Associations between oral microbiome diversity and rheumatoid arthritis in U.S. adults: NHANES 2009–2012
DOI:
https://doi.org/10.2340/aos.v85.46064Keywords:
Oral microbiome, rheumatoid arthritis, alpha diversity, cross-sectional study, NHANESAbstract
Objective: Although links exist between periodontitis and rheumatoid arthritis (RA), and the gut microbiome has been implicated in RA pathogenesis, the role of oral microbiome diversity in RA remains insufficiently characterized. This study aimed to explore the association between oral microbiome diversity (including alpha and beta diversity) and RA status through a cross-sectional analysis of the National Health and Nutrition Examination Survey (NHANES).
Material and Methods: This cross-sectional study analyzed data from 1,544 participants aged ≥ 20 years derived from the 2009–2012 NHANES cycles. We employed multivariate logistic regression, restricted cubic splines (RCS), receiver operating characteristic (ROC) curve analysis, SHapley Additive exPlanations (SHAP) method and beta diversity assessment (Principal Coordinate Analysis [PCoA] and Permutational Multivariate Analysis of Variance [PERMANOVA]) to examine associations between oral microbiome diversity metrics and RA.
Results: After adjustments, four alpha diversity metrics (observed amplicon sequence variants [ASVs]: OR [95% CI] = 0.996 [0.992, 0.999], P = 0.043; Faith’s PD: OR [95% CI] = 0.943 [0.900, 0.988], P = 0.014; Shannon-Wiener index: OR [95% CI] = 0.786 [0.641, 0.965], P = 0.021; Simpson index: OR [95% CI] = 0.127 [0.018, 0.915], P = 0.037) were significantly inversely associated with the presence of RA. This relationship was approximately linear (P for nonlinear > 0.05) and moderated by socioeconomic factors (P for interaction < 0.05). ROC and SHAP analyses revealed that the Simpson index had the highest explanatory capacity for RA. However, beta diversity (Bray-Curtis, UniFrac distances) revealed no significant differences between RA and non-RA groups (all P > 0.05).
Conclusions: Higher oral microbiome alpha diversity is significantly associated with lower prevalence of RA. Oral microbial diversity may serve as a potential indicator associated with RA status. However, given the cross-sectional nature of this study, longitudinal and interventional studies are warranted to further elucidate causal relationships.
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References
Smith MH, Berman JR. What is rheumatoid arthritis? JAMA. 2022;327:1194. DOI: https://doi.org/10.1001/jama.2022.0786
Ma Y, Chen H, Lv W, Wei S, Zou Y, Li R, et al. Global, regional and national burden of rheumatoid arthritis from 1990 to 2021, with projections of incidence to 2050: a systematic and comprehensive analysis of the Global Burden of Disease study 2021. Biomark Res. 2025;13:47. DOI: https://doi.org/10.1186/s40364-025-00760-8
Su QY, Yang L, Qi XY, Wang MY, Cheng JW, Niu H, et al. Global, regional, and national burdens of rheumatoid arthritis among people aged 60 years and older from 1990 to 2021: a trend analysis for the Global Burden of Disease Study 2021. Front Public Health. 2025;13:1527680. DOI: https://doi.org/10.3389/fpubh.2025.1527680
Lin YJ, Anzaghe M, Schulke S. Update on the pathomechanism, diagnosis, and treatment options for rheumatoid arthritis. Cells. 2020;9 :880. DOI: https://doi.org/10.3390/cells9040880
Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet. 2016;388:2023–38. DOI: https://doi.org/10.1016/S0140-6736(16)30173-8
Littlejohn EA, Monrad SU. Early diagnosis and treatment of rheumatoid arthritis. Prim Care. 2018;45:237–55. DOI: https://doi.org/10.1016/j.pop.2018.02.010
Myasoedova E, Crowson CS, Kremers HM, Therneau TM, Gabriel SE. Is the incidence of rheumatoid arthritis rising? Results from Olmsted County, Minnesota, 1955–2007. Arthritis Rheum. 2010;62:1576–82. DOI: https://doi.org/10.1002/art.27425
Aletaha D, Smolen JS. Diagnosis and management of rheumatoid arthritis: a review. JAMA. 2018;320:1360–72. DOI: https://doi.org/10.1001/jama.2018.13103
Tan EM, Smolen JS. Historical observations contributing insights on etiopathogenesis of rheumatoid arthritis and role of rheumatoid factor. J Exp Med. 2016;213:1937–50. DOI: https://doi.org/10.1084/jem.20160792
Tan X, Wang Y, Gong T. The interplay between oral microbiota, gut microbiota and systematic diseases. J Oral Microbiol. 2023;15:2213112. DOI: https://doi.org/10.1080/20002297.2023.2213112
Koren N, Zubeidat K, Saba Y, Horev Y, Barel O, Wilharm A, et al. Maturation of the neonatal oral mucosa involves unique epithelium-microbiota interactions. Cell Host Microbe. 2021;29:197–209.e5. DOI: https://doi.org/10.1016/j.chom.2020.12.006
Yamazaki K. Oral-gut axis as a novel biological mechanism linking periodontal disease and systemic diseases: a review. Jpn Dent Sci Rev. 2023;59:273–80. DOI: https://doi.org/10.1016/j.jdsr.2023.08.003
Mikuls TR, Thiele GM, Deane KD, Payne JB, O’Dell JR, Yu F, et al. Porphyromonas gingivalis and disease-related autoantibodies in individuals at increased risk of rheumatoid arthritis. Arthritis Rheum. 2012;64:3522–30. DOI: https://doi.org/10.1002/art.34595
Fuggle NR, Smith TO, Kaul A, Sofat N. Hand to mouth: a systematic review and meta-analysis of the association between rheumatoid arthritis and periodontitis. Front Immunol. 2016;7:80. DOI: https://doi.org/10.3389/fimmu.2016.00080
Wells PM, Williams FMK, Matey-Hernandez ML, Menni C, Steves CJ. ‘RA and the microbiome: do host genetic factors provide the link? J Autoimmun. 2019;99:104–15. DOI: https://doi.org/10.1016/j.jaut.2019.02.004
National Center for Health Statistics. NHANES 2009–2012 Oral Microbiome. 2009–2012. Centers for Disease Control and Prevention. Atlanta, Georgia.
Loprinzi PD. Dose-response association of moderate-to-vigorous physical activity with cardiovascular biomarkers and all-cause mortality: considerations by individual sports, exercise and recreational physical activities. Prev Med. 2015;81:73–7. DOI: https://doi.org/10.1016/j.ypmed.2015.08.014
Willis AD. Rarefaction, alpha diversity, and statistics. Front Microbiol. 2019;10:2407. DOI: https://doi.org/10.3389/fmicb.2019.02407
Gower JC. Some distance properties of latent root and vector methods used in multivariate analysis. Biometrika. 1966;53:325–38. DOI: https://doi.org/10.1093/biomet/53.3-4.325
Anderson MJ. A new method for non-parametric multivariate analysis of variance. Austral Ecol. 2001;26:32–46. DOI: https://doi.org/10.1046/j.1442-9993.2001.01070.x
Yang S, He Y, Ma Y, Wang R, Wu Y, Wu W. Associations between the oral microbiome, number of teeth and frailty among American adults: a cross-sectional study from NHANES 2009–2012. Exp Gerontol. 2025;203:112727. DOI: https://doi.org/10.1016/j.exger.2025.112727
Hou K, Song W, He J, Ma Z. The association between non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) and prevalence of periodontitis among US adults: a cross-sectional NHANES study. Sci Rep. 2024;14:5558. DOI: https://doi.org/10.1038/s41598-024-56276-y
Krebs-Smith SM, Pannucci TE, Subar AF, Kirkpatrick SI, Lerman JL, Tooze JA, et al. Update of the healthy eating index: HEI-2015. J Acad Nutr Diet. 2018;118:1591–602. DOI: https://doi.org/10.1016/j.jand.2018.05.021
Xia XX, Li CX, Guo HR. Association between oral microbiome diversity and chronic obstructive pulmonary disease in the US population. J Transl Med. 2025;23:557. DOI: https://doi.org/10.1186/s12967-025-06553-9
Ke C, Zhang X, Wang X. Association between dietary inflammatory index and all-cause mortality in patients with osteopenia or osteoporosis: a retrospective cohort study from the NHANES 2007–2018. Prev Med Rep. 2024;45:102826. DOI: https://doi.org/10.1016/j.pmedr.2024.102826
Tang Y, Peng B, Liu J, Liu Z, Xia Y, Geng B. Systemic immune-inflammation index and bone mineral density in postmenopausal women: a cross-sectional study of the national health and nutrition examination survey (NHANES) 2007–2018. Front Immunol. 2022;13:975400. DOI: https://doi.org/10.3389/fimmu.2022.975400
Writing Committee M, Jones DW, Ferdinand KC, Taler SJ, Johnson HM, Shimbo D, et al. 2025 AHA/ACC/AANP/AAPA/ABC/ACCP/ACPM/AGS/AMA/ASPC/NMA/PCNA/SGIM guideline for the prevention, detection, evaluation and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Hypertension. 2025;82:e212–316.
American Diabetes Association Professional Practice C. 2. Classification and diagnosis of diabetes: standards of medical care in diabetes-2022. Diabetes Care. 2022;45:S17–38. DOI: https://doi.org/10.2337/dc22-S002
Bescos R, Ashworth A, Clarke C, Brookes ZL, Belfield L, Rodiles A, et al. Effects of Chlorhexidine mouthwash on the oral microbiome. Sci Rep. 2020;10:5254. DOI: https://doi.org/10.1038/s41598-020-61912-4
Rothman KJ. No adjustments are needed for multiple comparisons. Epidemiology. 1990;1:43–6. DOI: https://doi.org/10.1097/00001648-199001000-00010
Shi Y, Zhang L, Do KA, Peterson CB, Jenq RR. aPCoA: covariate adjusted principal coordinates analysis. Bioinformatics. 2020;36:4099–101. DOI: https://doi.org/10.1093/bioinformatics/btaa276
Anderson MJ. Permutational multivariate analysis of variance (PERMANOVA). Wiley StatsRef: Statistics Reference Online. John Wiley & Sons. Hoboken. p. 1–15.
Braga LH, Farrokhyar F, Bhandari M. Confounding: what is it and how do we deal with it? Can J Surg. 2012;55:132–8. DOI: https://doi.org/10.1503/cjs.036311
Greenland S, Senn SJ, Rothman KJ, Carlin JB, Poole C, Goodman SN, et al. Statistical tests, P values, confidence intervals, and power: a guide to misinterpretations. Eur J Epidemiol. 2016;31:337–50. DOI: https://doi.org/10.1007/s10654-016-0149-3
Chu XJ, Cao NW, Zhou HY, Meng X, Guo B, Zhang HY, et al. The oral and gut microbiome in rheumatoid arthritis patients: a systematic review. Rheumatology (Oxford). 2021;60:1054–66. DOI: https://doi.org/10.1093/rheumatology/keaa835
Tong Y, Zheng L, Qing P, Zhao H, Li Y, Su L, et al. Oral microbiota perturbations are linked to high risk for rheumatoid arthritis. Front Cell Infect Microbiol. 2019;9:475. DOI: https://doi.org/10.3389/fcimb.2019.00475
Kroese JM, Brandt BW, Buijs MJ, Crielaard W, Lobbezoo F, Loos BG, et al. Differences in the oral microbiome in patients with early rheumatoid arthritis and individuals at risk of rheumatoid arthritis compared to healthy individuals. Arthritis Rheumatol. 2021;73:1986–93. DOI: https://doi.org/10.1002/art.41780
Weiss GA, Hennet T. Mechanisms and consequences of intestinal dysbiosis. Cell Mol Life Sci. 2017;74:2959–77. DOI: https://doi.org/10.1007/s00018-017-2509-x
Nishimura K, Sugiyama D, Kogata Y, Tsuji G, Nakazawa T, Kawano S, et al. Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis. Ann Intern Med. 2007;146:797–808. DOI: https://doi.org/10.7326/0003-4819-146-11-200706050-00008
Lappin DF, Apatzidou D, Quirke AM, Oliver-Bell J, Butcher JP, Kinane DF, et al. Influence of periodontal disease, Porphyromonas gingivalis and cigarette smoking on systemic anti-citrullinated peptide antibody titres. J Clin Periodontol. 2013;40:907–15. DOI: https://doi.org/10.1111/jcpe.12138
Lourenco TGB, de Oliveira AM, Tsute Chen G, Colombo APV. Oral-gut bacterial profiles discriminate between periodontal health and diseases. J Periodontal Res. 2022;57:1227–37. DOI: https://doi.org/10.1111/jre.13059
Berthelot JM, Bandiaky ON, Le Goff B, Amador G, Chaux AG, Soueidan A, et al. Another look at the contribution of oral microbiota to the pathogenesis of rheumatoid arthritis: a narrative review. Microorganisms. 2021;10 :59. DOI: https://doi.org/10.3390/microorganisms10010059
Zhang X, Chen BD, Zhao LD, Li H. The gut microbiota: emerging evidence in autoimmune diseases. Trends Mol Med. 2020;26:862–73. DOI: https://doi.org/10.1016/j.molmed.2020.04.001
Brandl C, Bucci L, Schett G, Zaiss MM. Crossing the barriers: revisiting the gut feeling in rheumatoid arthritis. Eur J Immunol. 2021;51:798–810. DOI: https://doi.org/10.1002/eji.202048876
Tajik N, Frech M, Schulz O, Schalter F, Lucas S, Azizov V, et al. Targeting zonulin and intestinal epithelial barrier function to prevent onset of arthritis. Nat Commun. 2020;11:1995. DOI: https://doi.org/10.1038/s41467-020-15831-7
Gioia C, Lucchino B, Tarsitano MG, Iannuccelli C, Di Franco M. Dietary habits and nutrition in rheumatoid arthritis: can diet influence disease development and clinical manifestations? Nutrients. 2020;12 :1456. DOI: https://doi.org/10.3390/nu12051456
Adler NE, Newman K. Socioeconomic disparities in health: pathways and policies. Health Aff (Millwood). 2002;21:60–76. DOI: https://doi.org/10.1377/hlthaff.21.2.60
Brookes Z, Teoh L, Cieplik F, Kumar P. Mouthwash effects on the oral microbiome: are they good, bad, or balanced? Int Dent J. 2023;73 Suppl 2:S74–81. DOI: https://doi.org/10.1016/j.identj.2023.08.010
Zhang X, Zhang D, Jia H, Feng Q, Wang D, Liang D, et al. The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment. Nat Med. 2015;21:895–905. DOI: https://doi.org/10.1038/nm.3914
Sacks JJ, Harrold LR, Helmick CG, Gurwitz JH, Emani S, Yood RA. Validation of a surveillance case definition for arthritis. J Rheumatol. 2005;32:340–7.
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