Methotrexate promotes recovery of arthritis-induced alveolar bone loss and modifies the composition of the oral-gut microbiota

Arruda, José Alcides Almeida de; Corrêa, Jôice Dias; Singh, Youvika; Oliveira, Sicília Rezende; Machado, Caio Cavalcante; Schneider, Ayda Henriques; Medeiros, Julliane Dutra; Fernandes, Gabriel R.; Macari, Soraia; Barrioni, Breno Rocha; Santos, Mauro Augusto dos; Duffles, Letícia Fernanda; Nakaya, Helder Takashi Imoto; Fukada, Sandra Yasuyo; Graves, Dana T.; Cunha, Fernando Q.; Silva, Tarcı́lia Aparecida

doi:10.1016/j.anaerobe.2022.102577

Cited by 10 publications

(7 citation statements)

References 45 publications

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“…Relevant clinical data refer to the impact of MTX therapy on periodontal parameters. Contrary to the results observed by our group and others using an animal model of arthritis 42,43 in which MTX treatment protected against alveolar bone loss, in the present study there was apparently no effect of MTX on the periodontium. Other clinical studies have shown similar results, observing the stability of periodontal parameters in individuals with moderate to severe periodontitis after 16 months of antirheumatic treatment 72 .…”

Section: Discussioncontrasting

confidence: 99%

“…Oral MTX can be metabolized by the gut microbiota; in turn, the microbiome may be useful to predict the response to MTX and may also be a potential target to improve the response to this drug 41 . Studies in mice revealed that MTX affected the abundance of some species in the gut and protected against periodontal bone loss associated with arthritis and periodontal infection 42,43 . However, the literature is scarce about the synchronous impacts of MTX on the oral-gut microbiota in individuals with RA 16,44 .…”

Section: Introductionmentioning

confidence: 99%

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Methotrexate regimen and periodontal therapy change the oral-gut microbiota composition in rheumatoid arthritis

Oliveira

Arruda

Corrêa

et al. 2022

Preprint

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Objectives This study evaluated the influence of methotrexate (MTX) and periodontal therapy on the composition of the oral-gut microbiota of individuals with RA. Methods Thirty-seven individuals with RA were evaluated at three time points. The composition of the oral and gut microbiota was assessed by amplifying the V4 region of the 16S gene from subgingival plaques and stools. Results MTX tended to reduce the alpha diversity of the oral and gut microbiota, an effect that was partially reversed in the oral microbiota after periodontal treatment. The relative abundance of the oral microbiota was directly influenced by periodontal status. Conversely, periodontitis did not influence the gut microbiota. MTX treatment did not affect the periodontal condition; however, it modified the interactions between clinical parameters and the oral-gut microbiota, with the emergence of novel and simplified correlations. Porphyromonas gingivalis was linked to increased production of neutrophil extracellular traps (NET) regardless of periodontal status and this periodontopathogenic bacterium induced significant production of NET in vitro, particularly in individuals with RA. Conclusion MTX and periodontal treatment directly affected the composition and richness of the oral-gut microbiota, with the emergence of different microbial groups. P. gingivalis and NET typify the microbial-host interaction in RA and periodontitis.

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Methotrexate regimen and periodontal therapy change the oral-gut microbiota composition in rheumatoid arthritis

Oliveira

Arruda

Corrêa

et al. 2022

Preprint

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“…The arthritic rats were treated with SIL and/or MTX. MTX was given at a dose of 2 mg/kg/week, which mimicked the therapeutic dose used to treat RA in patients (~22.5 mg/week) [ 35 , 36 ]. Hepatotoxicity is known to occur in RA patients receiving a long-term administration of the therapeutic dose of MTX [ 13 , 37 , 38 , 39 ].…”

Section: Discussionmentioning

confidence: 99%

Silibinin’s Effects against Methotrexate-Induced Hepatotoxicity in Adjuvant-Induced Arthritis Rat Model

Khawaja,

El-Orfali

2024

Pharmaceuticals

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Methotrexate (MTX) is the first drug of choice to treat several diseases, including rheumatoid arthritis. However, its administration is accompanied by severe side effects, most commonly hepatotoxicity. Hence, alternative therapies with a lower toxicity and fewer side effects are needed. This study aimed to investigate the antioxidant and hepatoprotective effects of silibinin (SIL, natural agent) against MTX-induced hepatotoxicity in an adjuvant-induced arthritis (AIA) rat model. Arthritic rats were treated with SIL (100 mg/kg) and/or methotrexate (2 mg/kg). Non-arthritic rats, arthritic untreated rats, and arthritic rats who received the vehicle were followed in parallel. SIL alleviated the systemic consequences of arthritis by restoring lost weight, decreasing the erythrocyte sedimentation rate, and ameliorating joint damage, which was evident both micro- and macroscopically. Additionally, SIL prevented the histopathological alterations in the liver and significantly reduced the liver damage caused by MTX and AIA, as shown by a decrease in the markers of liver damage (ALT and AST). Furthermore, SIL relieved the oxidative stress induced by AIA and MTX in liver tissue by decreasing the lipid peroxidation (MDA) levels and enhancing the antioxidant defense system (GSH levels; catalase and superoxide dismutase (SOD) activities). In conclusion, our results suggest that SIL is a potent antioxidant and hepatoprotective agent in arthritic rats. It markedly attenuated the progression and severity of the arthritic disease and eased the oxidative stress in liver tissue by improving the pro-oxidant/antioxidant balance.

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“…AIA mice were induced, as previously reported [ 40 ]. Briefly, methylated bovine serum albumin (mBSA, Sigma-Aldrich) was dissolved in ddH 2 O and completed Freund's adjuvant (CFA, Sigma-Aldrich).…”

Section: Methodsmentioning

confidence: 99%

Regulatory role of PI16 in autoimmune arthritis and intestinal inflammation: implications for Treg cell differentiation and function

Sun,

Lin,

Wang

et al. 2024

J Transl Med

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Background Regulatory T cells (Tregs) are crucial in maintaining immune homeostasis and preventing autoimmunity and inflammation. A proportion of Treg cells can lose Foxp3 expression and become unstable under inflammation conditions. The precise mechanisms underlying this phenomenon remain unclear. Methods The PI16 gene knockout mice (PI16fl/flFoxp3Cre) in Treg were constructed, and the genotypes were identified. The proportion and phenotypic differences of immune cells in 8-week-old mice were detected by cell counter and flow cytometry. Two groups of mouse Naïve CD4+T cells were induced to differentiate into iTreg cells to observe the effect of PI16 on the differentiation and proliferation of iTreg cells, CD4+CD25+Treg and CD4+CD25− effector T cells (Teff) were selected and co-cultured with antigen presenting cells (APC) to observe the effect of PI16 on the inhibitory ability of Treg cells in vitro. The effects of directed knockout of PI16 in Treg cells on inflammatory symptoms, histopathological changes and immune cell expression in mice with enteritis and autoimmune arthritis were observed by constructing the model of antigen-induced arthritis (AIA) and colitis induced by dextran sulfate sodium salt (DSS). Results We identified peptidase inhibitor 16 (PI16) as a negative regulator of Treg cells. Our findings demonstrate that conditional knock-out of PI16 in Tregs significantly enhances their differentiation and suppressive functions. The conditional knockout of the PI16 gene resulted in a significantly higher abundance of Foxp3 expression (35.12 ± 5.71% vs. 20.00 ± 1.61%, p = 0.034) in iTreg cells induced in vitro compared to wild-type mice. Mice with Treg cell-specific PI16 ablation are protected from autoimmune arthritis (AIA) and dextran sulfate sodium (DSS)-induced colitis development. The AIA model of PI16CKO is characterized by the reduction of joint structure and the attenuation of synovial inflammation and in DSS-induced colitis model, conditional knockout of the PI16 reduce intestinal structural damage. Additionally, we found that the deletion of the PI16 gene in Treg can increase the proportion of Treg (1.46 ± 0.14% vs. 0.64 ± 0.07%, p < 0.0001) and decrease the proportion of Th17 (1.00 ± 0.12% vs. 3.84 ± 0.64%, p = 0.001). This change will enhance the shift of Th17/Treg toward Treg cells in AIA arthritis model (0.71 ± 0.06% vs. 8.07 ± 1.98%, p = 0.003). In DSS-induced colitis model of PI16CKO, the proportion of Treg in spleen was significantly increased (1.40 ± 0.15% vs. 0.50 ± 0.11%, p = 0.003), Th17 (2.18 ± 0.55% vs. 6.42 ± 1.47%, p = 0.017), Th1 (3.42 ± 0.19% vs. 6.59 ± 1.28%, p = 0.028) and Th2 (1.52 ± 0.27% vs. 2.76 ± 0.38%, p = 0.018) in spleen was significantly decreased and the Th17/Treg balance swift toward Treg cells (1.44 ± 0.50% vs. 24.09 ± 7.18%, p = 0.012). Conclusion PI16 plays an essential role in inhibiting Treg cell differentiation and function. Conditional knock out PI16 gene in Treg can promote the Treg/Th17 balance towards Treg dominance, thereby alleviating the condition. Targeting PI16 may facilitate Treg cell-based therapies for preventing autoimmune diseases and inflammatory diseases. The research provides us with novel insights and future research avenues for the treatment of autoimmune diseases, particularly arthritis and colitis.

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Methotrexate promotes recovery of arthritis-induced alveolar bone loss and modifies the composition of the oral-gut microbiota

Cited by 10 publications

References 45 publications

Methotrexate regimen and periodontal therapy change the oral-gut microbiota composition in rheumatoid arthritis

Methotrexate regimen and periodontal therapy change the oral-gut microbiota composition in rheumatoid arthritis

Silibinin’s Effects against Methotrexate-Induced Hepatotoxicity in Adjuvant-Induced Arthritis Rat Model

Regulatory role of PI16 in autoimmune arthritis and intestinal inflammation: implications for Treg cell differentiation and function

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