Gut Microbiome and Rheumatoid Arthritis–Associated Interstitial Lung Disease: What Does the Evidence Show?
Could the Gut Microbiome Help Explain Why Some People With Rheumatoid Arthritis Develop ILD?
Rheumatoid arthritis is best known as an inflammatory joint disease.
But it is a systemic autoimmune disease, and the lungs are among its most important extra-articular targets.
Interstitial lung disease can occur in a subset of patients with rheumatoid arthritis and may range from relatively limited abnormalities to progressive pulmonary fibrosis.
This condition is known as rheumatoid arthritis-associated interstitial lung disease, or RA-ILD.
One of the major unanswered questions is why certain patients with rheumatoid arthritis develop clinically important lung disease while others never do.
Known contributors include:
age
male sex
smoking
rheumatoid factor
anti-citrullinated protein antibodies
genetics
disease characteristics
environmental factors
But these factors do not explain everything.
An emerging area of research asks whether mucosal immunity and the microbiome might contribute to the pulmonary phenotype of rheumatoid arthritis.
This hypothesis is particularly interesting because abnormal immune responses at mucosal surfaces may begin years before joint symptoms appear.
The intestine, oral cavity and lungs are therefore increasingly being considered as interconnected immune environments rather than isolated organs.
Recent human microbiome studies have now directly compared patients with RA-ILD against rheumatoid arthritis patients without ILD.
The findings are intriguing.
But they are also inconsistent enough to require caution.
That combination makes RA-ILD one of the most important areas for careful, evidence-based gut–lung research.
What Is Rheumatoid Arthritis–Associated ILD?
RA-ILD refers to interstitial lung disease occurring in association with rheumatoid arthritis.
The most frequent HRCT patterns include:
usual interstitial pneumonia, or UIP
nonspecific interstitial pneumonia, or NSIP
Other patterns can occur.
The clinical course is highly variable.
Some patients have mild stable disease.
Others develop progressive pulmonary fibrosis characterized by:
worsening breathlessness
declining exercise capacity
falling FVC
impaired DLCO
increasing fibrosis on imaging
RA-ILD is clinically important because pulmonary involvement contributes substantially to morbidity and mortality in rheumatoid arthritis.
Understanding why it occurs is therefore a major research priority.
Why Is the Microbiome Already Important in Rheumatoid Arthritis?
Long before researchers focused specifically on RA-ILD, the gut microbiome had become an important field in rheumatoid arthritis itself.
RA is increasingly understood through the concept of mucosal origins of autoimmunity.
This hypothesis proposes that abnormal immune responses may begin at mucosal surfaces such as:
the gastrointestinal tract
oral cavity
respiratory tract
before clinically obvious joint disease develops.
One clue is the presence of autoantibodies such as:
anti-citrullinated protein antibodies, or ACPA
rheumatoid factor
before arthritis becomes clinically apparent.
The gut microbiome may influence these immune responses through:
mucosal barrier function
antigen exposure
T-cell regulation
microbial metabolites
molecular mimicry
post-translational protein modification
Recent 2026 reviews continue to support a mechanistic role for gut dysbiosis in rheumatoid autoimmunity while emphasizing that the exact causal pathways remain incompletely defined. (PubMed)
Why Ask a Separate Question About RA-ILD?
Because the microbiome associated with rheumatoid arthritis is not necessarily the same as the microbiome associated with rheumatoid lung involvement.
This distinction matters.
If both patients with RA-ILD and those with RA without lung disease show the same microbial alterations, the microbiome may be related mainly to rheumatoid autoimmunity.
But if RA-ILD patients show additional microbial characteristics that distinguish them from RA patients without ILD, those features might potentially relate to the pulmonary phenotype.
That is the critical scientific comparison.
And recent studies have attempted exactly that.
The 2024 Multikingdom Metagenomic Study
One important study used whole-metagenome shotgun sequencing to compare:
30 patients with RA-ILD
30 patients with RA without ILD
40 matched healthy controls
Rather than studying bacteria alone, investigators examined three microbial kingdoms:
bacteriome
mycobiome
virome
This is an important methodological advance because the intestinal ecosystem includes far more than bacteria.
The study found substantial alterations in gut microbial composition in both rheumatoid arthritis groups compared with healthy controls.
Across the study population, investigators identified differences involving hundreds of bacterial species, dozens of fungal species and thousands of viral operational taxonomic units. (PubMed)
Which Bacteria Were Different?
Several bacterial changes were shared by patients with rheumatoid arthritis regardless of lung involvement.
For example, organisms including:
Bifidobacterium longum
Dorea formicigenerans
Collinsella aerofaciens
were enriched in both RA groups.
Meanwhile, potentially health-associated organisms such as:
Faecalibacterium prausnitzii
several Bacteroides species
Roseburia inulinivorans
were reduced in both groups.
These findings suggest that a substantial part of the microbial signature may reflect rheumatoid arthritis itself, not necessarily ILD. (PubMed)
Was Anything Unique to RA-ILD?
Yes.
The 2024 study reported certain microbial features that appeared relatively enriched in the RA-ILD group.
One notable organism was:
Ruminococcus gnavus
which was described as uniquely enriched in RA-ILD relative to the comparison groups in that analysis. (PubMed)
This organism has attracted attention in other immune-mediated diseases because some strains may possess pro-inflammatory properties.
However, microbiome findings are context-dependent.
An association with RA-ILD does not demonstrate that R. gnavus causes lung fibrosis.
It may instead be:
a marker of altered immunity
a consequence of medications
related to diet or geography
linked with rheumatoid disease severity
Replication is necessary before it can be considered a reliable RA-ILD biomarker.
The Mycobiome: What About Fungi?
One of the strengths of the 2024 study was that it did not stop at bacteria.
The mycobiome refers to the fungal component of the microbiome.
Compared with healthy participants, the rheumatoid arthritis groups showed depletion of certain fungi, including:
Saccharomyces cerevisiae
Candida albicans
This is an interesting finding because it challenges the oversimplified idea that more Candida automatically means greater autoimmune disease.
Microbial ecology is much more complicated than classifying organisms as universally “good” or “bad.” (PubMed)
The Virome: Viruses Also Matter
The study also identified substantial differences in the intestinal virome.
Most gut viruses are bacteriophages—viruses that infect bacteria.
They can influence:
bacterial abundance
bacterial gene expression
microbial competition
ecosystem stability
The rheumatoid arthritis groups demonstrated changes in several viral families, including increased Siphoviridae and reductions in several others.
The biological implications remain uncertain, but this finding reinforces an important principle:
The gut microbiome is an ecosystem of bacteria, fungi and viruses—not merely a list of bacterial species. (PubMed)
A Separate Comparative Study: Prevotella and RA-ILD
Another human comparative study evaluated:
30 patients with RA-ILD
31 patients with RA without ILD
30 healthy controls
using 16S rRNA sequencing.
Investigators reported significant differences in microbial composition among groups.
The genus Prevotella emerged as one of the organisms showing differential abundance, and predicted microbial functional analysis suggested changes in several metabolic pathways in RA-ILD. (PubMed)
This adds additional evidence that RA-ILD may possess a microbial phenotype distinguishable from rheumatoid arthritis alone.
However, sequencing methods and statistical approaches differed from those used in the other studies.
This can make direct comparisons difficult.
What Is Special About Prevotella?
Prevotella has been extensively studied in rheumatoid arthritis.
Certain Prevotella species, especially Prevotella copri, have been associated with early or untreated RA in some populations.
Potential mechanisms include:
mucosal immune activation
Th17-related responses
altered intestinal-barrier function
antigenic stimulation
But Prevotella is a diverse genus.
Different strains may have different effects.
Diet also strongly influences Prevotella abundance.
Therefore, finding more Prevotella does not automatically mean that it is pathogenic.
Its significance depends on:
species
strain
host immune context
dietary environment
microbial community
The Important 2026 Study: A More Cautious Result
A newer study published in June 2026 used shotgun metagenomic sequencing to compare:
10 patients with RA-ILD
20 patients with RA without ILD
11 healthy controls
for a total of 41 participants.
This study is particularly useful because its results were more conservative.
There were no significant differences in alpha or beta diversity among the groups.
More importantly, after appropriate correction for multiple statistical comparisons, no genus remained significantly different between RA-ILD and RA without ILD. (PubMed)
This is scientifically important.
It means that we should not present a definitive RA-ILD microbial signature as established fact.
What Did the Exploratory 2026 Analysis Show?
Before correction for multiple comparisons, the investigators observed exploratory differences.
RA-ILD showed enrichment of:
Escherichia/Shigella
and depletion of organisms including:
Roseburia.
The reported abundance of Escherichia/Shigella was substantially higher in RA-ILD than in RA without ILD in the exploratory analysis. (PubMed)
However, because these differences did not survive FDR correction, they should be considered hypothesis-generating rather than definitive.
That distinction is essential.
Why Does FDR Correction Matter?
Microbiome studies can test hundreds or thousands of organisms simultaneously.
If enough comparisons are made, some differences will appear statistically significant simply by chance.
False discovery rate correction adjusts for this problem.
When a result disappears after FDR correction, it does not mean the observation is necessarily false.
It means the evidence is not strong enough to confidently distinguish it from chance within that dataset.
This is why the 2026 findings should not be translated into statements such as:
“Escherichia causes RA-ILD.”
The evidence does not support that conclusion.
What About Roseburia?
Roseburia is interesting because several species are associated with production of butyrate, a short-chain fatty acid.
Butyrate can influence:
intestinal epithelial health
immune regulation
Treg activity
inflammatory signaling
The exploratory depletion of Roseburia in RA-ILD therefore raises a plausible mechanistic hypothesis:
loss of butyrate-associated microbial function → altered immune regulation → greater systemic or pulmonary inflammatory signaling
But the evidence remains indirect.
A lower relative abundance of Roseburia does not automatically prove a clinically important butyrate deficiency.
And giving butyrate has not been shown to treat RA-ILD.
Clinical Correlations in the 2026 Study
The newer study also examined relationships between microbial patterns and clinical characteristics.
Certain butyrate-associated organisms showed inverse relationships with measures of rheumatoid disease activity.
This suggests that microbial metabolism may relate to systemic inflammatory burden. (PubMed)
Again, correlation does not tell us direction.
More active rheumatoid disease could alter the microbiome.
Or the microbiome could influence immune activity.
Or both could be influenced by medications, diet or other factors.
Why Are the Studies Not Identical?
This is expected in microbiome science.
Potential reasons include differences in:
sample size
ethnicity
geography
diet
medication exposure
rheumatoid disease activity
ILD severity
smoking
sequencing method
bioinformatic pipeline
statistical correction
Even sample collection and storage can affect results.
Therefore, individual bacterial findings should be interpreted cautiously until replicated across independent populations.
The Most Defensible Conclusion From Human Evidence
The current evidence supports the statement that:
Patients with RA-ILD appear to have alterations in intestinal microbial ecology, but a reproducible gut microbial signature that clearly distinguishes RA-ILD from rheumatoid arthritis without ILD has not yet been established.
That is a stronger scientific statement than claiming a specific bacterium causes the disease.
How Could the Gut Microbiome Influence RA-ILD?
Several mechanisms are plausible.
1. Mucosal Autoimmunity
Rheumatoid arthritis may begin partly at mucosal surfaces.
Environmental exposure and microbial signals could lead to local inflammation and protein modification.
In genetically susceptible individuals, these processes may contribute to development of autoantibodies such as ACPA.
The lung itself may also be a site of protein citrullination and immune activation.
This creates a potential mucosal network involving:
gut + mouth + lung + systemic immunity
rather than a simple gut-to-lung pathway.
2. Treg and Th17 Balance
Gut microorganisms influence the differentiation of immune cells.
Two particularly important populations are:
regulatory T cells
Th17 cells
Excessive Th17 activity and impaired regulatory responses are implicated in rheumatoid arthritis.
Dysbiosis could potentially shift this balance toward inflammatory immunity.
That systemic immune environment may then influence pulmonary inflammation and fibrosis.
Recent 2026 reviews of rheumatoid autoimmunity continue to identify altered Treg/Th17 signaling as one important microbiome-related pathway. (PubMed)
3. Intestinal Permeability
Another proposed mechanism involves intestinal-barrier function.
Tight junctions normally regulate movement of microbial molecules from the intestinal lumen into circulation.
Increased intestinal permeability has been investigated in rheumatoid arthritis.
If barrier integrity is impaired, microbial products may gain greater systemic exposure.
This may amplify innate and adaptive immune activation.
Recent 2026 literature specifically reviews the relationship between gut dysbiosis, intestinal permeability and rheumatoid arthritis pathogenesis. (PubMed)
Whether this mechanism specifically drives RA-ILD remains unknown.
4. Lipopolysaccharide and Innate Immunity
Gram-negative bacterial products such as LPS can activate:
TLR4 → NF-κB
and stimulate inflammatory cytokines.
These pathways are relevant to both rheumatoid autoimmunity and pulmonary inflammatory responses.
In theory, greater microbial translocation could amplify systemic inflammation and affect the pulmonary microenvironment.
Direct causal human evidence in RA-ILD is still lacking.
5. Short-Chain Fatty Acids
Microbial fermentation produces:
acetate
propionate
butyrate
SCFAs help regulate mucosal immunity and intestinal-barrier health.
The possible depletion of some butyrate-associated bacterial groups in RA-ILD makes this pathway especially interesting.
However:
butyrate-associated bacteria are not equivalent to measured butyrate activity, and neither has been established as a treatment target in RA-ILD.
6. Molecular Mimicry and Antigenic Stimulation
Microbial proteins can sometimes resemble human proteins closely enough to influence immune recognition.
This phenomenon is called molecular mimicry.
In genetically susceptible individuals, prolonged microbial exposure could theoretically contribute to abnormal autoreactive immune responses.
This has been proposed within rheumatoid arthritis pathogenesis.
Its specific relevance to pulmonary fibrosis remains uncertain.
7. Microbial Metabolites
Beyond SCFAs, intestinal microbes produce:
tryptophan metabolites
bile-acid derivatives
amino-acid metabolites
microbial peptides
These can influence systemic immune-cell function.
Future RA-ILD research may therefore focus less on individual bacterial names and more on microbial metabolic pathways.
This may ultimately prove more informative.
The Gut Is Not the Only Mucosal Site in RA-ILD
A key limitation of a purely gut-centered model is that rheumatoid arthritis may involve several mucosal ecosystems.
The oral microbiome has been extensively studied in RA.
Periodontal organisms and chronic oral inflammation may influence protein citrullination and autoimmune responses.
The lung also has its own microbiome and mucosal immune environment.
Therefore, the more accurate model may be:
gut–oral–lung–joint axis
rather than a one-directional gut–lung axis.
Smoking Adds Another Layer
Smoking is an established risk factor for RA-ILD and is particularly relevant in ACPA-positive rheumatoid arthritis.
Smoking can also alter:
respiratory microbiota
oral microbiota
intestinal microbiota
mucosal immunity
This creates an important confounding problem.
Some microbial differences attributed to RA-ILD could partly reflect smoking-related biology.
Good microbiome studies therefore need careful adjustment for smoking exposure.
Medications Also Matter
Patients with rheumatoid arthritis may receive:
methotrexate
corticosteroids
biologic therapies
JAK inhibitors
antibiotics
proton-pump inhibitors
NSAIDs
Each can potentially influence gastrointestinal physiology or microbial ecology.
Medication effects therefore need to be considered before interpreting an individual microbial signature as part of disease pathogenesis.
Does Gut Dysbiosis Cause RA-ILD?
At present, we cannot say that it does.
At least four possibilities remain:
Dysbiosis may contribute to disease.
Rheumatoid inflammation may alter the microbiome.
RA-ILD treatment or severity may alter the microbiome.
Shared environmental or immune factors may produce both.
A bidirectional model is likely.
Can the Gut Microbiome Predict Who Will Develop RA-ILD?
Not currently.
Research studies suggest microbial signatures may eventually have biomarker potential.
But no microbiome test has been validated to predict:
which RA patient will develop ILD
when ILD will begin
whether disease will progress
what HRCT pattern will occur
Established clinical risk factors remain much more useful today.
Can Commercial Stool Testing Diagnose RA-ILD?
No.
Research-grade shotgun metagenomics is not equivalent to a commercial stool microbiome report.
At present, no commercial stool test can determine:
whether a patient has RA-ILD
whether their fibrosis will progress
which rheumatological therapy should be used
whether antifibrotic treatment is required
which probiotic will improve lung disease
Commercial testing should not replace:
pulmonary function testing
HRCT
rheumatological assessment
specialist ILD evaluation
Should Patients With RA-ILD Take Probiotics?
There is no probiotic currently established as treatment for RA-ILD.
A probiotic may have a role for a separate gastrointestinal indication.
That is different from using it to modify pulmonary fibrosis.
No randomized human trial has shown that probiotics:
improve FVC
improve DLCO
slow fibrotic progression
reduce mortality
in RA-ILD.
What About Prebiotics or Fiber?
Diet influences the intestinal microbiome and SCFA production.
Supporting a nutritionally adequate dietary pattern may benefit:
metabolic health
bowel function
microbial diversity
cardiovascular risk
But there is no clinical evidence that increasing fiber specifically treats RA-ILD.
Dietary recommendations must also consider gastrointestinal tolerance and overall nutritional status.
Can Butyrate Treat RA-ILD?
No clinical evidence currently supports butyrate as treatment for RA-ILD.
The interest comes from:
butyrate-producing bacterial groups
Treg regulation
intestinal-barrier effects
anti-inflammatory properties
These are mechanistic arguments.
They are not evidence of pulmonary therapeutic efficacy.
Could Microbiome Therapy Become Relevant in the Future?
Possibly.
Future strategies could include:
precision prebiotics
defined microbial consortia
postbiotics
targeted metabolites
engineered bacteria
personalized dietary interventions
But future trials will need to show improvement in genuine pulmonary outcomes.
Changing stool bacteria alone will not be sufficient.
What Outcomes Would Matter?
A meaningful RA-ILD microbiome trial should evaluate outcomes such as:
FVC decline
DLCO
HRCT progression
symptoms
exercise capacity
progressive pulmonary fibrosis
hospitalization
survival
It should also control for:
rheumatoid disease activity
medications
smoking
diet
antibiotics
ILD pattern
Only then can causality begin to be addressed.
Functional and Integrative Medicine Perspective
RA-ILD requires genuine integration between rheumatology and pulmonary medicine.
An evidence-based functional and integrative approach can broaden the assessment to include:
gastrointestinal symptoms
nutrition
metabolic health
smoking
oral health
sleep
exercise
muscle mass
relevant environmental exposures
But this broader approach must remain anchored to the actual pulmonary phenotype.
Patients still require appropriate evaluation of:
HRCT pattern
lung function
disease progression
oxygen requirement
pulmonary hypertension when relevant
immunomodulatory therapy
antifibrotic therapy where appropriate
pulmonary rehabilitation
Gut health may become an additional layer.
It should not replace these priorities.
What We Know
Current human evidence shows that:
RA is associated with gut dysbiosis
RA-ILD patients also demonstrate altered intestinal microbial patterns
a 2024 multikingdom metagenomic study identified bacterial, fungal and viral alterations in RA-ILD
another comparative study identified differences involving Prevotella and predicted metabolic pathways
a 2026 shotgun metagenomic study found exploratory RA-ILD differences involving Escherichia/Shigella and Roseburia
(PubMed)
What We Do Not Know
The newer evidence also tells us what not to claim.
In the 2026 study:
alpha diversity was not significantly different
beta diversity was not significantly different
no genus remained significantly different between RA-ILD and RA without ILD after FDR correction
(PubMed)
Therefore, a definitive RA-ILD gut microbial signature has not yet been established.
We also do not know whether:
dysbiosis precedes lung disease
changing dysbiosis prevents RA-ILD
microbiome treatment slows progression
butyrate modification improves lung function
probiotics alter survival
What Does the Evidence Mean Clinically?
The microbiome is a credible research target in RA-ILD.
It may help us eventually understand why certain patients develop pulmonary disease and others do not.
But microbiome-directed treatment is not ready for routine RA-ILD care.
For now, the most appropriate clinical approach is to:
identify and treat the RA-ILD correctly
control relevant autoimmune disease
monitor lung function and imaging
address smoking and respiratory risk factors
maintain nutrition and physical capacity
investigate clinically meaningful gastrointestinal problems when present
The microbiome sits within this framework—not above it.
Conclusion
The gut microbiome is emerging as a potentially important component of rheumatoid arthritis-associated interstitial lung disease.
Human studies now show that RA-ILD is associated with alterations across the intestinal bacteriome, mycobiome and virome, and some studies have identified microbial differences between RA-ILD and rheumatoid arthritis without lung disease.
However, the most recent 2026 metagenomic study also provides an important warning against overinterpretation: after correction for multiple comparisons, no genus significantly distinguished RA-ILD from RA without ILD.
That means the evidence currently supports association and biological plausibility—not a definitive microbial cause or diagnostic signature.
The next phase of research needs to move beyond asking:
“Which bacteria are different?”
and instead ask:
“Which microbial functions and metabolites influence rheumatoid immunity, which occur before lung disease, and can changing them modify the clinical course of RA-ILD?”
If those questions can be answered, microbiome science could eventually contribute to risk prediction, biomarkers or precision treatments for autoimmune ILD.
For now, it represents a promising research frontier within integrative pulmonology, rather than an established therapeutic strategy.
About Dr. Samar Shadly
Dr. Samar Shadly is a Consultant Pulmonologist and Certified Functional Medicine Practitioner, with advanced subspecialty training in interstitial lung disease, pulmonary fibrosis, pulmonary hypertension and lung transplantation at the University of Toronto.
Her clinical approach combines evidence-based pulmonary medicine with functional and integrative medicine, with particular interest in autoimmune-associated interstitial lung disease, the gut–lung axis, nutrition, metabolic health and emerging microbiome science.
Living With Rheumatoid Arthritis and Interstitial Lung Disease?
If you have RA-associated interstitial lung disease and are looking for a comprehensive evaluation that considers your pulmonary disease together with relevant nutritional, gastrointestinal, metabolic and lifestyle factors, you can explore the available consultation options.
Contact us through the consultation page or WhatsApp to learn more about online consultations.
Functional and integrative care is intended to complement—not replace—appropriate rheumatological, pulmonary, immunomodulatory or antifibrotic treatment.
Medical Disclaimer: This article is educational and is not a substitute for individualized medical advice or specialist RA-ILD care.