007165.
doi: 10.3389/fimmu.2022.1007165 which may help guide future research efforts.
COPYRIGHT
© 2022 Zhao, Wei, Zhu, Xie, Hai, Li and KEYWORDS
Qin. This is an open-access article
distributed under the terms of the rheumatoid arthritis, gut microbiota, immune response, inflammation, drug treatment
Creative Commons Attribution License
(CC BY). The use, distribution or
reproduction in other forums is
permitted, provided the original
author(s) and the copyright owner(s)
are credited and that the original
publication in this journal is cited, in
accordance with accepted academic
practice. No use, distribution or
Introduction
reproduction is permitted which does
not comply with these terms. Rheumatoid arthritis (RA) is a chronic, immune-mediated disease in which multiple
immune cell types and signaling networks misfunction to elicit a maladaptive tissue
repair process; this leads to organ damage, predominantly in the vascular system, lungs,
and joints (1). RA affects ~1% of the population worldwide (2), and its pathogenesis may
be linked to genetic and environmental factors (3, 4). At present, the specific pathogenesis
of RA is not well understood.
Humans are one of the most complex microbial ecosystems on the planet, hosting
over 100 trillion bacteria, mainly in the distal gut (5). Some gut bacteria species can
induce autoimmunity in genetically predisposed animal models (6, 7). Dysbiosis of

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Zhao et al. 10.3389/fimmu.2022.1007165

specific bacterial lineages and alterations in gut microbiota shaping their function and phenotypes. The gut microbiota
metabolism led to changes in the host immune profile that mediates constant bidirectional communication with the host
contribute to RA (8). It has been proposed that the mechanism immune system in a delicate balance of inducing pathogenic
by which gut microbiota imbalance leads to RA may be related to infection or residing in the human body in a commensal state
regulation of immune function by metabolites produced by gut (27). The innate immune cells in the gut-associated lymphoid
microbes (9, 10). Immune T and B cells have position-specific tissue comprise the first-line of defense against xenobiotics from
phenotypes and functions in the mucosa, influenced by the the gastrointestinal tract. Disturbed gut microbiota can trigger the
microbiota (11). In turn, bacterial peptidoglycan components aberrant activation of innate immune cells, which leads to the
are found in the synovial tissue of RA patients, which may upregulation of proinflammatory cytokine including interleukin-
contribute to inflammation within the microenvironment of the 12 (IL-12), IL-23, and type I interferons, etc., as well as reduction
joint (12, 13). Substantial data published in the past few years of anti-inflammatory cytokines including transforming growth
demonstrate that an altered composition of the gut microbiota in factor b and IL-10, etc. (28). Moreover, the adaptive lymphocytes
RA patients is one of the major factors triggering aberrant are critical players in autoimmunity, and aberrant activation of T
systemic immunity (14–16). Notably, different strains of gut and B cells instigates RA. Gut pathogens with proinflammatory
bacteria can have profoundly different regulatory effects on capacities can reshape the immune milieu through innate immune
immune system function. Some strains can stimulate an overactivation, followed by aberrant activation of the adaptive
immune response, benefiting immunocompromised patients, immune system. Microbial antigens can be presented to CD4+ T
while others can suppress the immune response, affecting cells by dendritic cells and macrophages, leading to differentiation
immune regulation in RA patients (17–21). For example, of inflammatory T cell subtypes. Th17 cells are a subset of
segmented filamentous bacteria (SFB) have a unique ability to proinflammatory CD4+ T cells characterized by production of
drive T helper 17 (Th17) cell accumulation in the small interleukin-17 (IL-17) (23). Tregs are also derived from CD4+ T
intestine’s lamina propria through SFB-derived antigens cells, show instead immunosuppressive actions, and may inhibit
presented by dendritic cells (22–24). In contrast, the Th17 responses (29, 30). Studies have demonstrated that an
colonization of Bacteroides fragilis is associated with enhanced increased Th17/Treg ratio is closely related to RA, and that the
activity of regulatory T cells (Tregs), which may alleviate Th17/Treg balance is strongly regulated by gut microbiota and
autoimmune disease (25, 26). Therefore, the relative their metabolites (31, 32). Microbial antigens can also induce
abundance of different bacterial lineages may lead to changes overactivation of B lymphocytes with the help of T follicular
in the host immune profile and drive inflammatory responses helper cells, differentiating into plasma cells and producing
contributing to RA. pathogenic autoantibodies. This may influence the pathogenesis
This mini-review discusses the role of the gut microbiota in of RA (28). Therefore, the dysbiosis gut microbiota, inflammatory
the pathogenesis of RA, summarizes the diagnostic value of gut factors, and immune responses are interrelated and jointly affect
microbe-based biomarkers, and outlines mutual influences the development of RA (33) (Figure 1).
between the gut microbiota and some drugs used to treat RA.
Some suggestions and outlooks are also raised to guide future
research efforts. Intestinal barrier dysfunction

The intestinal mucosal barrier, formed and maintained by

the intestinal epithelium, serves to isolate harmful substances in
Role of the gut microbiota in the the intestinal lumen and prevent the invasion of pathogenic
pathogenesis of RA antigens. The gut integrity is impaired in RA patients, which
leads to the translocation of microbes across the gut barrier into
Numerous studies highlighted a critical role of the gut gut tissue and even circulation. Gut microbiota can promote the
microbiota in RA pathogenesis, through mechanisms overactivation of innate and adaptive immunity in the local
including mainly production of proinflammatory metabolites, tissue, resulting in systemic immune dysregulation (28). In
impairment of the intestinal mucosal barrier, and molecular addition, disturbed gut microbiota can also trigger the
mimicry of autoantigens. migration of autoreactive cells to the joints, causing local joint
inflammation (34). Autoreactive cells activate macrophages,
resulting in inflammatory cytokine production. Further,
Inflammatory factors and regulation of cytokines such as tumor necrosis factor-alpha (TNF-a), IL-6,
the immune response and IL-1 can induce fibroblasts to produce matrix
metalloproteinases and receptor activator of nuclear factor kB
The gastrointestinal tract hosts the majority of immune cells ligand, which mediate destruction of the bone and cartilage
in the body, with constant interaction with the gut microbiota tissue, leading to the development of RA (35) (Figure 1). A study

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Zhao et al. 10.3389/fimmu.2022.1007165

FIGURE 1
Gut microbiota in the pathogenesis of rheumatoid arthritis (RA) and effects of RA therapeutic drugs on the gut microbiota. (A) Changes in the composition of
gut microbiota at different stages of RA. Levels of Prevotella copri and Lactobacillus are increased, while those of Bacteroidetes, Bifidobacteria and Eubacterium
rectale are decreased, at an early stage; Abundance of Lactobacillus salivarius, Collinsella, and Akkermansia is increased, while that of Haemophilus spp. is
decreased, in the active RA phase. (B) RA treatment drugs can improve gut microbiota imbalance and relieve disease symptoms, mainly including methotrexate,
sulfasalazine, hydroxychloroquine, etanercept, and traditional Chinese medicine. (C) Gut microbiota can lead to damage of the epithelium and to the opening
of the paracellular pathway and can cross the epithelium and get in contact with the immune cells beneath the epithelial layer, which leads to inflammation.
Furthermore, bacterial antigens promote activation of autoreactive immune cells (B cell and T cell) in the lymphoid tissues, resulting in an imbalance between
regulatory T cells (Tregs) and T helper 17 (Th17) cells, leading to expansion of inflammatory response. Activated B cells produce autoantibodies (anti-citrullinated
protein antibody and rheumatoid factor). (D) Gut microbiota imbalance can trigger the migration of autoreactive cells to the joints, causing cartilage and bone
damage. ① Bacterial antigens trigger promotes inflammation in synovial membrane, attracting leukocytes into the tissue. ② Autoreactive cells activate
macrophages, resulting in inflammatory cytokine production. ③ Cytokines induce fibroblasts to produce MMPs (matrix metalloproteinases) and RANKL
(receptor activator of nuclear factor kB ligand), which mediate destruction of bone and cartilage tissue, leading to the development of RA.

has shown that Collinsella aerofaciens, a commensal gut transgenic mice subjected to collagen-induced arthritis (CIA) by
bacterium found to be overrepresented in RA patients, reduces disrupting the integrity of the intestinal mucosa (36). In contrast,
the expression of tight junction proteins in human intestinal Faecalibacterium prausnitzii, a prominent member of the
epithelial cells and increases disease incidence in HLA-DQ8 human commensal gut microbiota whose abundance is

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Zhao et al. 10.3389/fimmu.2022.1007165

reduced in patients with RA, was shown to sustain intestinal major advances, the mechanisms linking dysbiosis of the gut
barrier function, maintain Th17/Treg balance, and exert microbiota and RA remain still incompletely characterized.
significant anti-inflammatory effects (37). These findings
indicate that changes in gut microbiota diversity may impair
intestinal mucosal permeability, facilitating the onset of RA (38, Gut microbiota biomarkers for
39). can trigger the migration of autoreactive cells to the joints, diagnosing RA
causing cartilage and bone damage.
Early diagnosis of RA is critical to provide prompt treatment
to slow down joint damage. Scher et al. (2013) reported that the
Molecular mimicry abundance of Prevotella copri was increased, while that of
Bacteroidetes was decreased, in patients with early RA; the
Molecular mimicry is a mechanism by which pathogen- presence of P. copri was correlated with a reduction in the
derived antigens that share sequence homology with self- abundance of other bacterial groups, including many beneficial
peptides may lead to cross-activation of autoreactive T or B microbes (46). Transplanting gut microbiota (with a high
cells, triggering autoimmunity. Many identical peptides between abundance of Prevotella) from patients with early RA into
human tissues and gut microbes bind to HLA-II alleles. The germ-free SKG mice can induce severe arthritis (47). In
autoimmune candidates have been shown to be enriched in addition, increased number and species of intestinal
bacterial species belonging to the Firmicutes and Proteobacteria, Lactobacillus were observed in early RA patients than in
which may have a higher disease impact in genetically susceptible healthy individuals (48). Studies have shown that the
individuals (40). N-acetylglucosamine-6-sulfatase and filamin A monocontamination of germ-free IL-1 receptor antagonist–
were identified as T- and B-cell-targeted autoantigens in more deficient (IL1rn-/-) mice, which develop spontaneous arthritis
than 50% of RA patients (41). The HLA-DR-presented N- due to excessive IL-1 signaling, with indigenous Lactobacillus
acetylglucosamine-6-sulfatase peptide has marked sequence bifidus resulted in rapid onset of arthritis that reached incidence
homology with epitopes from sulfatase proteins of the Prevotella rate and severity scores comparable to those recorded in non–
sp. and Parabacteroides sp., whereas the HLA-DR-presented germ-free mice (49). It was in turn reported that in early RA
filamin A peptide has homology with epitopes from proteins of patients the fecal microbiota contained significantly less
the Prevotella sp. and Butyricimonas sp., another gut commensal Bifidobacteria, B. fragilis, and Eubacterium rectale than in
(41). In turn, the presence of shared sequences between Collinsella patients with fibromyalgia (50).
and DRB1*0401 suggested that Collinsella may induce RA In the active period of RA, depletion of Haemophilus spp. in
through molecular mimicry (36). These findings thus identify the patients’ gut, teeth, and saliva correlated negatively with RA
molecular mimicry as a plausible link between disrupted mucosal severity and serum antibody levels. In contrast, Lactobacillus
immune tolerance and systemic immunity in RA patients. salivarius was present in increased amounts in cases of very
active RA (16). Meanwhile, gut microbiota analysis revealed
higher relative abundances of the genera Collinsella and
Other factors Akkermansia in patients with active, compared to inactive, RA
disease status (51). A study indicated that treatment with
Gut microbiota composition can alter sex hormone levels to Collinsella exacerbated CIA in HLA-DQ8 transgenic mice (36).
affect the occurrence of RA. Sex hormone deficiency increases These observations reaffirm the impact of alterations in the gut
intestinal permeability, thereby increasing the number of Th17 microbiota on RA severity and suggest that changes in gut
cells in peripheral blood and the levels of osteoclastogenic microbiota composition may serve as markers for the
cytokines RANKL, IL-17 and TNF-a, promoting bone diagnosis of RA. However, further research is needed to
resorption (42). Clostridium can produce enzymes that conclusively identify reliable gut microbiota biomarkers for
catalyze the conversion of glucocorticoids into androgens, diagnosing RA (Figure 1).
exerting immunomodulatory effects (43). Implying a strong
connection between periodontitis and RA, Porphyromonas
gingivalis, a major pathogen in periodontitis, promotes Therapeutic modulation of the gut
citrullination of proteins and production of anti-citrullinated
protein antibodies, a hallmark of RA. This is mediated by
microbiota and impact of gut
production of peptidyl arginine deiminase (PAD) and microbes on the efficacy of
leukotoxin A, which triggers in turn endogenous PAD RA drugs
activation in neutrophils (44). Besides, several metabolites
including short-chain fatty acids, serotonin, as well as plant The gut microbiota was found to predict drug response in
enzymes in the gut can also influence RA (45). However, despite RA (52). On the other hand, in recent years oral probiotics and

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Zhao et al. 10.3389/fimmu.2022.1007165

fecal flora transplantation have shown promising results when system and appears to normalize lymphocyte activity by
used as adjuvant therapy for treating RA, by directly and regulating gut microbiota (68). A study in active RA patients
indirectly modulating the gut microbiota. Indirect regulation showed that sulfasalazine therapy led to a substantial fall in fecal
of gut microbiota in RA patients and animal models is also counts of Clostridium perfringens and Escherichia coli (69).
exerted by disease-modifying anti-rheumatic drugs (DMARDs), Furthermore, sulfasalazine treatment significantly altered fecal
traditional Chinese medicine (TCM) herbs and prescriptions, microflora of RA patients by reducing total aerobic bacteria,
and by adjusting diet structure. Bacteroides, and Escherichia coli, and increasing the numbers of
Bacillus (70). However, thorough characterization of the effects
of sulfasalazine therapy on the gut microbiota in RA is
Direct regulation of gut microbiota still lacking.
Treatment with etanercept, a TNF-a antagonist, was shown
Probiotics, defined as “live microorganisms that, when to beneficially impact gut microbiota composition. In RA
administered in adequate amounts, confer a health benefit on patients, etanercept treatment was associated with enrichment
the host” (53), can reduce the abundance of pathogenic bacteria of Cyanobacteria, including members of the Nostocophycideae
by competing for nutrition and colonization sites. At the same class and the Nostocales order (which were not represented
time, probiotics can alleviate RA symptoms by producing among naïve patients), as well as with decreased abundance of
antibiotics and strengthening the intestinal barrier, with Clostridiaceae and Deltaproteobacteria (71). In CIA mice,
beneficial modulation of the immune function (54). Studies etanercept treatment led to decreased microbial community
conducted in rats with adjuvant-induced arthritis (AIA) richness and diversity, increasing the abundance of Escherichia
showed that oral administration of L. casei or L. acidophilus and Shigella and decreasing the abundance of Clostridium XIVa,
reduced arthritic inflammation, pannus formation, and cartilage Tannerella, and Lactobacillus (72). In contrast,
destruction (55–57). More recently, it was reported that hydroxychloroquine treatment in RA patients was associated
administration of L. casei to AIA rats significantly suppressed with increased intestinal bacterial richness and diversity,
arthritis and protected against bone loss by reducing dysbiosis of suggestive of restoration of normal microbiota. In addition,
the gut microbiota (58). However, supplementation with L. the abundance of Faecalibacterium, found to be decreased
reuteri and L. rhamnosus GG did not significantly reduce RA prior to treatment, was positively correlated with the use of
disease activity (59, 60), suggesting that different Lactobacillus hydroxychloroquine (36, 71).
species may act differently on RA. Numerous studies indicated that TCM-based therapies
Fecal microbiota transplantation (FMT) refers to the provide significant curative effects and elicit minor adverse
introduction of gut microbiota obtained from the feces of a reactions in RA (73). Notably, part of the beneficial effects of
healthy donor into a patient’s gastrointestinal tract (61). TCM on RA may be ascribed to regulation of the intestinal flora.
Normalizing the gut microbiota through FMT may potentially Mei et al. (2021) showed that depletion of Clostridium celatum in
improve RA symptoms. A case of a patient with refractory RA RA patients could be reversed by treatment with the Huayu-
successfully treated with FMT indicated that FMT may have an Qiangshen-Tongbi formula (74). Administration of total
excellent therapeutic effect on RA (62). However, clinical studies glucosides of paeony to CIA rats corrected 78% of the
examining the efficacy of FMT in RA patients are so far scarce. taxonomic differences in microbial structure, while also
increasing the relative abundance of certain forms of beneficial
commensal bacteria (75). Similarly, most of the 19 types of
Indirect regulation of gut microbiota bacteria found to be altered at the family level in CIA rats could
be regulated by the Zushima tablet (76). It was also reported that
DMARDs may indirectly affect and remodel the structure Qingluo Tongbi decoction can effectively ameliorate arthritis in
and function of gut microbiota to regulate systemic immunity. AIA rats at least partly by decreasing inflammatory responses
Studies have demonstrated that microbial differences in the regulated by the gut microbiota (77).
gastrointestinal tract of RA patients may partially determine In addition to therapeutic drugs, dietary nutrients also affect
the bioavailability and subsequent clinical outcome of the composition and function of the gut microbiota and may
methotrexate (63, 64). In turn, methotrexate treatment was thus have an important impact on the prevention and treatment
shown to partially restore normal gut microbiota composition of RA. Dietary fiber, abundant in vegetarian diets, can improve
in RA patients (16, 65). Thus, the gut microbiota may be a gut microbiota composition in RA patients and reduce joint pain
predictor of clinical response to methotrexate, influencing the (78). Reducing the intake of carbohydrates can help improve the
treatment response rate. balance of intestinal flora and immune function (79, 80). The
Another DMARD, i.e. sulfasalazine, is cleaved by the action omega-3 polyunsaturated fatty acids can help to maintain
of bacterial azoreductases in the large intestine into sulfapyridine the intestinal barrier integrity and interact with host immune
and mesalazine (66, 67). Sulfapyridine affects the immune cells (81). A low ratio of omega-3/omega-6 fatty acids has been

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Zhao et al. 10.3389/fimmu.2022.1007165

shown to promote inflammation, increasing the risk of RA (82, Funding

83). Increased sodium intake can also increase the risk of RA
(84). Studies have confirmed that a high-salt diet may lead to National Natural Science Foundation of China (31960178,
dysbiosis of gut microbiota, which promotes the micro- 82160923, 81960863, 82160901, and 81960870); Construction
inflammatory state and autoimmune processes (85, 86). Project of National TCM Clinical Research Base (2018 No. 131);
Indeed, several clinical trials have demonstrated that RA Yunnan Provincial Fund for Medical Research Center: Clinical
severity can be alleviated through dietary interventions (87). Evaluation and Basic Research on the Treatment of rheumatoid
Thus, a better understanding of the mutual influences between arthritis and gout by TCM (202102AA310006); Clinical Trial for
the gut microbiota and some drugs or dietary nutrients will help the Treatment of Rheumatoid Arthritis with Warming yang and
to achieve optimal therapeutic effects for RA. Smoothening Meridians (201507001-07, registration number:
ChiCTR-INR-16010290); Clinical Cooperative Project of
Chinese and Western Medicine for Major and Knotty
Perspectives and conclusion Diseases; Yunnan Provincial Key Laboratory Construction
Project Funding; Yunnan Provincial Key Laboratory of
After decades of research, the fundamental role of the gut Chinese Medicine Rheumatology and Immunology; Yunnan
microbiota in health and disease is now firmly established. It is Provincial Ten Thousands Program Famous Doctor Special;
thus widely recognized that the gut microbiota can affect almost Yunnan Province Qingguo Wang Expert Workstation
all aspects of the host, and its dysregulation is associated with Construction Project (202005AF150017); Yunnan Applied
dysregulated immune tolerance and RA development. Indeed, Basic Research Projects- Union Foundation [2019FF002
changes in the gut microbiota can precede the onset of RA and (-031)]; Applied Basic Research Programs of Science and
are closely related to disease activity afterwards. Analysis of gut Technology Commission Foundation of Yunnan Province
microbiota composition can also predict susceptibility to RA, (2019FA007); Key Laboratory of Traditional Chinese Medicine
and has become a useful method to predict and control RA for Prevention and Treatment of Neuropsychiatric Diseases,
incidence. Furthermore, the human gut microbiota and their Yunnan Provincial Department of Education; Scientific
enzymatic products can affect the bioavailability, clinical efficacy, Research Projects for High-level Talents of Yunnan University
and toxicity of a wide array of drugs through direct and indirect of Chinese Medicine (2019YZG01); Young Top-Notch Talent in
mechanisms. Conversely, various medicines and active 10,000 Talent Program of Yunnan Province (YNWR-QNBJ-
ingredients modulate immune cell function by normalizing the 2019-235).
composition of the gut microbiota. Although significant
variations in some specific microbial communities have been
detected in association with RA, further research is needed to Conflict of interest
clarify the role of the gut microbiota in RA and its impact on the
m e c h a n i s m s o f a c t i o n a n d e ffi c a c y o f D M A R D s . The authors declare that the research was conducted in the
Notwithstanding, mounting evidence indicating that targeted absence of any commercial or financial relationships that could
modulation of the gut microbiota may alleviate RA suggests that be construed as a potential conflict of interest.
personalized treatment approaches based on patient
microbiome profiles may increase drug efficacy, lower toxicity
risk, and improve clinical outcome. Publisher’s note
All claims expressed in this article are solely those of the
Author contributions authors and do not necessarily represent those of their affiliated
organizations, or those of the publisher, the editors and the
All authors listed have made a substantial, direct and reviewers. Any product that may be evaluated in this article, or
intellectual contribution to the work, and approved it claim that may be made by its manufacturer, is not guaranteed
for publication. or endorsed by the publisher.

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