Methotrexate works remotely, from the gut

Wu, Ho‐Ting

doi:10.1016/j.chom.2021.02.016

“…It has been reported that higher doses of MTX treatment can reduce bacterial numbers, especially in the Bacteroides group [81,82]. With regard to the opposite effect with the MTX treatment observed in this study in Table 7 and Supplementary Table S4, we speculated that these differences may depend on the higher doses of MTX used in western countries (>15 mg/week) compared to those in Japan (~10 mg/week) as it has been reported that lower doses of MTX affect the intestinal bacteria composition and mucosal immunity differently than those with higher MTX doses [83,84]. We assume that lower doses of MTX treatment change intestinal bacterial composition, leading to higher total bacterial counts and lower serum anti-Pg-LPS IgA antibody levels expressing immune responses against bacteria and their toxins.…”

Section: Discussionmentioning

confidence: 68%

Oral and Intestinal Bacterial Substances Associated with Disease Activities in Patients with Rheumatoid Arthritis: A Cross-Sectional Clinical Study

Kitamura

¹

,

Shionoya

²

,

Suzuki

³

et al. 2022

Journal of Immunology Research

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Intestinal bacterial compositions of rheumatoid arthritis (RA) patients have been reported to be different from those of healthy people. Dysbiosis, imbalance of the microbiota, is widely known to cause gut barrier damage, resulting in an influx of bacteria and their substances into host bloodstreams in animal studies. However, few studies have investigated the effect of bacterial substances on the pathophysiology of RA. In this study, eighty-seven active RA patients who had inadequate responses to conventional synthetic disease-modifying antirheumatic drugs or severe comorbidities were analyzed for correlations between many factors such as disease activities, disease biomarkers, intestinal bacterial counts, fecal and serum lipopolysaccharide (LPS), LPS-binding protein (LBP), endotoxin neutralizing capacity (ENC), and serum antibacterial substance IgG and IgA antibody levels by multiple regression analysis with consideration for demographic factors such as age, sex, smoking, and methotrexate treatment. Serum LBP levels, fecal LPS levels, total bacteria counts, serum anti-LPS from Porphyromonas gingivalis (Pg-LPS) IgG antibody levels, and serum anti-Pg-LPS IgA antibody levels were selected for multiple regression analysis using Spearman’s correlation analysis. Serum LBP levels were correlated with disease biomarker levels, such as erythrocyte sedimentation rate ( p < 0.001 ), C-reactive protein ( p < 0.001 ), matrix metalloproteinase-3 ( p < 0.001 ), and IL-6 ( p = 0.001 ), and were inversely correlated with hemoglobin ( p = 0.005 ). Anti-Pg-LPS IgG antibody levels were inversely correlated with activity indices such as patient global assessments using visual analogue scale (VAS) ( p = 0.002 ) and painVAS ( p < 0.001 ). Total bacteria counts were correlated with ENC ( p < 0.001 ), and inversely correlated with serum LPS ( p < 0.001 ) and anti-Pg-LPS IgA antibody levels ( p < 0.001 ). These results suggest that substances from oral and gut microbiota may influence disease activity in RA patients.

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“…Dehydrocholic acid is a secondary bile acid and is an oxidation product of cholic acid ( Navarro Suarez et al, 2018 ). Recognizing that secondary bile acids are primarily formed through enterohepatic recirculation of primary bile acids with metabolism occurring via the gut microbiota ( Staley et al, 2017 ), changes in dehydrocholic acid levels secondary to MTX therapy support the findings that MTX efficacy in autoimmune arthritis may be related to its effect on the gut microbiota ( Artacho et al, 2020 ; Scher et al, 2020 ; Nayak et al, 2021 ; Wu, 2021 ). This potential relationship is further supported by the identification of biotin as a metabolite associated with MTX efficacy, as systemic biotin is at least partially generated through gut microbial metabolism ( Rowland et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Metabolomic Profiling Identifies Exogenous and Microbiota-Derived Metabolites as Markers of Methotrexate Efficacy in Juvenile Idiopathic Arthritis

Funk

¹

,

Becker

²

2021

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Variability in methotrexate (MTX) efficacy represents a barrier to early and effective disease control in the treatment of juvenile idiopathic arthritis (JIA). This work seeks to understand the impact of MTX on the plasma metabolome and to identify metabolic biomarkers of MTX efficacy in a prospective cohort of children with JIA. Plasma samples from a cohort of children with JIA (n = 30) collected prior to the initiation of MTX and after 3 months of therapy were analyzed using a semi-targeted global metabolomic platform detecting 673 metabolites across a diversity of biochemical classes. Disease activity was measured using the 71-joint count juvenile arthritis disease activity score (JADAS-71) and clinical response to MTX was based on achievement of ACR Pedi 70 response. Metabolomic analysis identified 50 metabolites from diverse biochemical classes that were altered following the initiation of MTX (p < 0.05) with 15 metabolites reaching a false-discovery rate adjusted p-value (q-value) of less than 0.05. Enrichment analysis identified a class-wide reduction in unsaturated triglycerides following initiation of MTX (q = 0.0009). Twelve of the identified metabolites were significantly associated with disease activity by JADAS-71. Reductions in three metabolites were found to be associated with clinical response by ACR Pedi 70 response criteria and represented several microbiota and exogenously derived metabolites including: dehydrocholic acid, biotin, and 4-picoline. These findings support diverse metabolic changes following initiation of MTX in children with JIA and identify metabolites associated with microbial metabolism and exogenous sources associated with MTX efficacy.

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“…The impairment of gut wall barrier function promotes the transfer of enterobacteria and hepatotoxins to the liver through the enterohepatic circulation [61], but some bacteria from microbiota can escape the liver firewall and reach the general circulation. Excessive enterohepatic circulation can cause a transient hepatic disease [62], a phenomenon commonly observed in patients with RA, especially following treatments such as methotrexate (which modify gut homeostasis [63], but cannot always restore gut impermeability). Notably, calcitriol treatment attenuates intestinal permeability, reduces bacterial translocation, and enriches potentially beneficial gut microbiota in cirrhotic rats [64].…”

Section: Translocation Of Some Oral Bacteria In Blood May Occur Following a First Step Of Migration Of Those Bacteria To Gutmentioning

confidence: 99%

“…The overpresentation of bacterial antigens to T cells following trained immunity of synoviocytes could finally lead to a chronic imbalance between various effector T cells (Th1 and Th1) and regulatory T cells in affected synovia, without the need for recognition of a limited set of autoantigens other than citrullinated peptides. This may also explain why drugs targeting presenting cells (including B cells) and/or drugs that can correct dysbiosis in various tissues (methotrexate also impacts microbiomes [63] are much more effective at treating RA than drugs targeting T cells (e.g., ciclosporin) are.…”

Section: Translocation Of Oral Bacteria In Blood Has Been Observed Including In Patients With Ramentioning

confidence: 99%

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Another Look at the Contribution of Oral Microbiota to the Pathogenesis of Rheumatoid Arthritis: A Narrative Review

Berthelot¹,

Bandiaky

²

,

Goff³

et al. 2021

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Although autoimmunity contributes to rheumatoid arthritis (RA), several lines of evidence challenge the dogma that it is mainly an autoimmune disorder. As RA-associated human leukocyte antigens shape microbiomes and increase the risk of dysbiosis in mucosae, RA might rather be induced by epigenetic changes in long-lived synovial presenting cells, stressed by excessive translocations into joints of bacteria from the poorly cultivable gut, lung, or oral microbiota (in the same way as more pathogenic bacteria can lead to “reactive arthritis”). This narrative review (i) lists evidence supporting this scenario, including the identification of DNA from oral and gut microbiota in the RA synovium (but in also healthy synovia), and the possibility of translocation through blood, from mucosae to joints, of microbiota, either directly from the oral cavity or from the gut, following an increase of gut permeability worsened by migration within the gut of oral bacteria such as Porphyromonas gingivalis; (ii) suggests other methodologies for future works other than cross-sectional studies of periodontal microbiota in cohorts of patients with RA versus controls, namely, longitudinal studies of oral, gut, blood, and synovial microbiota combined with transcriptomic analyses of immune cells in individual patients at risk of RA, and in overt RA, before, during, and following flares of RA.

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Methotrexate works remotely, from the gut

Cited by 5 publications

References 11 publications

Oral and Intestinal Bacterial Substances Associated with Disease Activities in Patients with Rheumatoid Arthritis: A Cross-Sectional Clinical Study

Oral and Intestinal Bacterial Substances Associated with Disease Activities in Patients with Rheumatoid Arthritis: A Cross-Sectional Clinical Study

Metabolomic Profiling Identifies Exogenous and Microbiota-Derived Metabolites as Markers of Methotrexate Efficacy in Juvenile Idiopathic Arthritis

Another Look at the Contribution of Oral Microbiota to the Pathogenesis of Rheumatoid Arthritis: A Narrative Review

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