The role of the gut microbiome in immune-mediated joint diseases

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Reference: October 2025 | Issue 10 | Vol 11 | Page 28

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Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are chronic, immune-mediated inflammatory joint diseases. Although they share overlapping clinical features such as joint pain, stiffness, and systemic involvement, they differ in their underlying immunopathology and genetic associations. RA is typically characterised by autoantibody production (rheumatoid factor [RF] and anti-citrullinated protein antibodies [ACPAs]), while PsA is often seronegative and more closely associated with the interleukin (IL)-23/IL-17 axis.

Emerging evidence implicates environmental triggers, particularly the gut microbiota, in initiating or modulating systemic inflammation in both conditions. In recent years, our understanding of autoimmune diseases has significantly improved through research advancement, with increasing recognition of the gut microbiome and metabolome emerging as one of the key regulators of the immune system and drivers of chronic systemic inflammation. These systems represent dynamic, modifiable factors that may influence disease onset, progression, and treatment responsiveness.

This review aims to synopsise current knowledge on the role of the gut microbiome and metabolome on RA and PsA, exploring emerging evidence on their impact in immune modulation and treatment-response variability, and highlight ongoing gaps and future research directions. A deeper understanding of these complex host-microbe interactions holds promise for advancement of more precise, personalised management, improving not only clinical, but also quality of life, and outcomes of these complex conditions.

Pathogenesis

RA is characterised by symmetrical, polyarticular synovitis, predominantly affecting small joints. It is driven by dysregulated adaptive immune responses, involving autoreactive B cells that produce RF and ACPAs, and autoreactive T cells that secrete pro-inflammatory cytokines such as tumour necrosis factor-α (TNF-α), IL-6, and IL-17.^1,2

PsA is a clinically heterogeneous disease associated with psoriasis, axial and peripheral joint inflammation, enthesitis, and dactylitis. Unlike RA, PsA is largely seronegative and strongly associated with the activation of the IL-23/IL-17 axis. Genetic susceptibility is influenced by several genes, particularly within the major histocompatibility complex (MHC) region – prominent key genes include HLA-B27 and HLA-C06:02.^3,4

A hallmark of both diseases is the dysregulation of T cell subsets, particularly the imbalance between regulatory T cells (Tregs), which promote tolerance, and Th17 cells, which drive inflammation.^5,6 This shift contributes to chronic systemic immune activation leading to inflammation.

Environmental factors such as smoking, infections, antibiotic exposure, and diet are believed to possibly modulate disease risk by altering mucosal immunity. The oral microbiome, for instance, has been implicated in RA pathogenesis. Periodontal pathogens such as Porphyromonas gingivalis may contribute to systemic autoimmunity through mechanisms like protein citrullination and mucosal immune activation, supporting the role of mucosal dysbiosis in disease initiation.⁷

The gut, as a major immune organ, has been increasingly implicated in systemic autoimmune disease via its influence on antigen presentation, tolerance, and immune modulation. Microbial dysbiosis, which is disruption of gut microbial composition and altered metabolite profiles, may trigger or exacerbate autoimmune responses.

What are the gut microbiome and metabolome?

The gut microbiome refers to the diverse community of micro-organisms that inhabit the gastrointestinal tract, including bacteria, viruses, fungi, and archaea. These organisms contribute to a wide range of physiological processes.

In healthy individuals, the microbiome exists in balanced symbiosis with the host. It contributes to host metabolism, immune modulation, and maintenance of mucosal barrier integrity, serving as mechanical protection against pathogens. In contrast, dysbiosis, which is a disruption in microbial composition, function, and/or spatial distribution, is increasingly associated with chronic autoimmune inflammatory diseases.

The gut metabolome encompasses a collection of small molecules (metabolites) produced by host and microbial metabolism. These include short-chain fatty acids (SCFAs), bile acids, and amino acid derivatives. These metabolites act as signalling molecules that influence the gut epithelium, antigen-presenting cells, and systemic immune response. For instance, SCFAs such as butyrate are known to enhance Treg development, while certain bile acids and tryptophan metabolites can affect Th17 differentiation through aryl hydrocarbon receptor (AhR).

Given the gut’s role in immune regulation, perturbations in its microbial and metabolic environment may have systemic consequences beyond the intestine.⁸ The integration of metagenomics and metabolomics has enhanced our understanding of these interactions, particularly in relation to systemic inflammatory and autoimmune conditions like RA and PsA.

Rheumatoid arthritis

Patients with RA exhibit distinct alterations in gut microbiota composition compared to healthy controls. Studies have shown specific taxa such as Prevotella copri are frequently enriched in individuals with new-onset, untreated RA, and have been associated with immune activation of Th17 cells.^2,9

In contrast, protective and beneficial commensals such as Bifidobacterium, Faecalibacterium prausnitzii, and Clostridium clusters IV and XIVa are often depleted. These microorganisms are known to produce butyrate, a key SCFA involved in maintaining intestinal barrier function and promoting Treg induction. Loss of these butyrate-producers will deplete Treg, which may skew immunity towards a Th17 dominant pro-inflammatory state.^10,11

Metabolomic studies in RA have revealed decreased SCFAs levels and increased inflammatory metabolites like trimethylamine N-oxide (TMAO), succinate, and altered bile acids.¹² Additionally, elevated levels of kynurenine, a tryptophan metabolite, also plays a role by activating the AhR receptor and T cell dynamics, further favouring Th17, leading to imbalance in the Treg and Th17 populations.¹

Microbial and metabolic changes are not confined to the gastrointestinal tract. Bacterial DNA and microbial metabolites have been detected in synovial fluid and tissue, suggesting translocation and reinforcing the concept of the ‘gut-joint’ axis. Supporting this is evidence from animal studies, where germ-free mice are protected from arthritis, and RA-like disease can be transmissible through faecal microbiota transplantation (FMT).¹³

These findings support exploring the therapeutic potential of microbiome-targeted interventions such as dietary modification, prebiotics, probiotics, and FMT. Additionally, microbiome and metabolome signatures may serve as promising early diagnostic or prognostic biomarkers in RA.

Psoriatic arthritis

Although the literature on PsA is less extensive, emerging data indicate similar patterns of dysbiosis and metabolomic disturbance. Patients with PsA often demonstrate reduced abundance of beneficial gut-barrier-maintaining taxa such as Akkermansia muciniphila, Faecalibacterium prausnitzii, and Bacteroides fragilis, alongside enrichment of pro-inflammatory species such as Ruminococcus gnavus and Collinsella.^3,14 These shifts may disrupt and impair mucosal immunity and epithelial barrier integrity, causing mucosal inflammation and increasing intestinal permeability.

Emerging metabolomic studies suggest that PsA may share similar disturbances with RA, including altered tryptophan and bile acid metabolism, which are implicated in Th17 differentiation via AhR signalling. While direct evidence in PsA remains limited, reduced SCFA levels and systemic detection of inflammatory metabolites have been observed in some cohorts, supporting the concept of a gut-joint axis extending beyond RA.¹⁵ Further targeted metabolomic studies in PsA are warranted to validate these findings.

Despite these overlaps, PsA also demonstrates unique gut-immune features. Notably, PsA is often associated with subclinical ileal inflammation rather than colonic involvement, consistent with other spondyloarthritides. Localised dysbiosis in the ileum may contribute to regional IL-23 production, a cytokine central to PsA pathogenesis.¹⁶ Moreover, the concept of ‘gut-skin-joint’ axis has been proposed, reflecting the interplay between mucosal immunity, cutaneous inflammation, and joint disease in PsA.¹⁴

Collectively, these findings support the notion that microbial dysbiosis and altered metabolite signalling likely contribute to systemic Th17-driven inflammation in PsA, paralleling RA, but with a distinct gut-regional profile and cytokine involvement. A deeper understanding of these mechanisms could enable the development of microbiome-targeted diagnostic tools and therapeutic strategies.

Treatment response

Despite advances in biologics and targeted therapies for RA and PsA, a substantial proportion of patients exhibit suboptimal or no clinical response to treatment. This variability has sparked growing interest in the role of the gut microbiome and metabolome as potential modulators of therapeutic efficacy and heterogeneity.

Emerging evidence suggests that specific microbial signatures may predict responsiveness to commonly used agents including methotrexate, TNF inhibitors, and IL-17 blockers.¹⁷ For example, higher baseline abundance of SCFA-producing bacteria such as Faecalibacterium and Roseburia has been associated with more favourable treatment responses, possibly through their enhancement of the Treg population and its anti-inflammatory pathways.

In contrast, pro-inflammatory taxa like Collinsella or Ruminococcus gnavus have been linked with poor outcomes, potentially due to promotion of Th17-mediated inflammation and impairment of mucosal barrier integrity.^3,12

Metabolic profiling provides complementary insights. Responders tend to exhibit higher levels of anti-inflammatory metabolites such as butyrate and other SCFAs, whereas non-responders have elevated levels of pro-inflammatory compounds such as succinate, lactate, and TMAO.¹² These metabolite patterns likely reflect microbial composition and its potential to modulate host immune cell function and inflammatory signalling.

Several hypotheses have been proposed to explain the variability in treatment response among patients with RA and PsA. One key factor is the immune microenvironment, which is thought to be significantly influenced by the gut microbiota. Gut microbiota influence on the Treg/Th17 balance is particularly relevant as this axis plays a central role in autoimmune pathogenesis and treatment responsiveness to immunomodulatory therapies.

Additionally, microbial metabolism of drugs may be a factor – activating, inactivating, or even degrading therapeutic compounds, thereby modifying the drug’s efficacy and toxicity by altering pharmacokinetics and pharmacodynamics across individuals.¹⁸ Furthermore, microbial metabolites in murine and in vitro human immune cells have been shown to modulate gene expression through epigenetic mechanisms like AhR activation. This pathway may influence Treg and Th17 cell balance, suggesting a biologically plausible link to treatment variability in RA and PsA. However, direct evidence in human cohorts remains limited.⁵

All these findings underscore the complexity of the gut microbiome, its metabolic products, and their influence on host immune regulation. These insights highlight the potential role of the gut microbiome and metabolome to serve as predictive markers and therapeutic targets.Understanding the distinction of microbial and metabolomic profiles in responders and non-responders could support the development of precision medicine approaches by tailoring treatment strategies to an individual’s unique immune-metabolic profile, thereby improving outcomes in RA and PsA.

Knowledge gaps

Despite compelling evidence linking the gut microbiome and metabolome to inflammatory arthritis, several critical knowledge gaps hinder the translation of these findings into clinical practice. These limitations affect efforts to develop predictive biomarkers and the possibility of personalised treatment strategies in RA and PsA.

One major challenge is distinguishing causality from correlation. While animal studies have shown that gut dysbiosis can trigger arthritis-like disease, most human studies remain observational and cross-sectional. Longitudinal cohort studies are essential to determine whether microbial or metabolomic alterations precede clinical onset or arise as a consequence of inflammation, particularly during the preclinical and early stages of disease.

There is also a lack of standardisation in microbiome and metabolome research. Differences in sample types (eg, stool versus mucosal biopsies), sequencing platforms, and analytic pipelines contribute to inconsistent findings across studies, limiting robust comparison of studies, and complicating the identification of reproducible, reliable microbial biomarkers.

Furthermore, while most research has focused on the colonic microbiome via stool samples, PsA may involve more localised ileal inflammation. Regional differences in microbial composition and immune interaction remain poorly understood, especially regarding how ileal dysbiosis may influence systemic cytokine profiles such as IL-23.

A significant gap also lies in the mechanistic understanding of how specific microbial taxa and their metabolites modulate immune pathways, particularly the Treg/Th17 axis, dendritic cell activation, and cytokine signalling. Although SCFAs and tryptophan metabolites have been linked to Treg dynamics and AhR activation, the context-specific roles of these pathways in RA versus PsA are not well defined. In addition, it is not fully understood whether these microbial-immune interactions occur locally in the gut or extend systematically to the synovial compartment. Multi-omics approaches integrating metagenomics, metabolomics, transcriptomics, and immunophenotyping are needed to address these unknowns.

Moreover, while the therapeutic potential of gut modulation – such as probiotics, prebiotics, and dietary interventions – is biologically plausible and has shown immunomodulatory effects in vitro and in animal models, its clinical efficacy in inflammatory arthritis remains uncertain. Several clinical trials and systematic reviews in RA have shown that probiotic supplementation can reduce inflammatory markers like C-reactive protein, but improvements in disease activity scores have been inconsistent.¹⁹

In PsA, a 12-week, randomised, controlled trial showed improvement in gut permeability biomarkers (for example, zonulin), yet no significant changes were observed in joint disease activity.²⁰ These findings highlight that although gut-targeted therapies may modulate immune responses, robust clinical benefit has yet to be clearly established in both conditions.

Further research

Addressing these knowledge gaps to help advance the clinical utility of microbiome-informed therapeutic strategies will require well-designed, integrative studies that bridge microbial ecology and immune pathophysiology, while accounting for host genetics, lifestyle, and therapeutic exposure. This can be achieved by prioritising mechanistic clarity, longitudinal tracking, and personalised approaches.

A critical step toward precision immunology in RA and PsA will be the assessment of immune cell subsets, particularly Tregs and Th17 cells, before and after treatment. Since microbial metabolites, like SCFAs and tryptophan derivatives, modulate these populations, profiling their longitudinal dynamics could provide mechanistic insight into how microbiome-targeted or conventional therapies exert their effects.

Evaluating Treg/Th17 balance and its correspondence to clinical response would help to identify immune phenotypes associated with treatment resistance or response, supporting a stratified approach to RA and PsA patient care.

Parallel longitudinal studies are also needed to track microbiome and metabolome changes from pre-clinical stages through treatment, thereby establishing causal links rather than mere associations. Interventional trials using diet, prebiotics, probiotics, or FMT could further test the therapeutic potential of modulating the gut ecosystem.

Lastly, integrating multi-omics data – microbiome, metabolome, transcriptome, immunophenotyping – and clinical response will increase the chance of identification of potential predictive biomarkers. These tools will form the foundation and support a precision medicine framework, tailoring treatments to a patient’s unique microbial and metabolic fingerprint, and improving long-term outcomes in RA and PsA patients.

Conclusion

The growing body of research on the gut microbiome and metabolome highlights their critical role in the pathogenesis and clinical trajectory of RA and PsA. Both conditions demonstrate characteristic patterns of microbial dysbiosis and metabolomic alterations that appear to influence immune responses, particularly the Treg/Th17 balance, gut barrier integrity, and systemic inflammation. Importantly, these microbial and metabolomic profiles are increasingly recognised as potential determinants of therapeutic response, offering a compelling rationale for their use as predictive biomarkers.

Despite these advances, major knowledge gaps remain, particularly regarding causality, standardisation, regional microbiome variation, and integration with immune effector mechanisms. Addressing these limitations will require longitudinal mechanistic studies and clinical trials that explore how gut microbiome composition and metabolite signalling affect both immune dynamics and treatment efficacy.

By embracing multiomic approaches and exploring microbiome-informed therapeutic strategies, we edge closer to a precision medicine framework – one in which treatment for RA and PsA is tailored not only to clinical and genetic factors, but also to each patient’s unique microbial and metabolic signature. These efforts and innovation hold the potential to improve outcomes, reduce trial-and-error prescribing, and ultimately, reshape the standard of care in inflammatory arthritis.