Gut Microbiome and Systemic Sclerosis–Associated Interstitial Lung Disease: Is There a Gut–Lung Connection?
Could the Gut Be Connected to Lung Fibrosis in Systemic Sclerosis?
Systemic sclerosis—also known as scleroderma—is a complex autoimmune disease that can affect multiple organs.
Two organ systems are particularly important:
the gastrointestinal tract and the lungs.
Gastrointestinal involvement is extremely common in systemic sclerosis. Patients may experience reflux, difficulty swallowing, delayed intestinal transit, constipation, diarrhea, bloating, malabsorption and small intestinal bacterial overgrowth (SIBO).
At the same time, interstitial lung disease (ILD) is one of the most important pulmonary complications of systemic sclerosis and a major contributor to disease-related morbidity and mortality.
For many years, these problems were largely considered separately.
The gut was the gut.
The lung was the lung.
Microbiome research is beginning to challenge that separation.
Increasing evidence suggests that patients with systemic sclerosis have an altered intestinal microbiome, or gut dysbiosis.
More importantly, new human research suggests that patients who develop systemic sclerosis-associated interstitial lung disease (SSc-ILD) may have intestinal microbial characteristics that differ from those of systemic sclerosis patients without ILD.
This has raised an important question:
Could the gut microbiome influence the development or progression of lung disease in systemic sclerosis?
The answer is not yet established.
But the evidence has become sufficiently compelling that the gut–lung axis is now a serious area of SSc-ILD research.
What Is Systemic Sclerosis–Associated ILD?
Systemic sclerosis is characterized by varying combinations of:
autoimmunity
vascular dysfunction
inflammation
abnormal fibroblast activation
tissue fibrosis
Fibrosis can affect the skin and several internal organs.
When the lungs are involved, patients may develop interstitial lung disease.
SSc-ILD can range from relatively mild radiological abnormalities to progressive fibrotic disease causing:
breathlessness
exercise limitation
cough
impaired gas transfer
declining lung function
The most common radiological pattern is nonspecific interstitial pneumonia (NSIP), although other patterns can occur.
The clinical course varies substantially between patients.
Some remain stable for years.
Others develop progressive pulmonary fibrosis.
Understanding why these differences occur is one of the major challenges in systemic sclerosis.
The microbiome may represent one piece of that puzzle.
Why Is the Gut Particularly Relevant in Systemic Sclerosis?
Systemic sclerosis is almost uniquely suited to studying the gut–lung axis because gastrointestinal dysfunction is so common.
Fibrosis, vascular abnormalities and autonomic or neuromuscular dysfunction can impair normal gastrointestinal movement.
This may affect:
the esophagus
stomach
small intestine
colon
Reduced motility changes the intestinal environment.
When intestinal contents remain stagnant for longer periods, microbial populations can change dramatically.
This can contribute to:
dysbiosis and SIBO.
At the same time, changes in diet, acid-suppressing medications, antibiotics and immune-modulating treatments may further modify the microbiome.
Therefore, a patient with systemic sclerosis may have several simultaneous factors capable of disrupting intestinal ecology.
What Is Gut Dysbiosis?
The intestinal microbiome contains trillions of microorganisms and an enormous collection of microbial genes.
These microorganisms help regulate:
digestion
vitamin metabolism
immune development
intestinal-barrier integrity
production of microbial metabolites
Dysbiosis refers to disruption of this ecosystem.
It may involve:
reduced microbial diversity
depletion of potentially beneficial organisms
expansion of opportunistic organisms
altered microbial metabolic activity
changes in immune–microbiome interactions
Studies have repeatedly demonstrated intestinal dysbiosis in systemic sclerosis.
The more recent question is whether particular patterns of dysbiosis are associated specifically with lung involvement.
The International SSc-ILD Gut Microbiome Study
One of the most important advances in this field came from an international investigation of the gut–lung axis in systemic sclerosis.
Researchers recruited 285 patients with systemic sclerosis from seven specialist centers across five continents.
Approximately 62.5% had interstitial lung disease.
Instead of using relatively limited bacterial sequencing techniques, researchers performed shotgun metagenomic sequencing.
This allowed much more detailed characterization of intestinal microbial species and their functional pathways.
Patients with SSc-ILD demonstrated a distinct intestinal microbial signature compared with systemic sclerosis patients without ILD.
The signature included increased abundance of several candidate pathobionts.
Even more interestingly, among patients with SSc-ILD, particular bacterial species and microbial functional pathways were associated with the radiological extent of ILD on HRCT.
This represents an important shift in the evidence.
The question is no longer simply:
“Do systemic sclerosis patients have dysbiosis?”
We can now ask:
“Are particular intestinal microbial patterns associated with the pulmonary phenotype and severity of systemic sclerosis?”
The answer appears to be yes.
However, association still does not prove causation.
Why Is This Study Important?
Previous microbiome studies in systemic sclerosis often came from relatively small, geographically limited cohorts.
That creates a problem.
The microbiome is strongly influenced by:
geography
ethnicity
habitual diet
medication
environment
lifestyle
A microbial signature identified in one country may not necessarily apply to patients elsewhere.
The multinational nature of the SSc-ILD study therefore makes the finding particularly interesting.
It suggests that relationships between intestinal microbial biology and ILD may persist despite substantial geographic variation.
Still, these findings require further validation.
Does Gut Dysbiosis Cause SSc-ILD?
We cannot currently say that it does.
Several explanations remain possible.
Possibility 1: Dysbiosis contributes to ILD
Altered microorganisms could affect immune regulation and microbial metabolite production, potentially influencing pulmonary inflammation and fibrosis.
Possibility 2: More severe systemic sclerosis causes both
Patients with more extensive systemic disease may develop both gastrointestinal dysfunction and pulmonary fibrosis.
Dysbiosis could therefore be a consequence or marker of disease severity.
Possibility 3: Gastrointestinal dysfunction drives dysbiosis
Impaired intestinal motility may create the environment that produces microbial changes.
Possibility 4: The relationship is bidirectional
This may ultimately be the most realistic model.
Systemic sclerosis damages gastrointestinal function.
GI dysfunction changes the microbiome.
The altered microbiome modifies immune and metabolic signaling.
Those signals may then influence systemic disease—including the lungs.
The cycle could reinforce itself.
How Could the Gut Microbiome Influence SSc-ILD?
Several mechanisms are biologically plausible.
1. Immune Dysregulation
Systemic sclerosis is fundamentally an immune-mediated disease.
Gut microorganisms interact with several immune-cell populations, including:
regulatory T cells
Th17 cells
dendritic cells
macrophages
B cells
Microbial signals help determine the balance between immune tolerance and immune activation.
Dysbiosis could therefore contribute to systemic immune dysregulation.
In a genetically susceptible person, this may potentially amplify pathways involved in autoimmunity and fibrosis.
This remains a hypothesis, but it has strong biological plausibility.
2. Microbial Metabolites
The gut microbiome produces biologically active compounds that can enter circulation.
These include:
short-chain fatty acids
tryptophan metabolites
bile-acid metabolites
microbial peptides
These molecules can influence immune cells far beyond the intestine.
This provides a mechanism through which intestinal organisms could affect pulmonary biology without bacteria themselves traveling to the lungs.
3. Short-Chain Fatty Acids and Butyrate
Certain gut bacteria ferment dietary substrates to produce short-chain fatty acids such as:
acetate
propionate
butyrate
Butyrate supports intestinal epithelial health and can influence immune regulation.
SCFAs can also affect regulatory T cells and inflammatory signaling.
A dysbiotic microbiome that alters SCFA production could therefore potentially modify systemic immune function.
Whether this contributes meaningfully to SSc-ILD progression in humans remains unknown.
4. Intestinal Barrier Dysfunction
The intestinal epithelium normally prevents uncontrolled movement of microbial products into circulation.
If barrier integrity becomes impaired, microbial molecules may gain greater systemic access.
One such molecule is lipopolysaccharide, or LPS.
LPS can activate innate immune pathways such as:
TLR4 → NF-κB
and increase inflammatory cytokine production.
Theoretically, this could contribute to systemic immune activation and profibrotic signaling.
However, direct evidence that increased intestinal permeability drives human SSc-ILD remains insufficient.
5. Fibroblast Activation
Systemic sclerosis is characterized by abnormal fibroblast activity.
Activated fibroblasts and myofibroblasts produce excessive:
collagen
fibronectin
extracellular matrix
TGF-β is one of the central signaling molecules driving this process.
Microbial metabolites and immune signals can influence pathways connected with TGF-β and fibroblast behavior experimentally.
This creates another potential bridge between intestinal biology and fibrosis.
SIBO: An Important Part of the Story
Small intestinal bacterial overgrowth is common in systemic sclerosis.
A previous systematic review estimated that SIBO occurs in approximately 39% of patients with systemic sclerosis, although prevalence varies substantially according to the population and diagnostic method.
Why is SIBO so common?
One major reason is impaired intestinal motility.
Normally, coordinated intestinal contractions help prevent excessive bacterial accumulation in the small intestine.
In systemic sclerosis, motility may be impaired.
This can lead to:
stasis → bacterial overgrowth → fermentation → symptoms and malabsorption
Symptoms may include:
bloating
abdominal distension
diarrhea
abdominal discomfort
excessive gas
nutritional deficiencies
weight loss
Severe or recurrent SIBO can contribute to malnutrition.
That matters greatly in a patient already coping with chronic lung disease.
Does SIBO Cause SSc-ILD?
This is an important distinction.
SIBO is common in systemic sclerosis.
ILD is also common.
But the coexistence of the two does not prove that SIBO causes pulmonary fibrosis.
Currently, there is insufficient evidence to conclude that treating SIBO slows SSc-ILD progression.
However, identifying and treating clinically significant SIBO may still be important because it can improve gastrointestinal symptoms and nutritional status.
Those benefits matter independently of any hypothetical pulmonary effect.
Reflux May Provide Another Gut–Lung Connection
Systemic sclerosis commonly affects the esophagus.
Patients may develop:
reduced lower esophageal sphincter pressure
impaired esophageal clearance
severe gastroesophageal reflux
swallowing dysfunction
This creates another potential route connecting the gastrointestinal tract and lungs:
microaspiration.
Small amounts of gastric or esophageal contents may reach the respiratory tract.
This mechanism is different from the systemic microbiome pathway.
The microbiome pathway involves metabolites and immune signals traveling through the body.
Microaspiration involves material physically entering the respiratory tract.
Both may potentially operate in the same patient.
Reflux, Microaspiration and Lung Fibrosis
Microaspiration has long been investigated as a possible contributor to lung injury in systemic sclerosis.
The concept is biologically plausible:
esophageal dysfunction → reflux → microaspiration → repetitive epithelial injury → pulmonary inflammation/fibrotic signaling
However, determining the exact contribution of reflux to SSc-ILD progression is difficult.
Nevertheless, severe reflux and swallowing dysfunction are clinically important and deserve appropriate assessment.
SIBO, Reflux and Dysmotility Are Different Problems
These conditions are sometimes incorrectly grouped together as simply “poor gut health.”
They are distinct.
GERD involves reflux of gastric contents.
Esophageal dysmotility involves abnormal movement through the esophagus.
SIBO involves excessive or abnormal microbial populations in the small intestine.
Gut dysbiosis refers more broadly to altered microbial ecology.
A patient can have one without the others.
An integrative assessment should therefore identify the actual gastrointestinal problem rather than applying a generic “gut healing” protocol.
Could Treating the Gut Improve SSc-ILD?
This remains one of the major unanswered questions.
Potential microbiome-directed approaches under investigation include:
dietary intervention
probiotics
prebiotics
antibiotics
prokinetics
fecal microbiota transplantation
targeted microbial metabolites
But no microbiome-directed intervention has yet been established as a treatment capable of slowing SSc-ILD.
Probiotics in Systemic Sclerosis
Probiotic and synbiotic interventions have been investigated in systemic sclerosis, particularly for gastrointestinal symptoms.
A recent systematic review evaluated probiotics, prebiotics and synbiotics in scleroderma and concluded that evidence remains insufficient and heterogeneous.
Importantly, there are currently no established recommendations supporting these interventions as treatments for SSc-ILD.
This is an important boundary.
A probiotic may potentially help a gastrointestinal symptom in selected patients.
That is different from treating pulmonary fibrosis.
Fecal Microbiota Transplantation
FMT is another emerging area.
The procedure transfers a complex microbial community from a donor into a recipient.
Small experimental studies in systemic sclerosis have explored microbiota transplantation and gastrointestinal outcomes.
The concept is scientifically interesting because FMT changes the microbial ecosystem more substantially than a conventional probiotic.
However, FMT is not established therapy for systemic sclerosis or SSc-ILD.
It should currently be regarded as investigational in this context.
Could the Microbiome Become a Biomarker?
This may actually occur before microbiome therapy becomes available.
The international SSc-ILD study raises the possibility that microbial signatures might eventually help identify:
patients at risk of ILD
different disease phenotypes
patients with more extensive pulmonary disease
biological pathways associated with progression
But substantial validation is required.
Microbiome profiles are influenced by many confounders, including medications and geography.
Therefore, stool microbiome testing is not currently part of standard SSc-ILD risk stratification.
Should Patients With SSc-ILD Have Commercial Microbiome Testing?
Not routinely for the purpose of managing their lung disease.
Commercial stool testing may provide information about gastrointestinal function in selected circumstances.
But no commercial microbiome test has been validated to:
diagnose SSc-ILD
predict progression
determine HRCT severity
select immunosuppressive treatment
select antifibrotic therapy
determine which probiotic will improve the lung disease
Research metagenomics should not be confused with routine commercial testing.
Nutrition Is Particularly Important in SSc-ILD
Patients with systemic sclerosis can be nutritionally vulnerable.
Potential contributors include:
dysphagia
reflux
gastroparesis
intestinal dysmotility
SIBO
diarrhea
malabsorption
reduced appetite
restrictive diets
Meanwhile, chronic lung disease can increase the importance of maintaining muscle mass and adequate nutrition.
Therefore, dietary interventions should be individualized.
A highly restrictive “microbiome diet” that produces weight loss or protein deficiency may ultimately be harmful.
What About a High-Fiber Diet?
Fiber can support microbial fermentation and SCFA production.
But systemic sclerosis is one of the clearest examples of why generic high-fiber recommendations can fail.
A patient with severe dysmotility or SIBO may experience substantial:
bloating
gas
abdominal pain
distension
after rapidly increasing fermentable fiber.
The appropriate diet depends on gastrointestinal phenotype and nutritional needs.
Functional Medicine and SSc-ILD
Systemic sclerosis-associated ILD is precisely the type of complex disease where an integrative framework can be useful—provided that evidence and priorities remain clear.
Conventional pulmonary and rheumatological assessment remains essential.
Depending on the patient, established treatment may involve:
immunomodulatory therapy
antifibrotic therapy
pulmonary monitoring
pulmonary rehabilitation
oxygen
transplantation evaluation
An integrative assessment can then examine additional clinically relevant factors such as:
reflux
aspiration risk
dysphagia
SIBO
intestinal dysmotility
nutritional status
vitamin and mineral deficiencies
muscle mass
sleep
physical activity
metabolic health
This is very different from claiming that the disease can be treated by “healing the gut.”
What We Know
We now know that:
intestinal dysbiosis occurs in systemic sclerosis
SIBO is common
gastrointestinal dysmotility strongly influences intestinal ecology
patients with SSc-ILD have distinct intestinal microbial characteristics
particular microbial species and functional pathways correlate with radiological ILD extent
This represents genuine human evidence for a gut–lung association.
What We Do Not Know
We still do not know whether:
dysbiosis causes SSc-ILD
microbial changes precede pulmonary disease
treating dysbiosis prevents ILD
treating SIBO slows fibrosis
probiotics improve lung function
FMT modifies ILD progression
microbiome signatures can reliably predict prognosis
These questions require prospective and interventional studies.
What Should Patients With SSc-ILD Do Today?
The practical message is not that every patient needs a microbiome protocol.
Instead, gastrointestinal health deserves appropriate clinical attention.
Symptoms such as:
persistent bloating
diarrhea
constipation
reflux
difficulty swallowing
early satiety
unexplained weight loss
should not automatically be accepted as unavoidable consequences of systemic sclerosis.
They may warrant evaluation for conditions such as:
SIBO
esophageal dysfunction
gastroparesis
malabsorption
nutritional deficiency
Treating these problems may improve quality of life and nutritional status even while we continue investigating their relationship with pulmonary disease.
The Future: From Gut Bacteria to Precision SSc-ILD Medicine
The next generation of research will need to go beyond identifying bacterial species.
Researchers will need to combine:
**metagenomics
metabolomics
immune profiling
HRCT quantification
pulmonary function
longitudinal outcomes**
The key question will become:
Do microbial changes occur before lung progression—and can changing those pathways alter the disease?
If the answer is yes, microbiome science could eventually produce new biomarkers or therapeutic targets for SSc-ILD.
The international multicenter findings make that possibility increasingly worthy of investigation.
Conclusion
The relationship between the gut microbiome and systemic sclerosis-associated interstitial lung disease has moved from an interesting theory toward a genuine area of human clinical research.
We now have multinational evidence demonstrating that patients with SSc-ILD possess distinct intestinal microbial characteristics and that specific microbial species and functional pathways are associated with the radiological extent of lung disease.
That is significant.
But it does not yet demonstrate that gut dysbiosis causes pulmonary fibrosis or that correcting the microbiome will slow SSc-ILD.
The most accurate interpretation is that the intestinal microbiome may be one component of a much larger network involving:
gastrointestinal dysmotility + microbial ecology + immune dysregulation + metabolism + autoimmunity + fibrosis.
For patients, gastrointestinal health deserves attention because reflux, dysmotility, SIBO and malnutrition are clinically important problems in their own right.
For researchers, the next challenge is considerably more ambitious:
Can changing the gut environment change what happens in the lungs?
That question may eventually open an entirely new therapeutic direction for autoimmune interstitial lung disease.
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 specialist pulmonary medicine with evidence-based functional and integrative medicine, with particular interest in the gut–lung axis, autoimmune-associated ILD, nutrition, metabolic health and gastrointestinal factors that may influence chronic lung disease.
Looking for a Comprehensive Approach to Systemic Sclerosis–Associated ILD?
If you are living with systemic sclerosis-associated interstitial lung disease and would like a comprehensive assessment that combines specialist ILD expertise with an evidence-based functional and integrative perspective, you can explore the available consultation options.
The assessment may include consideration of your pulmonary disease alongside relevant factors such as gastrointestinal symptoms, reflux, nutrition, metabolic health, lifestyle and other potentially modifiable contributors to overall health.
Contact us through the consultation page or WhatsApp to learn more about online consultation options.
Functional and integrative care is intended to complement—not replace—appropriate rheumatological, pulmonary, immunomodulatory or antifibrotic treatment.
Medical Disclaimer: This article is for educational purposes and does not constitute individualized medical advice. Patients with systemic sclerosis-associated ILD should remain under appropriate specialist pulmonary and rheumatological care.