Intestinal Dysbiosis, Tight Junction Proteins, and Inflammation in Rheumatoid Arthritis Patients: A Cross-Sectional Study
<p>Schematic representation of the gastrointestinal barrier, highlighting the tight junction (TJ) proteins analysed. Zonulin (red) modulates intestinal permeability by regulating TJ disassembly. Occludin (green) and claudin-1 (yellow) are structural proteins of the TJ that co-ordinately maintain the integrity and selective permeability of the barrier. When zonulin binds the EGFR (dark blue) and PAR2 (dark green) receptors, it activates a cascade of reactions that ultimately result in the displacement of occludin and claudin-1, leading to loosening of the TJs (2). When zonulin signalling stops, the TJs return to their closed basal state (1).</p> "> Figure 2
<p>Concentration of the distinct tight junction proteins analysed in faeces. Red: rheumatoid arthritis (RA) patients; blue: healthy controls. Data are shown as mean ± standard deviation for claudin-1 and median (p25–p75) for occludin and zonulin. Significance level: * <span class="html-italic">p</span> ≤ 0.05.</p> ">
Abstract
:1. Introduction
2. Results
2.1. Cohort
2.2. Tight Junction Proteins Quantification by ELISA
2.3. Gut Microbiota Association Study
2.4. Biomarkers
3. Discussion
4. Materials and Methods
4.1. Cohort/Study Design
4.2. Clinical and Laboratory Variables
4.3. Tight Junction Protein Quantification in Faeces
4.4. Microbiota Data
4.5. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Variable | RA Patients (n = 82) | Healthy Controls (n = 82) | p-Value |
---|---|---|---|
Age (years), mean (SD) | 56.3 (11.1) | 56.3 (10.9) | 0.986 |
Sex (woman), n (%) | 63 (76.8) | 63 (76.8) | 1.000 |
Caucasian, n (%) | 81 (98.8) | 81 (98.8) | 1.000 |
BMI (Kg/m2), mean (SD) | 28.3 (5.3) | 27.0 (4.2) | 0.072 |
Smoking | 0.028 | ||
Never, n (%) | 35 (42.7) | 50 (61.0) | |
Ex-smoker, n (%) | 20 (24.4) | 9 (11.0) | |
Smoker, n (%) | 27 (32.9) | 23 (28.0) | |
Comorbidities | |||
Arterial hypertension, n (%) | 25 (30.5) | 20 (24.4) | 0.382 |
Diabetes Mellitus, n (%) | 6 (7.3) | 2 (2.4) | 0.147 |
Dyslipidaemia, n (%) | 19 (23.2) | 16 (19.5) | 0.567 |
WHO obesity, n (%) | 29 (35.4) | 18 (22.0) | 0.057 |
Clinic-analytic characteristics | |||
Evolution time (months), median (p25–p75) | 91.3 (77.6–122.7) | - | - |
Diagnosis delay (months), median (p25–p75) | 8.1 (4.6–14.2) | - | - |
Erosions, n (%) | 52 (63.4) | - | - |
RF > 10 U/mL, n (%) | 66 (80.5) | 0 (0.0) | <0.001 |
ACPA > 20 U/mL, n (%) | 67 (81.7) | 0 (0.0) | <0.001 |
Treatment | |||
Synthetic DMARDs, n (%) | 75 (91.5) | - | - |
Methotrexate, n (%) | 59 (72.0) | 0 (0.0) | <0.001 |
Leflunomide, n (%) | 9 (11.0) | 0 (0.0) | 0.002 |
Sulfasalazine, n (%) | 10 (12.2) | 0 (0.0) | 0.001 |
Hydroxychloroquine, n (%) | 6 (7.3) | 0 (0.0) | 0.013 |
Biologic DMARDs, n (%) | 27 (32.9) | 0 (0.0) | <0.001 |
Anti-TNFα, n (%) | 20 (24.4) | 0 (0.0) | <0.001 |
Anti-IL-6, n (%) | 6 (7.3) | 0 (0.0) | 0.013 |
Rituximab, n (%) | 1 (1.2) | 0 (0.0) | 0.316 |
Glucocorticoid at protocol, n (%) | 17 (20.7) | 0 (0.0) | <0.001 |
Variable | RA Patients (n = 82) | Healthy Controls (n = 82) | p-Value |
---|---|---|---|
DAS28-ESR average value, mean (SD) | 3.0 (0.7) | - | - |
Remission-Low activity, n (%) | 52 (63.4) | - | - |
Moderate-High activity, n (%) | 30 (36.6) | - | - |
DAS28-ESR at index-date, mean (SD) | 2.9 (1.0) | - | - |
Remission-Low activity, n (%) | 53 (64.6) | - | - |
Moderate-High activity, n (%) | 29 (35.4) | - | - |
HAQ average value, mean (SD) | 0.6 (0.5) | - | - |
HAQ at index-date, mean (SD) | 0.7 (0.6) | - | - |
Laboratory parameters | |||
ESR (mm/h), median (IQR) | 13 (7.2–21.0) | 11.0 (6.0–16.0) | 0.044 |
Haemoglobin (g/dL), median (p25–p75) | 13.2 (12.3–14.4) | 14.0 (12.8–14.9) | 0.018 |
Leukocytes (109/L), median (p25–p75) | 6375.0 (5410.0–8102.5) | 6040.0 (4980.0–7700.0) | 0.014 |
Platelet (109/L), mean (SD) | 243,426.8 (64,859.3) | 236,146.3 (55,291.8) | 0.440 |
Total cholesterol (mg/dL), mean (SD) | 202.1 (36.5) | 209.5 (35.6) | 0.188 |
LDL cholesterol (mg/dL), median (p25–p75) | 115.9 (101.1–139.2) | 123.5 (101.7–148.5) | 0.150 |
HDL cholesterol (mg/dL), median (p25–p75) | 58.0 (51.0–65.2) | 61.5 (50.7–73.2) | 0.202 |
Triglycerides (mg/dL), median (p25–p75) | 89.5 (67.7–142.2) | 86.5 (69.0–125.2) | 0.699 |
Homocysteine (mg/dL), median (p25–p75) | 14.1 (12.0–17.1) | 11.6 (9.6–14.9) | 0.001 |
Adipocytokines, lipoproteins, and interleukins | |||
Leptin (ng/mL), median (p25–p75) | 15.5 (8.3–33.1) | 19.1 (8.7–35.1) | 0.628 |
Resistin (ng/mL), mean (SD) | 7.6 (3.3) | 7.8 (3.2) | 0.817 |
Adiponectin (µg/mL), mean (SD) | 12,104.5 (6228.4) | 10,202.7 (6263.6) | 0.118 |
IL-6 (pg/mL), median (p25–p75) | 11.0 (5.3–23.3) | 4.1 (2.7–5.7) | <0.001 |
CRP (mg/L), median (p25–p75) | 3.4 (2.9–7.0) | 2.9 (2.0–3.0) | <0.001 |
IL-1β (pg/mL), median (p25–p75) | 4.3 (4.1–4.4) | 2.8 (2.6–4.1) | <0.001 |
TNFα (pg/mL), median (p25–p75) | 4.7 (3.5–11.1) | 3.5 (3.0–4.4) | <0.001 |
IGF-1 (pg/mL), mean (SD) | 164.8 (85.5–226.3) | 139.1 (48.9–298.9) | 0.462 |
LDL-oxidase (UI/mL), median (p25–p75) | 2.5 (0.8–5.6) | 1.2 (0.3–2.7) | 0.065 |
Physical activity and Mediterranean diet | |||
IPAQ (METs), median (p25–p75) | 334.5 (198.0–792.0) | 647.0 (336.7–990.0) | 0.002 |
Sedentariness, n (%) | 54 (65.9) | 38 (46.3) | 0.042 |
MEDAS (≥9), n (%) | 52 (63.4) | 47 (57.3) | 0.425 |
Variable | Occludin (pg/mL) | Claudin-1 (pg/mL) | Zonulin (ng/mL) |
---|---|---|---|
Age (years) | −0.054 | −0.293 * | 0.267 * |
BMI (Kg/m2) | −0.014 | −0.177 | 0.093 |
Evolution (months) | 0.127 | −0.114 | 0.082 |
Diagnosis delay (months) | 0.209 | −0.121 | 0.152 |
RF (U/mL) | 0.041 | 0.136 | −0.080 |
ACPA (U/mL) | −0.026 | −0.193 | 0.082 |
DAS28-ESR average | −0.143 | −0.116 | 0.011 |
HAQ average | −0.271 * | −0.161 | 0.095 |
ESR (mm/h) | −0.032 | −0.045 | −0.048 |
Leptin (ng/mL) | −0.014 | 0.013 | −0.113 |
Resistin (ng/mL) | −0.157 | −0.285 | 0.101 |
Adiponectin (µg/mL) | −0.174 | −0.151 | −0.129 |
IL-6 (pg/mL) | 0.038 | −0.290 * | −0.129 |
CRP (mg/mL) | −0.141 | −0.327 * | 0.122 |
IL-1β (pg/mL) | 0.019 | 0.190 | 0.181 |
TNFα (pg/mL) | 0.055 | 0.092 | 0.266 * |
IGF-1 (pg/mL) | 0.120 | −0.075 | 0.145 |
LDL-oxidase (UI/mL) | 0.078 | 0.155 | 0.023 |
IPAQ (METs) | −0.018 | −0.250 | 0.011 |
Variable | B Univariant (CI95%) | B Multivariant (CI95%) | p-Value |
---|---|---|---|
Age (years) | 0.172 (−0.117, 0.461) | ||
Sex (woman) | 1.137 (−6.291, 8.565) | ||
CRP (mg/L) | −0.511 (−1.334, 0.312) | −2.690 (−5.370, −1.013) | 0.048 |
Smoking | −0.675 (−0.905, 5.555) | ||
Obesity | 0.567 (−3.395, 4.529) | ||
Genus Veillonella | 6.001 (−0.480, 12.482) | ||
Family Lachnospiraceae | −9.136 (−2.048, −20.321) |
Variable | Univariant (CI95%) | Multivariant (CI95%) | p-Value |
---|---|---|---|
Age (years) | −0.396 (−0.767, −0.025) | −0.314 (−0.682, 0.055) | 0.093 |
Sex (woman) | 3.891 (−5.925, 13.706) | ||
CRP (mg/L) | −0.731 (−1.331, −0.130) | −0.619 (−1.222, −0.015) | 0.045 |
ACPA+ | −9.967 (−20.365, 0.432) | ||
Smoking | −4.306 (−12.280, 3.668) | ||
Obesity | 0.758 (−4.003, 5.519) | ||
Genus Veillonella | 7.542 (−0.633, 15.716) | ||
Family Lachnospiraceae | 7.157 (−7.670, 21.984) |
Variable | Univariant (CI95%) | Multivariant (CI95%) | p-Value |
---|---|---|---|
Age (years) | 0.283 (−0.662, 1.228) | ||
Sex (woman) | 6.433 (−26.042, 38.906) | ||
CRP (mg/mL) | 0.203 (−1.621, 1.214) | ||
ACPA+ | 5.676 (−17.211, 28.563) | ||
Smoking | −14.680 (−34.158, 4.797) | ||
Obesity | 0.890 (−10.010, 7.120) | ||
Genus Veillonella | 39.080 (14.658, 63.502) | 39.000 (14.650, 63.600) | 0.004 |
Family Lachnospiraceae | 30.800 (−4.496, 66.096) |
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Mucientes, A.; Lisbona-Montañez, J.M.; Mena-Vázquez, N.; Ruiz-Limón, P.; Manrique-Arija, S.; García-Studer, A.; Ortiz-Márquez, F.; Fernández-Nebro, A. Intestinal Dysbiosis, Tight Junction Proteins, and Inflammation in Rheumatoid Arthritis Patients: A Cross-Sectional Study. Int. J. Mol. Sci. 2024, 25, 8649. https://doi.org/10.3390/ijms25168649
Mucientes A, Lisbona-Montañez JM, Mena-Vázquez N, Ruiz-Limón P, Manrique-Arija S, García-Studer A, Ortiz-Márquez F, Fernández-Nebro A. Intestinal Dysbiosis, Tight Junction Proteins, and Inflammation in Rheumatoid Arthritis Patients: A Cross-Sectional Study. International Journal of Molecular Sciences. 2024; 25(16):8649. https://doi.org/10.3390/ijms25168649
Chicago/Turabian StyleMucientes, Arkaitz, José Manuel Lisbona-Montañez, Natalia Mena-Vázquez, Patricia Ruiz-Limón, Sara Manrique-Arija, Aimara García-Studer, Fernando Ortiz-Márquez, and Antonio Fernández-Nebro. 2024. "Intestinal Dysbiosis, Tight Junction Proteins, and Inflammation in Rheumatoid Arthritis Patients: A Cross-Sectional Study" International Journal of Molecular Sciences 25, no. 16: 8649. https://doi.org/10.3390/ijms25168649