Animal models of rheumatoid arthritis (RA) are essential for understanding the disease’s mechanisms and developing new treatments. Recent research highlights the microbiome’s significant roles in RA pathogenesis, influencing disease susceptibility and progression. These models allow researchers to investigate the causal relationships between specific microbial species and arthritis development. Despite challenges in translating findings to human conditions, animal models are crucial for uncovering microbiome-related therapeutic strategies, advancing our understanding of RA, and improving patient outcomes.
Key points
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Animal models are essential for uncovering the causal roles of microorganisms in the pathogenesis of rheumatoid arthritis (RA).
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Both the onset and severity of arthritis are modulated by the microbiome and its metabolites.
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Key mechanisms include immune cell regulation, molecular mimicry, and gut barrier maintenance.
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Combining microbiome research with animal models offers promising insights into novel RA therapies.
| ACPA | anticitrullinated protein antibodies |
| CAIA | collagen antibody-induced arthritis |
| CFA | complete Freund’s adjuvant |
| CIA | collagen-induced arthritis |
| DA | Dark Agouti |
| DCA | deoxycholic acid |
| EBV | Epstein-Barr virus |
| HTLV-I | human T-lymphotropic virus type 1 |
| IAA | indoleacetic acid |
| IA | indoleacrylic acid |
| Ig | immunoglobulin |
| ILA | indolelactic acid |
| IL | interleukin |
| IL1rn−/− | interleukin -1 receptor antagonist knockout |
| IPA | indolepropionic acid |
| LCA | lithocholic acid |
| PAD | peptidylarginine deiminase |
| RA | rheumatoid arthirits |
| RA-FLSs | RA fibroblast-like synoviocytes |
| SCFA | short chain fatty acids |
| SPF | specific pathogen-free |
| SFB | segmented filamentous bacteria |
| Tfh | T follicular helper |
| Th17 | T helper 17 |
| TLR | Toll-like receptor |
Introduction
Animal models of rheumatoid arthritis (RA) are essential for understanding the mechanisms driving the disease and developing new therapeutic strategies. By mimicking the pathologic features of human RA, these models provide a controlled environment to investigate the immune and molecular pathways involved in disease progression and explore genetic and environmental factors influencing RA development. ,
Recent research has increasingly focused on the microbiome’s role in RA pathogenesis, highlighting its substantial impact on disease susceptibility and progression. The microbiome, comprising a diverse community of microorganisms residing within and on the body, interacts intricately with the host’s immune system, affecting inflammatory responses and potentially altering disease outcomes. Integrating microbiome research with animal models offers a powerful approach to understanding the complex interactions between microbial communities and RA, providing insights previously inaccessible.
A notable feature of many experimental arthritis models is their reliance on microbial products to induce disease. For instance, Complete Freund’s Adjuvant (CFA), containing heat-killed mycobacteria, is commonly used to induce RA-like conditions in animal models. CFA serves as a potent immune activator, initiating a robust inflammatory response that closely resembles the chronic inflammation observed in human RA. This dependence on microbial components underscores their pivotal role in triggering and modulating autoimmune responses, providing valuable insights into RA mechanisms. By manipulating the microbiome in controlled experimental settings, researchers can investigate the causal relationships between specific microbial species and arthritis development.
This review elaborates on the effects of the microbiome on arthritis susceptibility in animal models, the modulation of the microbiome and its metabolites on the onset and severity of arthritis, and the key mechanisms by which the microbiome and its metabolites regulate arthritis progression.
Microbial regulation of susceptibility in experimental arthritis models
Various animal arthritis models have been employed to elucidate the contribution of the microbiome to RA, including spontaneous, induced, and gene-manipulated models. , Studies using germ-free or antibiotic-treated animals have demonstrated significant differences in susceptibility to arthritis, underscoring the microbiome’s critical role in disease modulation.
Collagen-Induced Arthritis
Collagen-induced arthritis (CIA) is a widely utilized model for studying arthritis induced in susceptible rodents through intradermal injections of native type II collagen emulsified in CFA. It is well established that specific laboratory mouse strains, like (Dilute Brown Non-Agouti 1 Jackson, a specific inbred laboratory mouse strain commonly used in autoimmune disease research, particularly for modeling RA [DBA/1J]), exhibit high susceptibility to CIA, while others, including C57BL/6J, are resistant. Research has revealed that the gut microbiome significantly impacts CIA susceptibility. Transplantation of fecal microbiota of C57BL/6J mice to DBA/1J mice conferred resistance to CIA in the latter, suggesting the presence of arthritis-resistant gut microbes in C57BL/6J mice. Research has found that C57BL/6J mice had high abundance of Bacteroides fragilis , and transplantation of B fragilis prevented CIA in DBA/1J mice. RA patients also showed decreased abundance of B fragilis in the gut microbiota compared to healthy controls. Moreover, another study demonstrated differences in microbiota composition before arthritis onset between CIA-susceptible and CIA-resistant DBA/1J mice. CIA-susceptible DBA/1J mice had a higher abundance of Lactobacillus , along with increased serum interleukin (IL)-17 and splenic T helper 17 cells (Th17) cells, consistent with previous studies showing that Lactobacillus is more abundant in RA patients. , Germ-free DBA/1J mice conventionalized with microbiota from CIA-susceptible mice exhibited higher arthritis induction frequency compared to those with microbiota from CIA-resistant mice. Additionally, studies with HLA transgenic mice (HLA-DRB∗0401 and HLA-DRB∗0402) revealed that ∗0401 mice, susceptible to CIA, had gut microbiota dominated by Clostridium -like bacteria, whereas ∗0402 mice, resistant to CIA, had microbiota enriched with Porphyromonadaceae and Bifidobacteria . These findings indicate that genes interact with gut microbiota to influence the immune environment, suggesting that the gut microbiome could serve as a biomarker and contributor to arthritis susceptibility.
CIA development is highly dependent on the microbiota. In CIA mouse models, gut inflammation and alterations in microbiota composition precede the manifestation of joint lesions, suggesting a causative link between microbiota dysbiosis and arthritis onset. Pretreatment with antibiotics has been shown to significantly reduce the severity of arthritis, levels of autoantibody CII, IL-17A, and IL-22 9 , indicating that early perturbations in gut microbiota during immune priming may initiate inflammatory arthritis. Mice that were not depleted of microbiota but were treated with antibiotics exhibited CIA severity akin to controls. Also, arthritis severity was unaffected by treatment of antibiotics in collagen antibody-induced arthritis (CAIA) mice. This suggests that the severity of arthritis is not modulated by antibiotics per se, but rather by the microbiota that influences the immune responses leading to arthritis. Furthermore, eliminating intestinal microbiota during established arthritis reduced intestinal Th17 cells and attenuated arthritis, suggesting potential therapeutic benefits of modulating gut microbiota post onset. This is consistent with findings that oral antibiotics like sulfasalazine and minocycline reduce RA disease activity in patients with disease duration less than 1 year. ,
In CIA rat models, contrasting susceptibilities have been observed. Dark Agouti (DA) rats are susceptible, while Fisher (F344) rats are resistant. Germ-free DA rats showed enhanced arthritis and humoral response compared to conventional DA rats, while neither germ-free nor conventional F344 rats developed arthritis. This contrast underscores the complex and varied interactions between the microbiome and host in different animal models of arthritis, emphasizing the necessity for diverse approaches to fully understand the microbiome’s impact on RA pathogenesis.
SKG Mice
SKG mice spontaneously develop T cell-mediated chronic autoimmune arthritis due to a mutation in the gene encoding the (Src Homology 2, a protein domain involved in signal transduction by binding phosphorylated tyrosine residues [SH2]) domain of (Zeta-chain-associated protein kinase 70, a tyrosine kinase essential for T cell receptor signaling [ZAP-70]), a critical signal transduction molecule in T cells. These mice show variable arthritis development depending on environmental conditions and microbial exposure, demonstrating the significant role of microbiota in disease expression. Notably, these mice do not typically develop chronic arthritis under specific pathogen-free (SPF) or germ-free conditions, despite sustained thymic production of arthritogenic T cells and their presence in the peripheral circulation. However, arthritis can be induced in SPF-housed (a mouse strain derived from BALB/c, originally identified in Sakaguchi’s laboratory [SKG mice]), but not in GF mice, through intraperitoneal injection of zymosan, a fungal β-glucan.
Interestingly, when SPF-housed SKG mice were treated with antibiotics, they did not develop arthritis following zymosan injection. Conversely, arthritis could be induced in these mice through the administration of a defined bacterial consortium known as altered Schaedler flora, particularly effective with curdlan injection. Moreover, monocolonization of germ-free SKG mice with Prevotella copri alone was sufficient to induce arthritis upon fungal injection.
K/BxN Mice
K/BxN T cell receptor transgenic mice develop spontaneous arthritis characterized by elevated autoantibodies targeting glucose-6-phosphate isomerase when housed in SPF conditions. Treatment with antibiotics effectively suppresses disease progression along with reductions in T follicular helper (Tfh) and germinal center B cell populations. Conversely, in germ-free environments, these mice do not develop arthritis, concomitant with diminished populations of Th17 cells observed in both the small intestine and spleen. Notably, mono-colonization with segmented filamentous bacteria (SFB) alone is adequate to induce Th17 cell-dependent arthritis in this model. These observations underscore the pivotal role of gut microbiota and specific immune cell subsets in the pathogenesis of autoimmune arthritis in (a transgenic mouse model of autoimmune arthritis, generated by crossing KRN T cell receptor (TCR) transgenic mice (K) with non-obese diabetic (NOD) mice (BxN) [K/BxN mice]).
Interleukin-1 Receptor Antagonist Knockout Mice
Interleukin (IL)-1 receptor antagonist knockout ( IL1rn −/− ) mice spontaneously develop T cell-mediated arthritis due to excessive IL-1 signaling. In these mice, the Th17 cell population is significantly increased in the intestinal lamina propria, and this phenotype can be transferred to wild-type mice via the microbiota. The enhanced Th17 response and the spontaneous arthritis observed in IL1rn −/− mice are highly dependent on the presence of commensal microbiota. Antibiotic treatment, which reduces the abundance of commensal microbiota such as Helicobacter species, effectively suppresses arthritis in IL1rn −/− mice. Notably, colonization of antibiotic-treated mice with SFB was sufficient to fully restore arthritis development.
Under germ-free conditions, IL1rn −/− mice do not develop arthritis. This is attributed to the reduced secretion of IL-17 and IL-1β, along with decreased stimulation of Toll-like receptor 2 (TLR2) and toll-like receptor 4 (TLR4). , Interestingly, mono-colonization with Lactobacillus bifidus induces arthritis in IL1rn −/− mice, highlighting the role of microbial species in disease pathogenesis. Furthermore, the transfer of conventional IL1rn −/− microbiota to germ-free IL1rn −/− mice reinduces arthritis, resulting in a severe disease phenotype comparable to that observed in conventionally raised IL1rn −/− mice. These findings emphasize the crucial role of commensal microbiota in influencing Th17 responses and the onset of autoimmune arthritis in IL1rn −/− mice.
In summary, microbes affect arthritis susceptibility in mice; germ-free environments or antibiotics reduce it. Conversely, in some rat strains, microbes induce immune tolerance, and germ-free conditions increase arthritis susceptibility. Thus, microbiome and environmental factors are crucial in arthritis research ( Table 1 ).
| Models | Induction | Antibiotic Treatment | Phenotypes in Different Facilities GF SPF CV | Ref. | ||
|---|---|---|---|---|---|---|
| CIA DBA/1 mice | Injection with CII emulsified in complete Freund’s adjuvant (CFA) | Reduced arthritis severity | Na | Normal arthritis | Na | Liu et al, 2016; Jubair et al, 2018; Rogier et al, 2017 |
| CIA Dark Agouti rats | Injection with CII emulsified in CFA | Na | Severe disease | Na | Less-severe disease | Breban et al, 1993 |
| CAIA DBA/1 mice | Injection with anti-CII antibody | Unaffected arthritis | Na | Normal arthritis | Na | Jubair et al, 2018 |
| SKG mice | Injection with zymosan | No arthritis | No arthritis | Zymosan-induced arthritis | Spontaneous arthritis | Sakaguchi et al, 2003; Yoshitomi et al, 2005; Maeda et al, 2016 |
| K/BxN mice | No | Reduced arthritis severity | Attenuated arthritis | Spontaneous arthritis | Na | Korganow et al, 1999; Block et al, 2016; Wu et al, 2010 |
| IL1rn −/− mice | No | Suppressed arthritis | No arthritis | Spontaneous arthritis | Spontaneous arthritis | Horai et al, 2000; Rogier et al, 2017; Abdollahi-Roodsaz et al, 2008 |
Microbiome and its metabolites in the modulation of experimental arthritis development
The microbiome and its metabolites play a pivotal role in modulating both the onset and severity of experimental arthritis. Numerous studies have demonstrated that specific microbial species and their metabolic products can influence immune responses, potentially exacerbating or mitigating disease severity. The intricate interactions between the microbiome and the immune system are crucial in determining the progression and development of arthritis. Understanding these interactions could provide valuable insights into new therapeutic strategies for managing arthritis by targeting the microbiome and its metabolites.
Microorganisms That Induce or Exacerbate Experimental Arthritis
Bacteria
Prevotella copri
Prevotella species, especially P copri , were the dominant fecal microbiota in early RA patients. , Additionally, antibodies against P copri were detectable in RA patients but not in healthy individuals. , When administered to germ-free SKG mice in conjunction with zymosan, fecal samples from RA patients enriched with P copri as well as those from healthy individuals could induce arthritis; however, RA patient-derived samples typically led to more severe arthritis. Moreover, strains of P copri isolated from RA patient feces exacerbated arthritis in CIA mice. Comparative studies further reveal that P copri strains derived from RA patients induced more severe arthritis in both the CIA and SKG mouse models compared to strains isolated from healthy controls. Genomic analysis of these strains revealed that P copri from RA patients contains a distinct genomic region identified as a conjugative transposon. This specific genomic feature is thought to contribute to the increased arthritogenicity of these strains, potentially explaining their enhanced ability to exacerbate arthritis.
Fusobacterium nucleatum
Recent research has identified an enrichment of Fusobacterium nucleatum in individuals with RA, which correlated positively with RA severity. Additionally, studies have shown that F nucleatum exacerbated arthritis in CIA mice. Mechanistically, this exacerbation was driven by the delivery of protein FadA-containing outer membrane vesicles (OMVs) into the joints, which trigger local inflammation. This inflammatory process is mediated by targeting the Rab5a-YB-1 axis, highlighting a novel pathway by which F nucleatum can influence RA progression.
Eggerthella lenta
Studies have recently established a link between the expansion of Eggerthella lenta and the progression of severe RA. , In naïve mice, oral administration of E lenta induced the production of preclinical rheumatoid factor. Subsequently, when arthritis was induced in a humanized mouse model of CIA, severe disease manifestations were observed. This enhanced antibody response was particularly pronounced in female mice, consistent with the fact that females RA patients exhibited a higher average abundance of E lenta . In addition, expansion of E lenta was associated with elevated levels of C-X-C motif chemokine ligand 5（CXCL5), cluster of differentiation (CD)4 T cells, and both IL-17 and interferon gamma (IFNγ)-producing B cells. Furthermore, administration of E lenta led to gut dysbiosis, decreased levels of amino acids and nicotinamide adenine dinucleotide, and increased levels of microbe-dependent bile acids and succinyl carnitine, collectively contributing to systemic senescent-like inflammation.
Subdoligranulum didolesgii
A 2022 study by Chriswell and colleagues utilized dual family immunoglobulin (Ig)G/IgA anticitrullinated protein antibodies (ACPA) monoclonal antibodies derived from plasmablasts of individuals at risk for or with early RA to identify a novel bacterium, Subdoligranulum didolesgii Isolate 7 31 . This bacterium spontaneously induced inflammatory arthritis in gnotobiotic and antibiotics-treated SPF DBA/1 mice. In contrast, S didolesgii Isolate 1 did not induce arthritis. S didolesgii Isolate 7 triggered B and T cell-dependent joint inflammation, characterized by significant increases in complement, IgG, and IgA deposition at the joints, expanded splenic Th17 populations, and elevated antitype II collagen antibodies. Furthermore, serum transfer from mice colonized with S didolesgii Isolate 7 into uncolonized mice resulted in the spontaneous induction of arthritis. These findings illustrate a pathway of RA pathogenesis in which a specific intestinal bacterial strain can induce systemic autoantibody production and promote antibody deposition and immune activation in the joints.
Collinsella
The relative abundance of Collinsella has been observed to be elevated in RA patients. Inoculation of C aerofaciens into HLA-DQ8 mice with CIA resulted in a marked exacerbation of arthritis severity. In vitro experiments have demonstrated that Collinsella enhances gut permeability and stimulates the expression of IL-17A, implying its potential role as an arthritogenic bacterium in the human intestinal environment.
Segmented filamentous bacteria
Segmented filamentous bacteria (SFB) are essential for the maturation of the host’s immune system, especially in promoting the development of Th17 and Tfh cells, which are crucial for mucosal immunity. Introducing SFB into germ-free K/BxN mice reconstituted the Th17 cell population in the lamina propria and triggered the production of autoantibodies, leading to the rapid development of arthritis. Moreover, SFB gavage markedly worsened arthritis in SPF K/BxN mice. This exacerbation was due to the induction of differentiation and migration of gut T follicular helper (Tfh) cells to systemic lymphoid sites, resulting in increased autoantibody production and the aggravation of arthritis. Additionally, SFB can induce arthritis in antibiotics-treated IL1rn −/− mice under SPF conditions.
Lactobacillus
Research has reported an enrichment of Lactobacillus in RA patients and in CIA-susceptible DBA/1 mice. , In animal models, arthritis can be effectively induced using the cell walls of Lactobacillus strains such as Lactobacillus plantarum or Lactobacillus casei . Additionally, introducing L casei , Lactobacillus fermentum , Lactobacillus murini , or Lactobacillus acidophilus into germ-free F344 rats with adjuvant-induced arthritis resulted in exacerbated disease severity. Moreover, mono-colonization of germ-free IL1rn −/− mice with L bifidus has been shown to induce arthritis via TLR4 activation.
Porphyromonas gingivalis
Porphyromonas gingivalis , a prominent periodontal bacterium, is distinguished as the sole pathogen known to express bacterial peptidylarginine deiminase (PAD). , Studies indicated that immune responses targeting P gingivalis and its virulence factors, particularly the PAD enzyme, were associated with RA severity and levels of ACPA. , In CIA model, oral administration of P gingivalis has been shown to aggravate arthritis by promoting IL-17 production. Mice infected with the wild-type strain exhibited higher levels of autoantibody production and greater joint damage compared to those infected with PAD-deficient mutants, implicating PAD in the exacerbation of RA pathogenesis. In addition, immunization with P gingivalis enolase could induce autoimmunity to mammalian α-enolase and arthritis in DR4-IE–transgenic mice. These findings highlight the significant role of P gingivalis and its PAD enzyme in RA pathogenesis.
Streptococcus
Streptococcus is among the first bacteria to colonize the oral cavity, and their presence varies significantly in patients with RA. Studies have documented both increases and decreases in the abundance of Streptococcus spp. in the oral microbiomes of individuals with RA. , Additionally, an increased prevalence of Streptococcus has been observed in the guts of RA patients and those genetically predisposed to the disease, even before its onset. ,
Research has shown that nonviable fragments of streptococcal cell wall peptidoglycan-polysaccharide can induce inflammatory arthritis in specific mouse and rat strains when administered systemically. , In vitro experiments indicate that different strains of Subdoligranulum parasalivarius , isolated from the oral microbiota of RA patients, can variably stimulate the production of proinflammatory cytokines such as tumor necrosis factor alpha and interleukin-6, suggesting that these effects are strain-specific. Furthermore, systemic administration of cell wall components from S parasalivarius strains associated with both RA patients and healthy controls has been observed to induce chronic arthritis in a similar manner, highlighting the significant role these bacterial components play in modulating inflammatory responses and contributing to the pathogenesis of arthritis.
Fungus
The fungi constitute a minor proportion, typically ranging from 0.1% to 1.0%, of the intestinal microbiota, collectively referred to as the mycobiota. The human gut mycobiota plays a crucial role in immune system training against infections and various immunologic or inflammatory disorders. ,
Candida albicans , a well-known opportunistic pathogen, is a predominant component of the mycobiome. It is frequently detected among the dominant fungi and has been linked to numerous autoimmune disorders, including RA. Previous studies have implicated C albicans in the pathogenesis of RA, supported by evidence of Candida species enrichment in fecal samples from RA patients. , Experimental models have shown that gut colonization by C albicans exacerbates arthritis in mice. , Moreover, C albicans cell wall β-glucan has been identified as an adjuvant in the induction of autoimmune arthritis in DBA/1 mice, and it has also been shown to exacerbate disease severity in Institute of Cancer Research (ICR) mice with CIA. Further studies indicated that cell wall β-glucan derived from C albicans acted as a trigger for autoimmune arthritis in SKG mice. These findings underscore the significant role of C albicans and its cell wall β-glucan in the pathogenesis and exacerbation of autoimmune arthritis, highlighting its potential as a key factor in the development of RA.
Virus
A number of observations have suggested the involvement of Epstein-Barr virus (EBV) in the pathogenesis of RA. These include the presence of EBV in affected joint tissues, antigenic cross-reactions between EBV and human proteins, and elevated humoral and cellular anti-EBV immune responses in RA patients. Furthermore , EBV has been demonstrated to induce erosive arthritis in humanized mice, supporting the hypothesis of a causative role for EBV in RA.
Human T-lymphotropic virus type 1 (HTLV-I) is a retrovirus recognized as an oncogenic virus in humans. Initially identified as the causative agent of adult T cell leukemia, it has more recently been implicated in several autoimmune disorders. , Specifically, research has documented the presence of HTLV-I pro-viral DNA in both synovial fluid and tissue cells, with T cells in these areas being infected by HTLV-I. Moreover, RA patients exhibit a higher viral load in the synovium compared to non-RA individuals. These findings suggest a significant association between HTLV-I infection and the development or exacerbation of RA. Furthermore, transgenic mice carrying the HTLV-I env-pX region with its own long terminal repeat (LTR) promoter (HTLV-I Tg mice) have been shown to develop chronic inflammatory polyarthropathy with high incidence, further supporting a potential role of HTLV-I in RA pathogenesis ( Table 2 ).
| Microbial Exposure | Models | Breeding Facilities | Antibiotic Treatment | Phenotypes | Immune Cells | Mechanism | Ref. |
|---|---|---|---|---|---|---|---|
| RA and HC feces | SKG mice Injection with zymosan | GF | No | RA feces induced more severe arthritis | T helper 17 cells (Th17) ↑ | Molecular mimicry | Maeda et al, 2016 |
| Prevotella copri | SKG mice Injection with zymosan | GF | No | Induce arthritis | Th17 ↑ | Molecular mimicry | Maeda et al, 2016 |
| P copri isolated from RA | CIA DBA/1 mice | SPF | Yes | Exacerbate arthritis | Anti-CII↑ Th17 ↑ | Induced inflammatory microbial metabolites (succinate) | Jiang et al, 2022 |
| P copri isolated from RA and HC | CIA mice DBA/1 mice | SPF | Yes | P. copri RA – induced more severe arthritis than P. copri HC | Th17↑MHCII↑ cluster of differentiation (CD80)↑CD86↑ | Na | Takuro Nii et al, 2023 |
| P copri isolated from RA and HC | SKG mice Injection with zymosan | GF | No | P. copri RA – induced more severe arthritis than P copri HC | Th17 ↑ | Na | Takuro Nii et al, 2023 |
| F nucleatum | CIA DBA/1, C57 | SPF | No | Aggravate arthritis | Neu↑ Mϕ↑ interleukin (IL)-6↑ tumor necrosis factor alpha (TNF-α)↑ | Direct effects on joint tissues via OMVs, FadA-Rab5a-YB-1 axis | Hong et al, 2023 |
| E lenta | CIA HLA-DQ8 | SPF | No | Augment arthritis severity | Treg ↓ Tfh ↑ GCB ↑ | Dysbiosis of the gut microbiota and its metabolites | Baskar Balakrishnan et al, 2023 |
| Subdoligranulum didolesgi isolated from RA | DBA/1 mice Without CII | GF SPF | No Yes | Drive arthritis | Th17↑Anti-IgG↑Anti-immunoglobulin A (IgA)↑ Anti-CII↑ | Molecular mimicry | Chriswell et al, 2022 |
| C aerofaciens | CIA HLA-DQ8 mice | SPF | No | Exacerbate arthritis | CD4 + T cell proliferation↑ IL-17A ↑ | Leaky gut ↑ | Chen et al, 2016 |
| SFB | K/BxN mice | GF | No | Induce arthritis | Th17↑ Anti-GPI↑ | Modulation of immune cells | Wu et al, 2010 |
| SFB | K/BxN mice | SPF | No | Exacerbate arthritis | Tfh ↑ GCB ↑ Anti-GPI↑ | Modulation of immune cells (DC-IL-2 -Tfh) | Teng et al, 2016 |
| SFB | IL1rn −/− mice | SPF | Yes | Induce arthritis | Na | Na | Rogier et al, 2017 |
| L. bifidus | IL1rn −/− mice | GF | No | Induce arthritis | Th17 ↑ IL-17A ↑ | Modulation of immune cells (toll-like receptor 4 signaling) | Abdollahi-Roodsaz et al, 2008 |
| L. casei | AA F344 rats | GF | No | Severe arthritis | Na | Na | Kohashi et al, 1985 |
| Lactobacillus cell wall | LEW/SsNHsd rats | SPF | No | Induce arthritis | Na | Na | Simelyte et al, 2003 |
| P gingivalis | CIA DBA/1 | SPF | No | Exacerbate arthritis | Th17 ↑ IL-17A ↑ | peptidylarginine deiminase | Sato et al, 2017; Kazmierczak et al, 2013 |
| P gingivalis | AA, DR4-IE–transgenic mice | SPF | No | Trigger arthritis | Na | Molecular mimicry Enolase | Kinloch et al, 2011 |
| S parasalivarius | SKG mice | SPF | No | Trigger arthritis | IL-6 ↑, TNF-α ↑ | Na | Moentadj et al, 2021 |
| Streptococcal cell wall | Lewis rats F344 | CV GF | No No | Trigger arthritis Trigger arthritis | Na | SCW-specific T cell responses | Van Den Broek etal, 1989; van den Broek et al, 1992 |
| C albicans | CIA DBA/1 | SPF | No | Exacerbate arthritis | Na | Na | Sonoyama et al, 2011 |
| C albicans | SCW C57 | SPF | No | Exacerbate arthritis | Th17↑ | Na | Zheng et al, 2012 |
| C albicans cell wall | CIA ICR | SPF | No | Exacerbate arthritis | TNF-a↑interferon (IFN)-γ↑ Anti-CII ↑ | Na | Yordanov et al, 2005 |
| C albicans cell wall | CIA DBA/1 | SPF | No | As adjuvant to induce arthritis | Anti-CII ↑ | Na | Hida et al, 2005 |
| C albicans cell wall | SKG | SPF | No | Trigger arthritis | IL-6 ↑ | Na | Shunsuke et al, 2007 |
| EBV | Humanized NOGP mice | SPF | No | Induce arthritis | Na | Molecular mimicry | von Herrath etal, 2011 |
| Human T-lymphotropic virus type 1 (HTLV-I) | HTLV-I Tg mice | Na | Na | Trigger arthritis | IL-1β ↑ IL-6 ↑ Anti-CII ↑ | Na | Iwakura et al, 1995 |
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