Available online on 15.03.2026 at http://jddtonline.info

Journal of Drug Delivery and Therapeutics

Open Access to Pharmaceutical and Medical Research

Copyright  © 2026 The  Author(s): This is an open-access article distributed under the terms of the CC BY-NC 4.0 which permits unrestricted use, distribution, and reproduction in any medium for non-commercial use provided the original author and source are credited

Open Access Full Text Article  Review Article

Exploring the Potential of Probiotics and Gut Microbiota Modulation in the Management of Rheumatoid Arthritis: A Review of Current Mechanisms and Therapeutic Strategies

Snehal Ambadas Gojare *, Pranoti Aher , Rachana Lokhande , Nikita Game , Priyanka Nanasaheb Khamkar 

Department of Pharmacology, Progressive Education Society’s Modern college of Pharmacy, Nigdi, Pune-044.

 

 

Introduction

Rheumatoid arthritis (RA) is a chronic autoimmune disorder that sparks widespread inflammation. It primarily targets the joints, triggering nonsuppurative proliferative synovitis that often progresses to joint fusion and breakdown of articular cartilage. Beyond the joints, RA can affect various tissues and organs, such as the skin, heart, lungs, blood vessels, and muscles ². While joints and tendons show large pathological changes, extra-articular issues occur less often. Women face 2-3 times higher risk than men, with RA touching about 1% of people worldwide ². Though its exact cause remains elusive, experts believe environmental and genetic factors team up to ignite an aberrant autoimmune reaction ³.

Clinicians often turn to two key drug types for managing rheumatoid arthritis: disease-modifying antirheumatic drugs (DMARDs) and nonsteroidal anti-inflammatory drugs (NSAIDs) ⁴. That said, NSAIDs and DMARDs have limitations, including side effects, risks of toxicity, and high costs ⁵.

Fig.1 shows a healthy joint i.e. smooth, cushioned cartilage, versus RA: eroded bone, swollen synovium, worn padding, tight space causing pain and stiffness.Researchers see the pre-clinical stage of RA as a key opportunity for intervention, where kicking off treatment before clinical symptoms appear could ward off major joint damage seen on X-rays and help secure lasting remission ⁶.

 

 

 

Figure 1: The joint's structure and its modifications in rheumatoid arthritis ⁶.

 

 

Pre-clinical RA represents an at-risk state that comes before clinical arthritis and full-blown RA ⁷. It often involves a breakdown in immune tolerance, leading to autoantibodies like those targeting rheumatoid factor or citrullinated proteins ⁸. A wealth of studies in humans and mouse models highlights the gut microbiota's central role in driving this early phase (Table 1) . Past work suggests gut dysbiosis disrupts immune self-tolerance and speeds RA progression, partly through molecular mimicry ⁹. In particular, peptides from gut bacteria can mimic RA autoantigens, sparking cross-reactive autoantibodies that attack joint cartilage ¹⁰. As shown in Fig.2, multi-omics analyses of the microbiome and its metabolitesshow these gut-derived compounds act as immunomodulators, influencing immune cell development and function.

 

 

Figure 2: Depiction of the role of the oral and gut microbiomes on RA ¹¹.

 

Probiotics boost health by ramping up beneficial gut bacteria. Strains like Lactobacillus and Bifidobacterium—naturally present in our bodies—show up in foods or supplements. Each person hosts a unique microbial community across sites like the mouth, skin, and intestines ¹².

Probiotics appear to work through three main mechanisms:

• Curbing harmful bacteria linked to allergies and infections.
• Balancing "good" and "bad" microbes in the body.
• Restocking healthy ones depleted by illness.

Lactobacillus and Bifidobacterium stand out as top probiotics, with well-documented perks such as:

• Easing gas and bloating.
• Warding off or softening colds and flu.
• Lowering blood pressure.
• Relieving inflammatory bowel conditions like Crohn's disease and ulcerative colitis.
• Accelerating recovery from certain gut infections.

 

Probiotics hold real potential for people with inflammatory arthritis ¹³. These beneficial microbes seem to aid treatment by lowering C-reactive protein (CRP), a key inflammation marker. RA patients often deal with gut lining inflammation too, which ramps up intestinal motility ¹⁴. That breach lets certain bacteria slip through the intestinal wall into the bloodstream, triggering systemic infections.Probiotics shine by calming gut immune overreactions, fortifying the intestinal barrier, and tackling widespread permeability issues alongside microbiome shifts. They're especially useful for conditions with weakened mucosal defenses, like viral infections or pro-inflammatory disorders ¹⁵. Overall, these supplements can team up to protect joints and bolster whole-body health.A recent journal study split 46 RA patients into two groups: one got daily Lactobacillus casei supplements, the other a placebo. Researchers found this probiotic approach could serve as a valuable add-on therapy for RA ¹⁶.

Pathophysiology of Rheumatoid Arthritis and the mechanisms of Probiotics

Interactions among the immune system, gut bacteria, and intestinal lining spark the widespread inflammation seen in RA. A core driver is the imbalance of pro-inflammatory cytokines like TNF, IL-1β, IFN-γ, IL-6, IL-12, and IL-17, which fuel the disease's destructive processes. Along the gut-joint axis in inflammatory arthritis, leaky gut walls expose the immune system to microbes, igniting a body-wide response that zeroes in on the joints with local inflammation ¹⁷.

Probiotics offer a practical way to fix gut dysbiosis and dial back the inflammatory cytokine storm tied to arthritis. Disrupted gut microbiota likely plays a pivotal role in kickstarting RA pathology ¹⁸.

Probiotics ramp up regulatory cytokines in the gut via tolerogenic dendritic cells (DCs) or Tregs. These cytokines travel to target organs, boosting Tregs that home in on inflamed sites. Probiotic byproducts like short-chain fatty acids (SCFAs) also curb systemic inflammation and tweak immune responses by shaping immune cell activity. SCFAs fine-tune leukocyte functions, including eicosanoid and chemokine production—and promote anti-inflammatory cytokines such as TNF, IL-2, IL-6, and IL-10 (Fig.3.) ¹⁹.

On top of that, probiotics and their metabolites strike a balance: fending off pathogenic bacteria invasion, adhesion, and spread while tolerating normal gut flora. This could help seal leaky gut walls, a key feature of the gut-joint axis in inflammatory arthritis.

Research also reveals that L. casei can dial down pro-inflammatory cytokines and ease RA symptoms in patients on disease-modifying antirheumatic drugs (DMARDs), pointing to a helpful synergy between the two.

In short, probiotics like these may tame RA's inflammatory drive by balancing cytokine production, strengthening the gut barrier, and teaming up effectively with DMARDs.

 

 

  

 

 

 

 

 

 

 

 

 

 

 

Figure 3: Mechanism of Probiotic in RA ¹⁹.

 

 

Table 1: List of research studies on the therapeutic effects of probiotics in humans and animals. 

Probiotics	Period	Study Framework	Main Findings	Ref
Lactobacillus casei ATCC 334	28Days (2*108 CFU/ml)	Preclinical trial	Histopathological examination revealed normal synovial membrane and cartilage, without any signs of bone destruction. The arthritis showed decreased severity, along with lower levels of pro-inflammatory cytokines.	20
Lactobacillus casei ATCC 334	30 days (2*108 CFU/day)	Preclinical trial	Joints exhibited less swelling, milder arthritis, and reduced bone damage. Correction of dysbiosis in the gut microbiota	21
Lactobacillus casei	12 weeks (4*108 CFU/G)	Preclinical trial	Clinical symptoms improved notably, with less paw swelling, reduced lymphocyte infiltration, and diminished cartilage destruction. A rise in the levels of anti-inflammatory cytokines (IL-10 and TGF-β) A reduction in pro-inflammatory cytokines CII-reactive T cell proliferation dropped, along with lower levels of Th1-type IgG isotypes (IgG2a and IgG2b).	22
Lactobacillus plantarum MTCC No. 1047	21 days (105, 107, 109 CFU/ animal)	Rat model of arthritis induced by Complete Freund’s adjuvant (CFA)	Suppression of the release of inflammatory markers such as CRP, ESR, RF, and TNF-α Improvement in the arthritic index, joint stiffness, gait performance, and mobility assessment	23
Lactobacillus casei 01	8 weeks (108CFU/day)	RCT with a double-blind protocol In Iran 46 RA patients	Reduction in SOD and GPx enzyme activity	24
Lactobacillus casei 01	8 weeks (108CFU/ day)	RCT with a double-blind protocol A group of 45 rheumatoid arthritis (RA) patients in Germany, aged between 20 and 80, with a disease duration of over one year.	Reduction in serum hs-CRP levels, tender and swollen joint counts, GH score, and DAS28 index A notable difference was found between the L. casei 01 and placebo groups in IL-10, IL-12, and TNF-α levels.	25
Lactobacillus rhamnosus GG (LGG)	12 Months (5* 109 CFU/ capsule, 2 capsule/ Day)	clinical trial with a double-blind A group of 21 rheumatoid arthritis (RA) patients in Finland, aged between 18 and 64, with a disease duration of at least one year.	Reduction in the average number of tender and swollen joints, as well as RA activity A slight rise in serum IL-1β.	26
Lactobacillus acidophilus,  Lactobacillus casei Bifidobacteriumbifidum	8 week (2*109 CFU/g each)	A randomized, double-blind, placebo-controlled study In Iran 54 patients with RA at the age of 25-70	Serum hs-CRP levels, insulin values, HOMA-IR, and HOMA-B all decreased. A rise in plasma NO, plasma glutathione, DAS-28, and VAS pain.	27
Lactobacillus acidophilus La-14, Lactobacillus caseiLc-11,  Lactobacillus Lactis	60 days (109 CFU/g each)	A randomized and double blind placebo- controlled study.  In Brazil 42 RA patients	A lowering in white blood cell count andTNF- α and IL-6 plasma levels. A decrease in NO metabolites and an increase in sulfhydryl groups and total antioxidant capacity for radical trapping.	28

 

 

Microbiome-induced molecular mimicry in Rheumatoid Arthritis

We've long known about molecular mimicry, but lately, eyes are turning to how our resident microbes pull it off. As per Table 2, studies show human-associated bacteria churn out proteins strikingly similar to our own. In certain cases, this resemblance throws the immune system off balance, potentially sparking autoimmune diseases ²⁹.

Citrullination—a normal bodily process—plays roles in key functions like cell death, final cell maturation, gene regulation, and reproductive growth ³¹. The enzyme PAD drives this by modifying various RA-linked autoantigens, such as vimentin, fibrinogen, enolase, and even proteins from P. gingivalis. Studies also confirm anti-CCP antibodies in RA patients ³².

 

 

Table 2: Microbiome-induced molecular mimicry in Rheumatoid Arthritis

Microbiome	Immune response	Stage of RA	Ref.
Bacteroidaceae, Lachnospiraceae, and S24-7	Elevated IL-17 levels in serum, along with a higher CD8+ T cell-to-Th17 ratio in the spleen; The spleen shows fewer dendritic cells, B cells, and Tregs.	The progression of RA	33
Haemophilus spp., Lactobacillus salivarius	Serum anti-CCP, RF, CRP, IgG and DAS28 levels were elevated.	Established RA	34
Prevotellacopri	The number of intestinal Th17 cells was increased; IL-17 levels were high in regional lymph nodes and lymph glands.	Early RA	35
Aggregatibacter actinomycetem comitans	Host neutrophils showed excessive citrullination, driven by dysregulated activation of citrullinating enzymes.	Pre-clinical RA	36
Anaeroglobusgeminatus	The presence of ACPAs/ rheumatoid factor was observed.	New onset RA	37
Crypto bacterium curtum	Large amount of citrulline were produced.	Established RA	38
Defluviitaleaceae_UGC-011, Neisseriaoralis, Prevotella_6	Serum tests revealed positive ACPA titers, with elevated levels of immunoglobulin G (IgG), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR).	Pre- clinical RA.	39

 

 

 

 

Gut Microbiota Modulation by Mediterranean Diet in Rheumatoid Arthritis

Environmental factors, not genetics, mainly reshape gut microbiota makeup. Diet stands out as a top influencer of this microbial balance. Experts increasingly view nutrition's power to tweak gut bacteria as a smart way to treat and prevent diseases like RA ⁴⁰. Plenty of studies probe how n-3 PUFAs affect RA symptoms ⁴¹. Boosting intake of EPA and DHA packs them into cell membranes, bumping out arachidonic acid (AA) from immune cell phospholipids ⁴². These fatty acids fuel pro-resolving mediators that help dial down inflammation and restore balance, curbing the cell's inflammatory bent ⁴⁴. Many studies confirm n-3 PUFAs improve other RA symptoms too, such as fewer tender joints (TJ) and swollen joints (SJ), plus shorter morning stiffness (MS) ⁴⁵. A meta-analysis by Gioxari et al. found that taking n-3 PUFAs by mouth significantly eased MS duration, TJ counts, erythrocyte sedimentation rate (ESR), and pain scores on visual scales ⁴⁶.

Patients needed fewer nonsteroidal anti-inflammatory drugs (NSAIDs) compared to placebo. Even with strong evidence for n-3 PUFAs in RA, studies suffer from inconsistencies in dosing, duration, and placebo choices ⁴⁷. RA patients seem to need at least 3g daily of EPA and DHA for 12 weeks or more to see meaningful drops in pain scores. One study showed that after 12 weeks on a Cretan Mediterranean diet (MD), RA patients with stable, low disease activity gained clear benefits in DAS-28 scores, HAQ, and two Short Form-36 measures ⁴⁸.

That study had some limitations, though: a small sample size, baseline DAS-28 scores as high as 7 (signaling active disease), significant BMI differences between groups, and no long-term follow-up beyond 12 weeks ⁵¹.

In another trial, McKellar et al. tested written guides versus cooking classes to promote the Mediterranean diet (MD) in women with RA. Over three months, the workshop group boosted their intake of fruits, vegetables, and legumes while shifting from saturated to monounsaturated fats ⁵². Compared to controls, they saw big gains in patient global assessment (PGA) at six months, pain scores at three and six months, morning stiffness (MS) at six months, and HAQ at three months ⁵³. This suggests stronger MD education leads to better results. Still, despite statistical wins, DAS-28 barely budged with modest changes overall—so larger studies are needed to confirm ⁵¹.

Conclusion

Rheumatoid arthritis (RA) continues to puzzle researchers as a tough autoimmune condition shaped by genetic, environmental, and immune triggers. One exciting frontier? The gut microbiome and probiotics, which show real potential in both sparking RA and helping control it. Through tricks like molecular mimicry and tweaking immune responses, gut bacteria drive disease onset and advance—particularly before symptoms fully hit.

Strains like Lactobacillus and Bifidobacterium make probiotics a hopeful add-on for RA care. They restore gut balance, tighten up leaky intestines, ease body-wide inflammation, and fine-tune immune activity. Clinical and animal studies back this, showing drops in symptoms, inflammatory signals, and even teamwork with standard DMARDs.

That said, promising early data calls for bigger, rigorous trials to confirm real-world benefits and safety over time. Weaving in probiotics and gut-focused tweaks could offer RA patients a fresh, affordable, gentler option—boosting daily life and lightening the disease's load.

List of Abbreviations

RA: Rheumatoid arthritis

NSAID: Non-steroidal anti-inflammatory drug

DMARDs: Disease-modifying antirheumatic drugs

CRP: C-reactive protein

COX: Cyclooxygenase

PPAD: Porphyromonas gingivalis peptidylarginine deiminase (PPAD)

PAD: Peptidyl arginine deiminase (PAD)

HAQ: Health Assessment Questionnaire

MD: Mediterranean diet

Funding: No funding

Ethics approval and consent to participate: Not applicable

Authors' contributions:

1. Ms. Snehal A Gojare- Conceptualization & Guidance
2. Ms. Pranoti Aher- Literature Searching
3. Ms. Rachana Lokhande- Literature Searching
4. Ms. Nikita Game -Paper writing & editing
5. Ms Priyanka N Khamkar- Paper writing & editing

Competing interests: None

Authorship: The manuscript has been read and approved by all authors.

Acknowledgements: None

References

1. Swathi KP, Jayaram S, Sugumar D, Rymbai E. Evaluation of anti-inflammatory and anti-arthritic property of ethanolic extract of Clitoriaternatea. Chinese herbal medicines. 2021 Apr 1;13(2):243-9. https://doi.org/10.1016/j.chmed.2020.11.004 PMid:36117501 PMCid:PMC9476680

2. Deshmukh R. Rheumatoid arthritis: Pathophysiology, current therapeutic strategies and recent advances in targeted drug delivery system. Materials Today Communications. 2023 Jun 1; 35:105877. https://doi.org/10.1016/j.mtcomm.2023.105877

3. Kochi Y, Suzuki A, Yamamoto K. Genetic basis of rheumatoid arthritis: a current review. Biochemical and biophysical research communications. 2014 Sep 19;452(2):254-62. https://doi.org/10.1016/j.bbrc.2014.07.085 PMid:25078624

4. Wang YZ, Sun SQ, Zhou YB. Extract of the dried heartwood of Caesalpiniasappan L. attenuates collagen-induced arthritis. Journal of ethnopharmacology. 2011 Jun 14;136(1):271-8. https://doi.org/10.1016/j.jep.2011.04.061 PMid:21557995

5. Shen X, Li C, Zhao H, Li S, Chen J, Kobayashi Y, Shen W. Inhibitory effects of a traditional Chinese herbal formula TBL-II on type II collagen-induced arthritis in mice. Journal of ethnopharmacology. 2011 Mar 24;134(2):399-405. https://doi.org/10.1016/j.jep.2010.12.033 PMid:21215307

6. Raza K, Klareskog L, Holers VM. Predicting and preventing the development of rheumatoid arthritis. Rheumatology. 2016 Jan 1;55(1):1-3. https://doi.org/10.1093/rheumatology/kev261 PMid:26224307 PMCid:PMC5854029

7. Gerlag DM, Raza K, Van Baarsen LG, Brouwer E, Buckley CD, Burmester GR, et al.EULAR recommendations for terminology and research in individuals at risk of rheumatoid arthritis: report from the Study Group for Risk Factors for Rheumatoid Arthritis. Annals of the rheumatic diseases. 2012 May 1;71(5):638-41. https://doi.org/10.1136/annrheumdis-2011-200990 PMid:22387728 PMCid:PMC3329228

8. Rooney CM, Mankia K, Mitra S, Moura IB, Emery P, Wilcox MH. Perturbations of the gut microbiome in anti-CCP positive individuals at risk of developing rheumatoid arthritis. Rheumatology. 2021 Jul 1;60(7):3380-7. https://doi.org/10.1093/rheumatology/keaa792 PMid:33313854

9. Jubair WK, Hendrickson JD, Severs EL, Schulz HM, Adhikari S, Ir D, et al. Modulation of inflammatory arthritis in mice by gut microbiota through mucosal inflammation and autoantibody generation. Arthritis & rheumatology. 2018 Aug;70(8):1220-33. https://doi.org/10.1002/art.40490 PMid:29534332 PMCid:PMC6105374

10. Chen B, Sun L, Zhang X. Integration of microbiome and epigenome to decipher the pathogenesis of autoimmune diseases. Journal of autoimmunity. 2017 Sep 1; 83:31-42. https://doi.org/10.1016/j.jaut.2017.03.009 PMid:28342734

11. Rooney CM, Mankia K, Emery P. The role of the microbiome in driving RA-related autoimmunity. Frontiers in cell and developmental biology. 2020 Sep 29; 8:538130. https://doi.org/10.3389/fcell.2020.538130 PMid:33134291 PMCid:PMC7550627

12. Balasundaram D, Veerasamy V, Singarayar MS, Neethirajan V, Devanesan AA, Thilagar S. Therapeutic potential of probiotics in gut microbial homeostasis and Rheumatoid arthritis. International Immunopharmacology. 2024 Aug 20; 137:112501. https://doi.org/10.1016/j.intimp.2024.112501 PMid:38885604

13. Mohammed AT, Khattab M, Ahmed AM, Turk T, Sakr N, M. Khalil A, et al. The therapeutic effect of probiotics on rheumatoid arthritis: a systematic review and meta-analysis of randomized control trials. Clinical rheumatology. 2017 Dec; 36:2697-707. https://doi.org/10.1007/s10067-017-3814-3 PMid:28914373

14. Bedaiwi MK, Inman RD. Microbiome and probiotics: link to arthritis. Current opinion in rheumatology. 2014 Jul 1;26(4):410-5. https://doi.org/10.1097/BOR.0000000000000075 PMid:24841227

15. Kim JE, Chae CS, Kim GC, Hwang W, Hwang JS, Hwang SM, et al. Lactobacillus helveticus suppresses experimental rheumatoid arthritis by reducing inflammatory T cell responses. journal of functional foods. 2015 Mar 1; 13:350-62. https://doi.org/10.1016/j.jff.2015.01.002

16. Bungau SG, Behl T, Singh A, Sehgal A, Singh S, Chigurupati S, et al. Targeting probiotics in rheumatoid arthritis. Nutrients. 2021 Sep 26;13(10):3376. https://doi.org/10.3390/nu13103376 PMid:34684377 PMCid:PMC8539185

17. Liam J. O'Neil, DeshiréAlpízar-Rodríguez, Kevin D. Deane The Journal of Rheumatology Jan 2024, jrheum.2023-0334; DOI: 10.3899/jrheum.2023-0334 https://doi.org/10.3899/jrheum.2023-0334 PMid:38224993 PMCid:PMC10984790

18. Wang P, Tao JH, Pan HF. Probiotic bacteria: a viable adjuvant therapy for relieving symptoms of rheumatoid arthritis. Inflammopharmacology. 2016 Oct; 24:189-96. https://doi.org/10.1007/s10787-016-0277-0 PMid:27581587

19. Ferro M, Charneca S, Dourado E, Guerreiro CS, Fonseca JE. Probiotic supplementation for rheumatoid arthritis: A promising adjuvant therapy in the gut microbiome era. Frontiers in Pharmacology. 2021 Jul 23; 12:711788. https://doi.org/10.3389/fphar.2021.711788 PMid:34366867 PMCid:PMC8346200

20. Amdekar S, Singh V, Singh R, Sharma P, Keshav P, Kumar A. Lactobacillus casei reduces the inflammatory joint damage associated with collagen-induced arthritis (CIA) by reducing the pro-inflammatory cytokines: Lactobacillus casei: COX-2 inhibitor. Journal of clinical immunology. 2011 Apr; 31:147-54. https://doi.org/10.1007/s10875-010-9457-7 PMid:20838859

21. Pan H, Guo R, Ju Y, Wang Q, Zhu J, Xie Y, et al. A single bacterium restores the microbiome dysbiosis to protect bones from destruction in a rat model of rheumatoid arthritis. Microbiome. 2019 DSo JS, Lee CG, Kwon HK, Yi HJ, Chae CS, Park JA, et al. Lactobacillus casei potentiates induction of oral tolerance in experimental arthritis. Molecular immunology. 2008 Nov 1;46(1):172-80.ec;7:1-1. https://doi.org/10.1186/s40168-019-0719-1 PMid:31315667 PMCid:PMC6637628

22. So JS, Lee CG, Kwon HK, Yi HJ, Chae CS, Park JA, et al. Lactobacillus casei potentiates induction of oral tolerance in experimental arthritis. Molecular immunology. 2008 Nov 1;46(1):172-80. https://doi.org/10.1016/j.molimm.2008.07.038 PMid:18804867

23. Gohil P, Patel V, Deshpande S, Chorawala M, Shah G. Anti-arthritic activity of cell walls content of Lactobacillus plantarum in freund's adjuvant-induced arthritic rats: involvement of cellular inflammatory mediators and other biomarkers. Inflammopharmacology. 2018 Feb; 26:171-81. https://doi.org/10.1007/s10787-017-0370-z PMid:28685302

24. Vaghef-Mehrabany E, Homayouni-Rad A, Alipour B, Sharif SK, Vaghef-Mehrabany L, Alipour-Ajiry S. Effects of probiotic supplementation on oxidative stress indices in women with rheumatoid arthritis: a randomized double-blind clinical trial. Journal of the American College of Nutrition. 2016 May 18;35(4):291-9. https://doi.org/10.1080/07315724.2014.959208 PMid:25856220

25. Alipour B, Homayouni‐Rad A, Vaghef‐Mehrabany E, Sharif SK, Vaghef‐Mehrabany L, Asghari‐Jafarabadi M, et al. Effects of Lactobacillus casei supplementation on disease activity and inflammatory cytokines in rheumatoid arthritis patients: a randomized double‐blind clinical trial. International journal of rheumatic diseases. 2014 Jun;17(5):519-27. https://doi.org/10.1111/1756-185X.12333 PMid:24673738

26. Hatakka K, Martio J, Korpela M, Herranen M, Poussa T, Laasanen T, et al. Effects of probiotic therapy on the activity and activation of mild rheumatoid arthritis-a pilot study. Scandinavian journal of rheumatology. 2003 Aug 1;32(4):211-5. https://doi.org/10.1080/03009740310003695 PMid:14626627

27. Zamani B, Farshbaf S, Golkar HR, Bahmani F, Asemi Z. Synbiotic supplementation and the effects on clinical and metabolic responses in patients with rheumatoid arthritis: a randomised, double-blind, placebo-controlled trial. British journal of nutrition. 2017 Apr;117(8):1095-102. https://doi.org/10.1017/S000711451700085X PMid:28490394

28. Cannarella LA, Mari NL, Alcântara CC, Iryioda TM, Costa NT, Oliveira SR, et al. Mixture of probiotics reduces inflammatory biomarkers and improves the oxidative/nitrosative profile in people with rheumatoid arthritis. Nutrition. 2021 Sep 1; 89:111282. https://doi.org/10.1016/j.nut.2021.111282 PMid:34111674

29. Ermencheva P, Kotov G, Shumnalieva R, Velikova T, Monov S. Exploring the Role of the Microbiome in Rheumatoid Arthritis-A Critical Review. Microorganisms. 2024 Jul;12(7):1387. https://doi.org/10.3390/microorganisms12071387 PMid:39065155 PMCid:PMC11278530

30. Vossenaar ER, Zendman AJ, van Venrooij WJ, Pruijn GJ. PAD, a growing family of citrullinating enzymes: genes, features and involvement in disease. Bioessays. 2003 Nov;25(11):1106-18. https://doi.org/10.1002/bies.10357 PMid:14579251

31. Smit MD, Westra J, Vissink A, Doornbos-van der Meer B, Brouwer E, van Winkelhoff AJ. Periodontitis in established rheumatoid arthritis patients: a cross-sectional clinical, microbiological and serological study. Arthritis research & therapy. 2012 Oct; 14:1-0. https://doi.org/10.1186/ar4061 PMid:23075462 PMCid:PMC3580533

32. Quirke AM, Lugli EB, Wegner N, Hamilton BC, Charles P, Chowdhury M, Ytterberg AJ, et al. Heightened immune response to autocitrullinatedPorphyromonasgingivalispeptidylarginine deiminase: a potential mechanism for breaching immunologic tolerance in rheumatoid arthritis. Annals of the rheumatic diseases. 2014 Jan 1;73(1):263-9. https://doi.org/10.1136/annrheumdis-2012-202726 PMid:23463691 PMCid:PMC3888615

33. Liu X, Zeng B, Zhang J, Li W, Mou F, Wang H, Zou Q, et al. Role of the gut microbiome in modulating arthritis progression in mice. Scientific reports. 2016 Aug 2;6(1):30594. https://doi.org/10.1038/srep30594 PMid:27481047 PMCid:PMC4969881

34. 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. Nature medicine. 2015 Aug;21(8):895-905. https://doi.org/10.1038/nm.3914 PMid:26214836

35. Maeda Y, Kurakawa T, Umemoto E, Motooka D, Ito Y, Gotoh K, et al. Dysbiosis contributes to arthritis development via activation of autoreactive T cells in the intestine. Arthritis & rheumatology. 2016 Nov;68(11):2646-61. https://doi.org/10.1002/art.39783 PMid:27333153

36. Konig MF, Abusleme L, Reinholdt J, Palmer RJ, Teles RP, Sampson K, et al. Aggregatibacteractinomycetemcomitans-induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis. Science translational medicine. 2016 Dec 14;8(369):369ra176. https://doi.org/10.1126/scitranslmed.aaj1921 PMCid:PMC5384717

37. Scher JU, Ubeda C, Equinda M, Khanin R, Buischi Y, Viale A, et al. Periodontal disease and the oral microbiota in new‐onset rheumatoid arthritis. Arthritis & Rheumatism. 2012 Oct;64(10):3083-94. https://doi.org/10.1002/art.34539 PMid:22576262 PMCid:PMC3428472

38. Lopez‐Oliva I, Paropkari AD, Saraswat S, Serban S, Yonel Z, Sharma P, et al. Dysbioticsubgingival microbial communities in periodontally healthy patients with rheumatoid arthritis. Arthritis & Rheumatology. 2018 Jul;70(7):1008-13. https://doi.org/10.1002/art.40485 PMid:29513935 PMCid:PMC6019644

39. Giachetto PF, Cunha RC, Nhani Jr A, Garcia MV, Ferro JA, Andreotti R. Gene expression in the salivary gland of Rhipicephalus (Boophilus) microplus fed on tick-susceptible and tick-resistant hosts. Frontiers in Cellular and Infection Microbiology. 2020 Jan 21; 9:477. https://doi.org/10.3389/fcimb.2019.00477 PMid:32039052 PMCid:PMC6985549

40. Rothschild D, Weissbrod O, Barkan E, Kurilshikov A, Korem T, Zeevi D, et al. Environment dominates over host genetics in shaping human gut microbiota. Nature. 2018 Mar;555(7695):210-5. https://doi.org/10.1038/nature25973 PMid:29489753

41. Kolodziejczyk AA, Zheng D, Elinav E. Diet-microbiota interactions and personalized nutrition. Nature Reviews Microbiology. 2019 Dec;17(12):742-53. https://doi.org/10.1038/s41579-019-0256-8 PMid:31541197

42. Petersson S, Philippou E, Rodomar C, Nikiphorou E. The Mediterranean diet, fish oil supplements and Rheumatoid arthritis outcomes: Evidence from clinical trials. Autoimmunity reviews. 2018 Nov 1;17(11):1105-14. https://doi.org/10.1016/j.autrev.2018.06.007 PMid:30213690

43. Watson JE, Kim JS, Das A. Emerging class of omega-3 fatty acid endocannabinoids & their derivatives. Prostaglandins & other lipid mediators. 2019 Aug 1; 143:106337. https://doi.org/10.1016/j.prostaglandins.2019.106337 PMid:31085370 PMCid:PMC6685292

44. Chasov, V., Gilyazova, E., Ganeeva, I., Zmievskaya, E., Davletshin, D., Valiullina, A., &Bulatov, E. (2024). Gut Microbiota Modulation: A Novel Strategy for Rheumatoid Arthritis Therapy. Biomolecules, 14(12), 1653. https://doi.org/10.3390/biom14121653 PMid:39766360 PMCid:PMC11674688

45. Gioxari A, Kaliora AC, Marantidou F, Panagiotakos DP. Intake of ω-3 polyunsaturated fatty acids in patients with rheumatoid arthritis: A systematic review and meta-analysis. Nutrition. 2018 Jan 1; 45:114-24. https://doi.org/10.1016/j.nut.2017.06.023 PMid:28965775

46. Jiang J, Li K, Wang F, Yang B, Fu Y, Zheng J, et al. Effect of marine-derived n-3 polyunsaturated fatty acids on major eicosanoids: a systematic review and meta-analysis from 18 randomized controlled trials. PloS one. 2016 Jan 25;11(1): e0147351. https://doi.org/10.1371/journal.pone.0147351 PMid:26808318 PMCid:PMC4726565

47. Hoxha M. A systematic review on the role of eicosanoid pathways in rheumatoid arthritis. Advances in medical sciences. 2018 Mar 1;63(1):22-9. https://doi.org/10.1016/j.advms.2017.06.004 PMid:28818745

48. Lee YH, Bae SC, Song GG. Omega-3 polyunsaturated fatty acids and the treatment of rheumatoid arthritis: a meta-analysis. Archives of medical research. 2012 Jul 1;43(5):356-62. https://doi.org/10.1016/j.arcmed.2012.06.011 PMid:22835600

49. Abdulrazaq M, Innes JK, Calder PC. Effect of ω-3 polyunsaturated fatty acids on arthritic pain: A systematic review. Nutrition. 2017 Jul 1; 39:57-66. https://doi.org/10.1016/j.nut.2016.12.003 PMid:28606571

50. Berbert AA, Kondo CR, Almendra CL, Matsuo T, Dichi I. Supplementation of fish oil and olive oil in patients with rheumatoid arthritis. Nutrition. 2005 Feb 1;21(2):131-6. https://doi.org/10.1016/j.nut.2004.03.023 PMid:15723739

51. Conaghan PG, Hensor EM, Keenan AM, Morgan AW, Emery P, YEAR Consortium. Persistently moderate DAS-28 is not benign: loss of function occurs in early RA despite step-up DMARD therapy. Rheumatology. 2010 Oct 1;49(10):1894-9. https://doi.org/10.1093/rheumatology/keq178 PMid:20542894

52. McKellar G, Morrison E, McEntegart A, Hampson R, Tierney A, Mackle G, et al. A pilot study of a Mediterranean-type diet intervention in female patients with rheumatoid arthritis living in areas of social deprivation in Glasgow. Annals of the rheumatic diseases. 2007 Sep 1;66(9):1239-43. https://doi.org/10.1136/ard.2006.065151 PMid:17613557 PMCid:PMC1955146

53. Sköldstam L, Hagfors L, Johansson G. An experimental study of a Mediterranean diet intervention for patients with rheumatoid arthritis. Annals of the rheumatic diseases. 2003 Mar 1;62(3):208-14. https://doi.org/10.1136/ard.62.3.208 PMid:12594104 PMCid:PMC1754463