Received: October 19, 2025
Accepted: October 27, 2025
Publication Date: December 1, 2025

Cite this article as: Şahin N, Salbaş E. The gut-joint connection: Microbiome’s role in rheumatic disease. Arch Rheumatol. 2025; 40(4):413-421.

Abstract

The human gut microbiome is a pivotal regulator of systemic immunity and a central factor in the pathogenesis of rheumatic diseases. An imbalance in this microbial community, known as “dysbiosis,” can trigger and perpetuate autoimmune responses through the “gut-joint axis.” A key mechanism underpinning this connection is increased intestinal permeability (“leaky gut”), which facilitates the translocation of microbial products like lipopolysaccharide into the systemic circulation, thereby provoking chronic inflammation. Concurrently, dysbiosis disrupts the critical homeostatic balance between pro-inflammatory Th17 cells and regulatory T cells, an immunological hallmark of conditions such as rheumatoid arthritis (RA), ankylosing spondylitis, and systemic lupus erythematosus (SLE).

Specific microbial signatures, including the expansion of Prevotella copri in RA and Ruminococcus gnavus in SLE, are emerging as potential diagnostic biomarkers. This deeper understanding is paving the way for innovative therapeutic strategies. Interventions aimed at modulating the gut microbiota, such as targeted diets, probiotics, prebiotics and fecal microbiota transplantation, represent a promising frontier for the personalized management of rheumatic diseases. This review explores the foundational mechanisms linking the microbiome to autoimmunity and discusses the clinical potential of harnessing the gut-joint axis to improve patient outcomes.

Keywords: Arthritis, autoimmune disease, dysbiosis, gut-joint axis, intestinal permeability, microbiome, rheumatology, Th17, Treg balance

Introduction and Basic Mechanisms

The human body harbors an ecosystem comprising human cells alongside bacteria, archaea, viruses, and fungi, termed the human microbiome.¹^-³ The majority of the microbial load resides in the large intestine, hosting >1500 species across >50 phyla, with Bacteroidetes and Firmicutes constituting the bulk of adult gut bacteria.¹^,⁴^,⁵ The microbiota maintains a symbiotic “eubiosis” balance with the host, performing metabolic, protective, and immune-regulatory functions: fermentation of fibers, vitamin synthesis, and short-chain fatty acid (SCFA) production; prevention of pathogen colonization and support of barrier integrity; and education of mucosal immune responses are among the primary ones.¹^,³^,⁶^-⁸ These mutual interactions have heightened interest in the microbiome’s role in the etiology of autoimmune and rheumatic diseases.¹^,²^,⁸^-¹³

Barrier Integrity and “Leaky Gut”

Tight junctions in the intestinal epithelium limit passage from the lumen to systemic circulation; disruption of zonulin-mediated regulation increases permeability, allowing microbial products such as lipopolysaccharide (LPS) to leak and elevate tumor necrosis factor-α (TNF-α)/Interleukin-6 (IL-6) production via the TLR4–MyD88 pathway, thereby amplifying systemic inflammation.³^,⁹^,¹⁴^-²⁰ In ankylosing spondylitis (AS), epithelial and vascular barrier disruption with elevated zonulin levels has been reported; similarly, increased permeability consistent with dysbiosis has been noted in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE).²¹^-²⁵ This barrier dysfunction contributes to microbial product leakage and peripheral immune tolerance breakdown, supporting autoantigenic stimulation and heightened immune signaling⁹ (Figure 1).

Figure 1.

Dysbiotic gut microbiota and the gut-joint axis mechanism in rheumatic diseases. Schematic representation of the gut-joint axis linking intestinal dysbiosis to systemic inflammation and joint destruction in rheumatic diseases. The illustration depicts the intestinal lumen densely populated by microbial communities. Dysbiosis—characterized by increased Prevotella, Collinsella, Ruminococcus, Clostridioides difficile, and Porphyromonas gingivalis alongside decreased Faecalibacterium, Bifidobacterium, and Lactobacillus—leads to disruption of the intestinal epithelial barrier (“leaky gut”). This increased permeability allows microbial products such as lipopolysaccharides (LPS) to enter the lamina propria and circulation, activating dendritic cells and macrophages via pro-inflammatory cytokines (e.g., IL-6, IL-1β, TNF-α, IL-23). The resulting skew toward Th17 differentiation (via IL-23 and IL-17 signaling) and reduced regulatory Tactivity promotes osteoclastogenesis, synovial inflammation, and bone destruction in joints. The figure integrates intestinal, immune, and skeletal compartments, illustrating the central mechanistic pathway by which gut dysbiosis contributes to rheumatic disease pathogenesis.

Helper T 17/Regulatory T Balance

The gut microbiota regulates the balance between helper T 17 (Th17) and regulatory T (Treg) cells, which play a central role in the pathogenesis of rheumatic diseases.¹⁴^,²⁶^-²⁹ The Th17 cells produce IL-17 to promote autoimmune inflammation, whereas Treg cells maintain immune tolerance. Gut dysbiosis disrupts this balance. For instance, segmented filamentous bacteria colonization activates Th17 cells, whereas certain commensals like Bacteroides fragilis can restore equilibrium.¹⁴^,²⁸^,³⁰ The SCFAs, particularly butyrate, support Treg cell formation, exerting immunomodulatory effects and limiting autoimmune responses. This Th17/Treg imbalance is a fundamental feature of many autoimmune diseases, including RA, SLE, and AS.¹⁴^,²⁸^,³¹^-³⁶

Microbial Metabolites

Molecules produced by the microbiota, such as SCFAs, tryptophan metabolites, and bile acids, profoundly influence host physiology and immune responses.⁶^,¹²^,³⁷ Short-chain fatty acids, generated from dietary fiber fermentation, include butyrate, which possesses potent anti-inflammatory properties. Butyrate mitigates inflammation and bone loss in conditions like osteoarthritis (OA), AS, and RA by regulating Treg cells and improving gut barrier function.⁷^,¹²^,³¹^,³⁴^,³⁶^-⁴⁰ Indoles from tryptophan metabolism act via the aryl hydrocarbon receptor (AhR) in immune modulation.¹⁸^,⁴¹^-⁴³ In patients with RA, anti-inflammatory tryptophan metabolites decrease, whereas pro-inflammatory metabolites increase.¹⁸

Main Points

In the pathogenesis of rheumatic diseases, an imbalance in the gut microbiota (dysbiosis) is not just a consequence but also a central triggering factor.
Increased intestinal permeability (“leaky gut”) is a key mechanism leading to the entry of microbial products (e.g., lipopolysaccharide) into the systemic circulation and triggering chronic inflammation.
The microbiome modulates the sensitive balance between pro-inflammatory (Th17) and anti-inflammatory regulatory T cells in the immune system, and disruption of this balance intensifies autoimmune responses.
The “gut-joint axis” concept explains how events in the gut directly affect joint health through systemic inflammation, immune cell migration, and microbial metabolites.
Targeting the microbiome offers significant potential for innovative and personalized treatment strategies, including diet, probiotics, prebiotics and fecal microbiota transplantation (FMT).

Molecular Mimicry

This mechanism triggers autoimmunity through the structural resemblance between microbial antigens and host proteins.³⁸^,⁴⁴^,⁴⁵ For example, enolase produced by Porphyromonas gingivalis, which is associated with RA, can elicit autoimmunity against human enolase.⁴⁴^,⁴⁶ Similarly, strains of Ruminococcus gnavus linked to SLE may initiate cross-reactive immune responses against host double-stranded DNA (dsDNA).¹⁴ Aggregatibacter actinomycetemcomitans induces citrullination, linking periodontal infection to RA autoimmunity.⁴⁵ This illustrates how even normal microbial community members can prompt the immune system to attack the host tissues.

Gut-Joint Axis

This concept denotes a bidirectional relationship between the gut microbiota and joint health.⁵^,⁴⁶^,⁴⁷ Gut microbiota dysbiosis contributes to the development of various joint diseases, including RA, AS, psoriatic arthritis (PsA), and OA.⁵^,⁴⁸^-⁵¹ The axis functions through mechanisms like systemic inflammation from leaky gut, circulation of microbial metabolites like SCFAs to joints, and migration of gut-activated immune cells to joints.⁷^,¹⁹^,⁵²^,⁵³ In germ-free (microbe-free) animal models, particularly HLA-B27 transgenic mice, the prevention of gut and joint inflammation strongly supports the central role of the microbiota in these diseases.¹⁷^,⁴⁴^,⁵⁴^,⁵⁵

Inflammatory Arthritides and Microbiome Dysbiosis

Evidence is mounting that imbalances in the gut and oral microbiota play critical roles in the pathogenesis of inflammatory arthritides. Microbiome dysbiosis is strongly associated with the onset and progression of these diseases (Table 1).²⁶^,⁴⁵^,⁵⁰

**Table 1** Summary of Microbiota Changes in Rheumatic Diseases
Disease	Increased Bacteria in Disease	Decreased Bacteria in Disease	Potential Mechanisms and Effects
Rheumatoid arthritis (RA)	Prevotella copri, Porphyromonas gingivalis (oral), Aggregatibacter actinomycetemcomitans	Faecalibacterium prausnitzii, Roseburia, Bifidobacterium	Molecular mimicry (citrullination, ACPA production), Th17 increase, increased intestinal permeability, systemic inflammation
Ankylosing spondylitis (AS)	Ruminococcus gnavus, Klebsiella pneumoniae, Staphylococcus, Escherichia, Streptococcus	Dialister, Lachnoclostridium, Oscillibacter, Faecalibacterium, Roseburia	IL-23/IL-17 activation, leaky gut, subclinical gut inflammation, HLA-B27 association
Psoriatic arthritis (PsA)	Actinobacteria (Megamonas), Howardella, Methanobrevibacter, Sutterella	Rikenellaceae, Eubacterium brachy, Bacteroidales	IBD-like dysbiosis, IL-17 increase, reduced bacterial diversity, modulation with tofacitinib
Systemic lupus erythematosus (SLE)	Ruminococcus gnavus, Bacteroides thetaiotaomicron, Ruminococcus intestinalis, Akkermansia muciniphila	Firmicutes (general decrease), Odoribacter splanchnicus, Bacteroides fragilis	Molecular mimicry (dsDNA cross-reaction), Th17/Treg imbalance, leaky gut, IFN-I dysregulation
Sjögren’s syndrome (SS)	Lactobacillus salivarius, Bacteroides fragilis, Ruminococcus gnavus, Streptococcus parasanguinis	Faecalibacterium, Haemophilus parainfluenzae, Roseburia	Oral/intestinal dysbiosis, Th17 increase, anti-inflammatory SCFA decrease, systemic activity association
Systemic sclerosis (SSc)	Fusobacterium, Ruminococcus, Erwinia, Eggerthella lenta, Clostridium bolteae	Bacteroidetes (general decrease), Faecalibacterium, Clostridium	Th17 induction, homocysteine production, leaky gut, vasculopathy and inflammation
Osteoarthritis (OA)	Firmicutes (increase), Bilophila, Desulfovibrio, Streptococcus	Roseburia, Bacteroidetes (general decrease), Bacteroides acidifaciens (in non-obese)	LPS leakage, metaflammation, SCFA imbalance (acetic acid increase), joint destruction
Gout disease	Proteobacteria (increase), Verrucomicrobia	Firmicutes (decrease), Bifidobacterium	Uric acid metabolism disruption, purine metabolism abnormalities, alpha diversity decrease

Rheumatoid Arthritis and Microbiome Dysbiosis

In RA, autoimmune responses are thought to originate from the mucosal surfaces.²⁸ Patients with RA exhibit a profile in both oral and gut microbiota characterized by reduced beneficial bacteria and increased pro-inflammatory bacteria.⁹

Gut Dysbiosis: Increased Prevotella copri and Decreased Faecalibacterium prausnitzii:

In RA patients, particularly those with new-onset RA, an increase in Prevotella copri has been observed.²⁸^,³⁰ P. copri is identified as a pro-inflammatory bacterium that exacerbates arthritis in experimental models and promotes T-cell differentiation into Th17 cells, fueling systemic inflammation.²⁷^,²⁸^,³⁶^,⁵⁶^,⁵⁷ Conversely, beneficial bacteria like Faecalibacterium prausnitzii, which possess anti-inflammatory properties and produce butyrate, are decreased.¹⁵^,²⁵^,⁵⁸ Faecalibacterium prausnitzii has been shown to alleviate inflammatory arthritis in experimental models.²⁷^,⁵⁰^,⁵⁹ This imbalance can lead to impaired gut barrier function and systemic inflammation.¹⁰^,¹⁵^,²⁰^,²⁶

Oral Microbiome: Role of Porphyromonas gingivalis, Citrullination, and anti-citrullinated protein Antibodies:

The oral microbiome, particularly through periodontal diseases, plays a significant role in RA pathogenesis.⁶⁰^,⁶¹ Porphyromonas gingivalis, a key pathogen in periodontal disease, is associated with RA onset.⁴⁴ This bacterium citrullinates proteins via its unique microbial peptidylarginine deiminase enzyme, triggering the production of anti-citrullinated protein antibodies (ACPA).⁴⁴^,⁵⁴^,⁶¹ These ACPAs cross-react with human citrullinated peptides, thereby initiating autoimmunity.⁴⁴ The ACPA-positive individuals have an increased risk of RA, often accompanied by a dysbiotic oral microbiome with elevated levels of P. gingivalis.⁹^,³⁸^,⁴⁵

Axial Spondyloarthritis, Psoriatic Arthritis, and Microbiome Dysbiosis

Axial spondyloarthritis (AxSpA) and PsA are inflammatory arthritides closely linked to the gut microbiome. There is a strong clinical and genetic connection between these diseases and inflammatory bowel disease (IBD).²²^,⁶²^,63 Dysbiotic features observed in patients with IBD, such as reduced phylogenetic diversity, lower Firmicutes proportion and particularly decreased F. prausnitzii, are also seen in patients with PsA.⁹^,³⁴^,⁵⁴^,⁶²^,⁶³

Subclinical gut inflammation is common in patients with AxSpA and PsA. HLA-B27 transgenic rats do not develop inflammation under germ-free conditions, suggesting that commensal bacteria are triggers.¹⁷^,³⁶^,⁴⁴^,⁵⁵ The IL-23/IL-17 signaling pathway plays a central role in AxSpA pathogenesis, and microbial signals can activate this pathway.³⁵^,³⁶^,³⁹^,⁶² Microbiota dysbiosis drives immune dysregulation by shifting T cell differentiation toward a Th17-dominant phenotype and increasing IL-17 production.²⁷^,⁶⁴ Specific microbial differences have been identified in both AxSpA and PsA;

Axial spondyloarthritis: Reduced bacterial diversity³⁹^,⁴⁴^,⁵⁷ with increased abundance of genera such as Klebsiella, R. gnavus, and Streptococcus and decreased abundance of Dialister and Faecalibacterium.³⁹^,⁴⁴^,⁵⁵^,⁵⁷^,⁶⁵ Additionally, Proteobacteria and Pasteurellaceae levels were normalized after TNF inhibitor therapy.⁶⁶
Psoriatic arthritis: Reduced bacterial diversity, similar to IBD.⁹^,³⁴^,⁵⁴^,62 Increased Actinobacteria phylum and decreased Rikenellaceae family.⁴⁹^,⁶³

Evidence in Other Diseases

Systemic Lupus Erythematosus

Patients with SLE exhibit marked changes in the gut microbiota, with a decreased abundance of Firmicutes and an increased abundance of Bacteroidetes.²⁸ Notably, R. gnavus abundance increases during active disease periods and correlates with disease activity.⁹^,¹⁴^,²⁸^,⁴⁴ Antibodies against R. gnavus may cross-react with host DNA, triggering anti-dsDNA antibody responses.¹⁴^,²⁸ Increased intestinal permeability and abnormalities in Type I interferon production are key contributors to SLE pathogenesis.⁹^,¹⁴^,³⁴^,⁶⁷

Sjögren’s Syndrome

Sjögren’s syndrome (SS) is associated with distinct changes in both oral and intestinal microbiota.¹³^,⁶⁸^,⁶⁹ Oral dysbiosis in the oral microbiota⁴⁵^,⁷⁰ and severe dysbiosis in the gut microbiota are common and correlate with systemic disease activity.²⁵^,⁶⁸^,⁶⁹ Similar to RA and SLE, SS shows common alterations like decreased anti-inflammatory butyrate-producing bacteria (e.g., Faecalibacterium) and increased pro-inflammatory bacteria (e.g., Streptococcus).²⁵

Systemic Sclerosis

In systemic sclerosis (SSc), a unique gut microbial composition is identified, with decreased protective butyrate-producing bacteria and increased harmful genera like Fusobacterium.²⁵^,³⁷ Increased intestinal permeability may also play a role in the pathogenesis of SSc.²⁵^,³⁷^,⁷¹

Vasculitides and Metabolic Diseases

Children with IgA vasculitis (HSP) have been found to have increased abundance of Fusobacteria and decreased abundance of Firmicutes.⁷² Behçet’s disease shows changes toward increased abundance of Bifidobacteria in the gut.²¹ Osteoarthritis, traditionally considered non-inflammatory, is now linked to low-grade systemic inflammation (metaflammation) and gut microbiota. Leaked LPS from the gut can initiate obesity-related inflammation, worsening OA progression.¹⁹^,⁴⁶^,⁷³ In Gout, the microbiome’s impact on purine metabolism and uric acid levels is under investigation, with reduced microbial diversity observed in patients.²⁵^,⁷⁴

Factors Influencing the Microbiome: Diet, Lifestyle, and Medications

Understanding the factors that shape the composition and function of the microbiome can offer new strategies for disease management. These factors primarily include diet, lifestyle, and medications.²^,¹²^,⁷⁵

Diet and Metabolism: Primary Shapers of the Microbiome

Diet is one of the most potent environmental factors that can rapidly alter the gut microbiota composition.²^,³⁰^,⁷⁶ Western-style diets that are low in fiber and high in fat can lead to pro-inflammatory changes by reducing butyrate-producing bacteria.²⁸^,³⁹^,⁴² In contrast, fiber-rich diets (prebiotics) and fermented foods (probiotics) enhance SCFA production and modulate the immune system, providing benefits.¹¹^,¹²^,³¹^,³⁶^,⁶⁸ Particularly, butyrate can inhibit systemic inflammation by activating Treg cells and strengthening the gut barrier.³²^,⁴⁵^,⁷²^,⁷⁷ Strategies such as fecal microbiota transplantation (FMT) also hold promise for correcting dysbiosis.¹³^,¹⁴^,⁴⁴^,⁷⁵^,⁷⁶^,⁷⁸

Lifestyle and Medications: Interactions on the Microbiome

Smoking can contribute to oral microbiome dysbiosis,³³^,⁴⁴ while chronic stress adversely affects the gut-brain axis.⁴³^,⁴⁷^,⁷⁹^,⁸⁰ Medications have a strong effect on the microbiome. Antibiotics are the most potent agents that alter microbiota composition and diversity.²^,⁸^,¹⁸^,²⁸^,³⁰^,⁵⁴ Nonsteroidal anti-inflammatory drugs and proton pump inhibitors can damage the gut barrier and alter the microbiome composition, contributing to inflammation.²²^,³⁹^,⁵⁴^,⁸¹^-⁸³ Disease-modifying antirheumatic drugs and biologics can modulate the microbiome. For example, methotrexate and sulfasalazine may reduce the levels of B. fragilis and Enterobacteriaceae in the gut.²⁶ The TNF inhibitors can increase microbiota diversity in patients with AS, approximating a healthy profile.¹⁷^,³⁶^,³⁹^,⁶⁶^,⁷¹ Janus kinase inhibitors, such as tofacitinib, are associated with significant changes in certain gut bacterial lineages in patients with PsA and may exert therapeutic effects by modulating plasma metabolites and the gut microbiota.²³^,⁶³

Microbiome Research in Special Populations, Pain, Virome, and Cardiovascular Comorbidities

Microbiome research extends beyond bacteria to include viruses (virome) and fungi (mycobiome), which broadens the understanding of disease pathogenesis.

The microbiome shaped during early life is critical for immune system development.⁵⁴ Marked dysbiosis in both oral and gut microbiota has been observed in childhood autoimmune diseases, such as juvenile idiopathic arthritis (JIA). Notably, reductions in beneficial butyrate-producing bacteria, such as F. prausnitzii, highlight the potential of microbiome-based approaches in JIA treatment.⁸⁴

In chronic pain conditions like fibromyalgia (FMS), the gut microbiome plays a critical role in pathogenesis via the “gut-brain axis.”⁴⁷^,80 Metabolites produced by gut microbes, such as SCFAs, can directly or indirectly influence the central nervous system and modulate pain perception. This may be a common denominator in comorbid conditions like FMS, chronic fatigue syndrome, and irritable bowel syndrome.⁴⁷^,⁸⁰

The unseen aspects of the microbiome, including the virome and mycobiome, also contribute to autoimmunity. Viruses like Epstein-Barr virus may initiate autoimmune responses through molecular mimicry.¹⁴^,⁴⁴^,⁴⁵ Similarly, changes in gut fungal composition (mycobiome) are thought to play a role in diseases like IBD and modulate immune responses.¹⁵^,⁷⁶

Cardiovascular Comorbidities in Rheumatic Diseases

Rheumatic diseases often co-occur with cardiovascular diseases due to systemic effects of chronic inflammation.⁸⁰ This systemic inflammation is closely linked to endothelial cell activation and atherosclerosis.³⁷ The ability of the microbiome to modulate inflammatory responses is a key mechanism linking rheumatic diseases and cardiovascular comorbidities.

Role of Animal Models in Understanding Mechanisms and Limitations in Translation to Human Studies

Animal models, particularly gnotobiotic models (germ-free or colonized with known microorganisms), are indispensable for studying host-microorganism interactions.⁵⁴ For instance, destabilization of the medial meniscus mouse models demonstrated that gut microbiome dysbiosis accelerates OA progression.¹⁹ Experiments using “humanized” germ-free SKG mice with human gut microbiota revealed that protein tyrosine phosphatase non-receptor type 2 haploinsufficiency variably exacerbates mannan-induced arthritis when colonized with feces from RA patients, showing increased T cell-driven inflammation in the joints.²⁴ Similarly, dextran sulfate sodium-induced colitis models and collagen-induced arthritis models are used to examine the effects of microbiota on inflammation.⁵⁰^,⁸⁵

However, translating the findings from animal models to humans faces significant limitations. The most prominent constraint is the difference in bacterial composition between humans and animals.¹⁹ Additionally, host genetics and environmental factors may not fully reflect the complex disease phenotypes seen in humans.⁷⁵ Thus, while animal models are critical for mechanistic insights, rigorous human studies are essential for clinical application.⁷⁵

Clinical Horizons and Conclusion

The microbiome has emerged as a potential biomarker source for disease diagnosis, prognosis prediction, and treatment response determination. For example, the microbiome composition in patients with FMS can be distinguished from that in healthy individuals with high accuracy.⁵⁶ Distinct microbiota and metabolite profiles have been identified among different uveitis types.²¹ Specific bacterial species like Bacteroides caecimuris, Mediterranea massilliensis, Bacteroides coprophilus, Clostridium_sp_7_3_54FAA and Bifidobacterium bifidum may aid in differentiating patients with SS from healthy individuals and correlate with disease severity.¹³ In patients with AS, species such as R. gnavus could serve as markers, with TNF inhibitor therapy shifting the microbiome toward a healthy profile.³⁹^,⁶⁶

However, most current studies are correlational and insufficient to prove causality.¹³^,⁵⁶ Methodological variations and population heterogeneity also limit generalizability.¹³^,³⁹^,⁵⁶

Therapeutic strategies, including dietary interventions, prebiotics, probiotics, postbiotics (SCFAs), and FMT, show promise. Probiotics have demonstrated the potential to improve inflammation and symptoms.¹⁴^,¹⁵^,⁴⁷^,⁵⁰^,⁶⁷^,⁷⁹^,⁸⁶ SCFAs, such as butyrate, have been shown to reverse bone loss and reduce inflammation in animal models.²^,³⁶^,⁴⁷^,⁶⁶ The FMT, proven effective in Clostridioides difficile infections, also yields encouraging results in autoimmune diseases such as SLE and RA.¹³^,¹⁴^,²⁸^,⁸⁷

The greatest challenges in fully harnessing the microbiome in clinical practice include distinguishing causality from correlation, overcoming inter-study heterogeneity, and understanding each individual’s unique microbiome structure.¹³^,⁴³^,⁴⁹^,⁵⁶ In the future, personalized treatment strategies that integrate microbiota profiling, host genetics, and other factors could redefine therapeutic paradigms for rheumatic and other chronic diseases.²^,⁴⁷

In conclusion, the gut microbiota is an indispensable player in human health and disease. As knowledge in this field translates to clinical practice, it holds immense potential for the diagnosis, prognosis, and treatment of diseases. Future research should facilitate the integration of microbiome-based therapies into clinical routines using personalized and targeted strategies. The microbiome opens doors to a new era of a healthier future in medicine.

Data Availability Statement:

The data that support the findings of this study are available on request from the corresponding author.

Peer-review: Externally peer-reviewed.

Author Contributions: Concept – E.S., N.Ş.; Design – E.S., N.Ş.; Supervision – N.Ş.; Resources – E.S.; Materials – E.S.; Data Collection and/or Processing – E.S.; Analysis and/or Interpretation – E.S.; Literature Search – E.S.; Writing – E.S., N.Ş.; Critical Review – E.S., N.Ş.

Declaration of Interests: The authors have no conflicts of interest to declare.

Funding: The authors declare that this study received no financial support.

References

1. Song Z, Song R, Liu Y, Wu Z, Zhang X. Effects of ultra-processed foods on the microbiota-gut-brain axis: the bread-and-butter issue. Food Res Int. 2023;167:112730. [CrossRef]

2. La Placa G, Covino M, Candelli M, Gasbarrini A, Franceschi F, Merra G. The impact of microbiota on musculoskeletal injuries. Cells. 2025;14(7):554. [CrossRef]

3. Saponaro F, Bertolini A, Baragatti R, et al. Myokines and microbiota: new perspectives in the endocrine muscle-gut axis. Nutrients. 2024;16(23):4032. [CrossRef]

4. Rooney CM, Jeffery IB, Mankia K, Wilcox MH, Emery P. Dynamics of the gut microbiome in individuals at risk of rheumatoid arthritis: a cross-sectional and longitudinal observational study. Ann Rheum Dis. 2024:ard-2024-226362. [CrossRef]

5. Gilat R, Yazdi AA, Weissman AC, et al. The gut microbiome and joint microbiome show alterations in patients with knee osteoarthritis versus controls: A systematic review. Arthroscopy. 2025;41(4):1226-1238. [CrossRef]

6. Ciancarelli I, Morone G, Iosa M, Cerasa A, Calabrò RS, Tozzi Ciancarelli MG. Neuronutrition and its impact on post-stroke neurorehabilitation: modulating plasticity through diet. Nutrients. 2024;16(21):3705. [CrossRef]

7. Ran C, Xu Y, Wang Q, et al. Gut microbiota from osteoarthritic patients without obesity aggravates osteoarthritis progression in rats by enriching acetic acid. Microb Pathog. 2025;207:107911. [CrossRef]

8. Veseli I, Chen YT, Schechter MS, et al. Microbes with higher metabolic independence are enriched in human gut microbiomes under stress. Elife. 2025;12:RP89862. [CrossRef]

9. Amarnani A, Silverman GJ. Understanding the roles of the microbiome in autoimmune rheumatic diseases. Rheumatol Immunol Res. 2023;4(4):177-187. [CrossRef]

10. Li Z, Wen M, Tang C, et al. Gut microbiota orchestrates skeletal muscle development and metabolism in germ-free and SPF pigs. Front Microbiol. 2025;16:1615884. [CrossRef]

11. Tran M, Huh JR, Devlin AS. The role of gut microbial metabolites in the T cell lifecycle. Nat Immunol. 2025;26(8):1246-1257. [CrossRef]

12. Yang W, Cong Y. Gut microbiota-derived metabolites in the regulation of host immune responses and immune-related inflammatory diseases. Cell Mol Immunol. 2021;18(4):866-877. [CrossRef]

13. Belvoncikova P, Maronek M, Gardlik R. Gut dysbiosis and fecal microbiota transplantation in autoimmune diseases. Int J Mol Sci. 2022;23(18):10729. [CrossRef]

14. Mo C, Bi J, Li S, et al. The influence and therapeutic effect of microbiota in systemic lupus erythematosus. Microbiol Res. 2024;281:127613. [CrossRef]

15. Jena PK, Wakita D, Gomez AC, et al. Intestinal microbiota contributes to the development of cardiovascular inflammation and vasculitis in mice. Circ Res. 2025;136(8):e53-e72. [CrossRef]

16. Long A, Kleiner A, Looney RJ. Immune dysregulation. J Allergy Clin Immunol. 2023;151(1):70-80. [CrossRef]

17. Scher JU, Nayak R, Clemente JC. Microbiome research in autoimmune and immune-mediated inflammatory diseases: lessons, advances and unmet needs. Ann Rheum Dis. 2025;84(1):9-13. [CrossRef]

18. Moulin D, Millard M, Taïeb M, et al. Counteracting tryptophan metabolism alterations as a new therapeutic strategy for rheumatoid arthritis. Ann Rheum Dis. 2024;83(3):312-323. [CrossRef]

19. Liu S, Xu H, Liu L, et al. Gut microbiome dysbiosis accelerates osteoarthritis progression by inducing IFP-SM inflammation in "double-hit" mice. Arthritis Res Ther. 2025;27(1):137. [CrossRef]

20. Naveed M, Atta A, Rui B, et al. Combination of Withania coagulans and Fagonia cretica ameliorates hyperuricemia by re-modulating gut microbiota-derived spermidine and traumatic acid. Phytomedicine. 2025;145:157079. [CrossRef]

21. Liu M, Li M, Jin S, Wang X, Geng J, Liu X. Differential intestinal microbes and metabolites between Behcet's uveitis and Fuchs syndrome. Heliyon. 2024;10(20):e39393. [CrossRef]

22. Rashid M, Pereira HS, Alissa A, et al. Microbiome dysbiosis in spinal pathology: mechanisms, evidence, and research limitations. Brain Spine. 2025;5:104272. [CrossRef]

23. Wang X, Sun C, Yang X, et al. Exploring the potential mechanism of tofacitinib therapy for ankylosing spondylitis through gut microbiome and plasma metabolomics. Clin Rheumatol. 2025;44(7):2793-2808. [CrossRef]

24. Sendo S, Vela AJ, Ro M, et al. Interaction between haploinsufficiency of PTPN2 and patient microbiome promotes autoimmune arthritis in mice. J Autoimmun. 2025;156:103452. [CrossRef]

25. Wang Y, Wei J, Zhang W, et al. Gut dysbiosis in rheumatic diseases: A systematic review and meta-analysis of 92 observational studies. EBioMedicine. 2022;80:104055. [CrossRef]

26. Godha Y, Kumar S, Wanjari A. Role of gut microbiota in the development and management of rheumatoid arthritis: A narrative review. Cureus. 2023;15(11):e49458. [CrossRef]

27. Jin J, Cai X, Rao P, Xu J, Li J. Microbiota and immune dynamics in rheumatoid arthritis: mechanisms and therapeutic potential. Best Pract Res Clin Rheumatol. 2025;39(1):102035. [CrossRef]

28. Miyauchi E, Shimokawa C, Steimle A, Desai MS, Ohno H. The impact of the gut microbiome on extra-intestinal autoimmune diseases. Nat Rev Immunol. 2023;23(1):9-23. [CrossRef]

29. Shin YH, Bang S, Xavier R, Clardy J. Eggerthella lenta produces a cryptic pro-inflammatory lipid. J Am Chem Soc. 2025;147(29):25180-25183. [CrossRef]

30. Xu X, Zhou J, Xie H, et al. Immunomodulatory mechanisms of the gut microbiota and metabolites on regulatory T cells in rheumatoid arthritis. Front Immunol. 2025;16:1610254. [CrossRef]

31. Christovich A, Luo XM. Gut microbiota, leaky gut, and autoimmune diseases. Front Immunol. 2022;13:946248. [CrossRef]

32. Habiballah DN, Li F, Jiang L. Immune metabolic restoration in systemic lupus erythematosus: the impact of gut microbiota, probiotics, and nutritional synergy. Front Immunol. 2025;16:1602235. [CrossRef]

33. Mattos MCO, Vivacqua A, Carneiro VMA, Grisi DC, Guimarães MDCM. Interaction of the systemic inflammatory state, inflammatory mediators, and the oral microbiome. Adv Exp Med Biol. 2025;1472:121-132. [CrossRef]

34. Wang X, Yuan W, Yang C, et al. Emerging role of gut microbiota in autoimmune diseases. Front Immunol. 2024;15:1365554. [CrossRef]

35. Yang L, Wang K, Liu B, et al. Dysbiosis of gut microbiota in ankylosing spondylitis patients. J Inflamm Res. 2025;18:7841-7854. [CrossRef]

36. You K, Yang L, Su Z, et al. Butyric acid modulates gut microbiota to alleviate inflammation and secondary bone loss in ankylosing spondylitis. Biomedicines. 2024;13(1):9. [CrossRef]

37. Kim S, Park HJ, Lee SI. The microbiome in systemic sclerosis: pathophysiology and therapeutic potential. Int J Mol Sci. 2022;23(24):16154. [CrossRef]

38. Li J, He J, Kuhn KA, Li Z. Animal models informing the role of the microbiome and its metabolites in rheumatoid arthritis. Rheum Dis Clin North Am. 2025;51(2):325-346. [CrossRef]

39. Ng BCK, Lassere M. The role of the gastrointestinal microbiome on rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and reactive arthritis: A systematic review. Semin Arthritis Rheum. 2025;70:152574. [CrossRef]

40. Song S, Wen X, Chen F, et al. Qu-zhuo-tong-bi decoction exerts gouty arthritis therapy by skewing macrophage polarization through butanoate metabolism. Chin Med. 2025;20(1):115. [CrossRef]

41. Generali E, Bose T, Selmi C, Voncken JW, Damoiseaux JGMC. Nature versus nurture in the spectrum of rheumatic diseases: classification of spondyloarthritis as autoimmune or autoinflammatory. Autoimmun Rev. 2018;17(9):935-941. [CrossRef]

42. Joseph YD, Ladd AL, Bhutani N. Hand osteoarthritis: molecular mechanisms, randomized controlled trials, and the future of targeted treatment. Int J Mol Sci. 2025;26(10):4537. [CrossRef]

43. Yang L, You K, Wang K, et al. Limosilactobacillus reuteri prevents progression of ankylosing spondylitis in mice by restoring gut microbiota-metabolism homeostasis. J Transl Med. 2025;23(1):715. [CrossRef]

44. Fehringer M, Vogl T. Molecular mimicry in the pathogenesis of autoimmune rheumatic diseases. J Transl Autoimmun. 2025;10:100269. [CrossRef]

45. Yang Y, Hong Q, Zhang X, Liu Z. Rheumatoid arthritis and the intestinal microbiome: probiotics as a potential therapy. Front Immunol. 2024;15:1331486. [CrossRef]

46. He M, Kolhoff F, Mont MA, Parvizi J. Is osteoarthritis a state of joint dysbiosis? Antibiotics (Basel). 2025;14(6):609. [CrossRef]

47. Dipalma G, Marinelli G, Ferrante L, et al. Modulating the gut microbiota to target neuroinflammation, cognition and mood: A systematic review of human studies with relevance to fibromyalgia. Nutrients. 2025;17(14):2261. [CrossRef]

48. Aloisi AM, Casini I. Fibromyalgia: chronic pain due to a blood dysfunction? Int J Mol Sci. 2025;26(9):4153. [CrossRef]

49. Pan B, Guo Q, Cai J, et al. Investigating the causal impact of gut microbiota on arthritis via inflammatory proteins using Mendelian randomization. Sci Rep. 2024;14(1):27433. [CrossRef]

50. Shan L, Chelliah R, Rahman SME, Hwan Oh D. Unraveling the gut microbiota's role in rheumatoid arthritis: dietary pathways to modulation and therapeutic potential. Crit Rev Food Sci Nutr. 2025;65(17):3291-3301. [CrossRef]

51. Tsai CC, Chu TY, Hsu PC, Kuo CY. The role of methyl Canthin-6-one-2-carboxylate in targeting the NLRP3 inflammasome in rheumatoid arthritis treatment. Curr Issues Mol Biol. 2025;47(4):254. [CrossRef]

52. Wang X, Xu H, Chao Y, et al. Integration of metabolomics and 16S ribosomal RNA sequencing to elucidate the pathogenesis of ankylosing spondylitis. Immun Inflamm Dis. 2025;13(3):e70183. [CrossRef]

53. Jia L, Yuan J, Chen Y, et al. Lactobacillus kefiranofaciens and its enhancement effect on the anti-inflammatory function of CII/Gln in MIA-induced osteoarthritis by protecting the intestinal barrier and gut microecology. Int J Food Sci Nutr. 2025;76(5):530-543. [CrossRef]

54. Manasson J, Abramson SB, Scher JU. The microbiome in rheumatic diseases. In: Hochberg MC, Gravallese EM, Smolen JS, et al., eds. Rheumatology, 2-Volume Set. 22. ed. Elsevier; 2022:183-192.

55. Manasson J, Shen N, Garcia Ferrer HR, et al. Gut microbiota perturbations in reactive arthritis and postinfectious spondyloarthritis. Arthritis Rheumatol. 2018;70(2):242-254. [CrossRef]

56. Minerbi A, Gonzalez E, Brereton NJB, et al. Altered microbiome composition in individuals with fibromyalgia. Pain. 2019;160(11):2589-2602. [CrossRef]

57. Ahmed S, Mahapatra S, Mishra R, et al. 16S RNA-based metagenomics reveal previously unreported gut microbiota associated with reactive arthritis and undifferentiated peripheral spondyloarthritis. Rheumatol (Oxf Engl). 2025;64(2):870-879. [CrossRef]

58. Zhang L, Liu G, Huang X, He F. Effects of protein supplementation on muscle mass, muscle strength, and physical performance in older adults with physical inactivity: a systematic review and meta-analysis. BMC Geriatr. 2025;25(1):228. [CrossRef]

59. Zhao T, Wei Y, Zhu Y, et al. Gut microbiota and rheumatoid arthritis: from pathogenesis to novel therapeutic opportunities. Front Immunol. 2022;13:1007165. [CrossRef]

60. Lin T, Xu Z, Chen J, et al. Bibliometric and visualized analysis of the relationship between rheumatoid arthritis and periodontitis-related bacteria using CiteSpace software. Front Microbiol. 2025;16:1589331. [CrossRef]

61. Yu X, Mankia K, Do T, Meade J. Oral microbiome dysbiosis and citrullination in rheumatoid arthritis. Adv Exp Med Biol. 2025;1472:185-199. [CrossRef]

62. Kupczyk D, Bilski R, Szeleszczuk Ł, Mądra-Gackowska K, Studzińska R. The role of diet in modulating inflammation and oxidative stress in rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. Nutrients. 2025;17(9):1603. [CrossRef]

63. Picchianti Diamanti A, Panebianco C, Di Gioia V, et al. A case series report on the effect of tofacitinib on joint inflammation and gut microbiota composition in psoriatic arthritis patients naive to biologic agents. Microorganisms. 2024;12(12):2387. [CrossRef]

64. Guan Y, Li F, Li N, Yang P. Decoding Behcet's uveitis: an In-depth review of pathogenesis and therapeutic advances. J Neuroinflammation. 2024;21(1):133. [CrossRef]

65. Stoll ML, DeQuattro K, Li Z, et al. Impact of HLA-B27 and disease status on the gut microbiome of the offspring of ankylosing spondylitis patients. Children (Basel). 2022;9(4):569. [CrossRef]

66. Yuan YX, Feng SR, Wu AY, et al. Influence of TNF-alpha inhibitors on gut microbiota and immune modulation in treating ankylosing spondylitis: insights into therapeutic mechanisms and clinical implications. J Inflamm Res. 2024;17:11741-11752. [CrossRef]

67. Duarte Luiz J, Manassi C, Magnani M, Cruz AGD, Pimentel TC, Verruck S. Lactiplantibacillus plantarum as a promising adjuvant for neurological disorders therapy through the brain-gut axis and related action pathways. Crit Rev Food Sci Nutr. 2025;65(4):715-727. [CrossRef]

68. Deng C, Xiao Q, Fei Y. A glimpse into the microbiome of Sjogren's syndrome. Front Immunol. 2022;13:918619. [CrossRef]

69. Manasson J, Blank RB, Scher JU. Response to: 'microbiome in Sjogren's syndrome: here we are' by van der Meulen et al. Ann Rheum Dis. 2022;81(7):e115. [CrossRef]

70. Tseng YC, Yang HY, Lin WT, et al. Salivary dysbiosis in Sjogren's syndrome and a commensal-mediated immunomodulatory effect of salivary gland epithelial cells. NPJ Biofilms Microbiomes. 2021;7(1):21. [CrossRef]

71. Bellocchi C, Volkmann ER. Advancing gastrointestinal microbiota research in systemic sclerosis: lessons learned from prior research and opportunities to accelerate discovery. Rheum Dis Clin North Am. 2025;51(2):213-231. [CrossRef]

72. Liang M, Deng Z, Wu W, Dong Q, Fan J. Study on the correlation between intestinal flora and cytokines in children with Henoch-Schonlein purpura. Cytokine 2025;191:156959. [CrossRef]

73. Sun N, Zhao Y, Zhang A, He Y. Gut microbiota and osteoarthritis: epidemiology, mechanistic analysis, and new horizons for pharmacological interventions. Front Cell Infect Microbiol. 2025;15:1605860. [CrossRef]

74. Wang Z, Li Y, Liao W, et al. Gut microbiota remodeling: A promising therapeutic strategy to confront hyperuricemia and gout. Front Cell Infect Microbiol. 2022;12:935723. [CrossRef]

75. Britton GJ, Mogno I, Chen-Liaw A, et al. Inflammatory disease microbiomes share a functional pathogenicity predicted by C-reactive protein. bioRxiv; January 18 2025. [CrossRef]

76. Carrillo-Serradell L, Liu-Tindall J, Planells-Romeo V, et al. The human mycobiome: composition, immune interactions, and impact on disease. Int J Mol Sci. 2025;26(15):7281. [CrossRef]

77. Zdybel K, Śliwka A, Polak-Berecka M, Polak P, Waśko A. Postbiotics formulation and therapeutic effect in inflammation: A systematic review. Nutrients. 2025;17(13):2187. [CrossRef]

78. Fernandez E, Wargo JA, Helmink BA. The microbiome and cancer: A translational science review. JAMA. 2025;333(24):2188-2196. [CrossRef]

79. Cesaro A, Broset E, Salimando GJ, et al. Using synthetic biology to understand the gut-brain axis. Cell Rep Phys Sci. 2025;6(3). [CrossRef]

80. Neumeister MW, Neumeister EL. Fibromyalgia. Clin Plast Surg. 2020;47(2):203-213. [CrossRef]

81. Guo X, Guo L, Lu QZ, et al. Effect of electroacupuncture combined with Tuina therapy on gut microbiota in patients with knee osteoarthritis. World J Gastroenterol. 2025;31(18):105495. [CrossRef]

82. Meijers B, Zadora W, Lowenstein J. A historical perspective on uremia and uremic toxins. Toxins (Basel). 2024;16(5):227. [CrossRef].

83. Tong S, Zhang P, Cheng Q, et al. The role of gut microbiota in gout: is gut microbiota a potential target for gout treatment. Front Cell Infect Microbiol. 2022;12:1051682. [CrossRef]

84. Cole LD, Kuhn KA. It takes a village: juvenile idiopathic arthritis and the microbiome. Rheum Dis Clin North Am. 2025;51(2):233-282. [CrossRef]

85. He H, Dong X, Cao L, et al. Oral microbiota-regulating and inflammation-targeted polymersome-hydrogels for RNAi therapy of ulcerative colitis. Bioact Mater. 2025;53:32-44. [CrossRef]

86. Bilski J, Pierzchalski P, Szczepanik M, Bonior J, Zoladz JA. Multifactorial mechanism of sarcopenia and sarcopenic obesity. Role of physical exercise, microbiota and myokines. Cells. 2022;11(1):160. [CrossRef]

87. Belelli D, Lambert JJ, Wan MLY, Monteiro AR, Nutt DJ, Swinny JD. From bugs to brain: unravelling the GABA signalling networks in the brain-gut-microbiome axis. Brain. 2025;148(5):1479-1506. [CrossRef]

Invited Review

The Gut-Joint Connection: Microbiome’s Role in Rheumatic Disease