Fecal Microbiota Transplantation in Systemic Sclerosis and Pulmonary Fibrosis: What Does the Evidence Show?

Why Is FMT Being Studied in Systemic Sclerosis?

Systemic sclerosis is a multisystem autoimmune disease.

Gastrointestinal involvement is extremely common and can include:

• esophageal dysmotility

• gastroparesis

• intestinal dysmotility

• SIBO

• diarrhea

• constipation

• bloating

• malabsorption

At the same time, systemic sclerosis is associated with alterations in the intestinal microbiome.

This has led researchers to ask whether deliberately changing gut microbial communities could improve disease-related gastrointestinal symptoms.

One of the most powerful ways to modify the microbiome is fecal microbiota transplantation, or FMT.

Unlike a conventional probiotic containing a small number of organisms, FMT transfers an entire microbial community.

Systemic sclerosis is one of the few autoimmune diseases in which FMT has actually progressed into randomized controlled human trials.

The results, however, are more complicated than the early enthusiasm suggested.

What Is Fecal Microbiota Transplantation?

FMT involves transferring intestinal microorganisms from a screened donor or standardized microbial preparation into the gastrointestinal tract of a recipient.

Delivery methods may include:

• colonoscopy

• enema

• nasoenteric administration

• gastroduodenal administration

• capsules

The best-established medical role for FMT is recurrent Clostridioides difficile infection.

Its use in autoimmune diseases remains investigational.

Why Systemic Sclerosis?

Several features make SSc interesting for microbiome intervention.

Patients often have:

dysmotility → microbial stasis → SIBO/dysbiosis → gastrointestinal symptoms

The gut microbiome may also interact with systemic immunity.

This creates the possibility that microbiome modification could potentially influence:

• GI symptoms

• intestinal immune responses

• microbial metabolites

Whether it can influence systemic sclerosis itself is far less certain.

The 2020 Randomized Pilot Trial

A landmark pilot study published in 2020 enrolled 10 patients with systemic sclerosis and gastrointestinal symptoms.

Patients were randomized to:

• anaerobic cultivated human intestinal microbiota, ACHIM, n=5

• placebo, n=5

FMT or placebo was administered at weeks 0 and 2.

Four of five FMT recipients experienced improvement in symptoms such as:

• bloating

• diarrhea

• fecal incontinence

at one or more follow-up time points, compared with two of four evaluable placebo recipients.

Microbiome diversity and composition changed more substantially after FMT.

The investigators concluded that the intervention showed a possible GI benefit and justified larger trials. (PubMed⁠)

This pilot generated considerable interest.

But five actively treated patients are far too few to establish efficacy.

Why the Pilot Was Still Important

The pilot demonstrated that:

• microbiome transplantation was technically feasible in SSc

• the intestinal microbiome could be modified

• symptom improvement was possible

• further controlled trials were warranted

It represented proof of concept.

But it was not definitive evidence.

The Larger ReSScue Phase 2 Trial

The crucial next step was the ReSScue phase 2 randomized, double-blind, placebo-controlled trial.

The trial was conducted across four university hospitals in Norway.

It enrolled 67 participants with systemic sclerosis and moderate-to-severe lower GI symptoms.

Participants were randomized:

• 33 to ACHIM

• 34 to placebo

The intervention was given at weeks 0 and 2.

The primary endpoint was change in the patient’s worst lower GI symptom—bloating or diarrhea—at 12 weeks.

The result was important:

FMT did not produce a statistically significant improvement in the primary GI outcome compared with placebo. (PubMed⁠)

This is a key update that should change how FMT in systemic sclerosis is presented clinically.

Why Did the Larger Trial Matter So Much?

The original pilot suggested benefit.

The larger phase 2 trial did not confirm improvement in the primary endpoint.

This is a classic example of why small pilot studies should not be translated prematurely into treatment protocols.

Small studies can generate large apparent treatment effects because of:

• chance

• patient selection

• placebo response

• heterogeneity

• statistical instability

The larger trial provided a more reliable estimate.

Safety Findings

In the phase 2 trial, adverse events were mostly mild, short-lived gastrointestinal symptoms.

However, one participant experienced a duodenal perforation during gastroscopy. (PubMed⁠)

The earlier pilot also documented serious procedure-related complications in placebo recipients, including laryngospasm and duodenal perforation during gastroduodenoscopy. (PubMed⁠)

These complications emphasize that FMT delivery method matters.

FMT is not inherently a harmless “natural microbiome treatment.”

Does FMT Improve Systemic Sclerosis?

There is currently insufficient evidence that FMT modifies systemic sclerosis itself.

The trials primarily evaluated gastrointestinal symptoms.

They did not establish improvement in:

• skin fibrosis

• pulmonary fibrosis

• FVC

• DLCO

• pulmonary hypertension

• survival

This distinction is extremely important.

What About SSc-ILD?

Systemic sclerosis-associated ILD is one of the most important complications of SSc.

Recent human microbiome research has identified a distinct intestinal microbial signature in SSc-ILD.

This provides an important rationale for future research.

But FMT has not been shown to improve SSc-ILD.

There is no clinical evidence that FMT:

• improves FVC

• improves HRCT fibrosis

• prevents ILD progression

in systemic sclerosis.

Could FMT Affect Pulmonary Fibrosis?

This is where animal studies become particularly interesting.

Several experiments demonstrate that changing the intestinal microbiome through fecal transfer can alter pulmonary fibrosis severity.

FMT Can Transfer a More Severe Fibrosis Phenotype in Mice

One important study compared germ-free mice and conventionally colonized mice.

Germ-free mice developed less bleomycin-induced lung fibrosis.

Mice with different microbial environments developed different fibrosis severity.

When researchers transplanted fecal microbiota associated with severe fibrosis into germ-free mice, those animals developed more severe fibrosis than animals receiving microbiota from mice with the less severe phenotype.

The effect was associated with increased:

IL-6 → STAT3 → IL-17A signaling. (PubMed⁠)

This is strong preclinical evidence that intestinal microbial communities can modify pulmonary fibrosis.

FMT Can Also Transfer a Protective Microbiome

Another experiment investigated polydatin in bleomycin-induced pulmonary fibrosis.

Polydatin altered the gut microbiome and reduced fibrosis.

When fecal microbiota from polydatin-treated mice were transferred into antibiotic-depleted mice, the transferred microbiome also reduced fibrosis compared with microbiota from untreated fibrotic animals. (PubMed⁠)

This provides another important proof of concept:

microbiota may carry biological information capable of modifying lung fibrosis.

But FMT Does Not Always Work

A 2026 experimental study investigating a traditional formulation found microbiome remodeling associated with reduced early bleomycin fibrosis.

A probiotic intervention partially reproduced the protective phenotype.

FMT, however, showed limited efficacy in that experiment. (PubMed⁠)

This is important because it demonstrates that microbiome transfer is not predictably therapeutic.

Microbial effects may depend on:

• donor ecology

• recipient ecology

• timing

• disease stage

• host immune status

• microbial metabolites

A 2026 TLR5 Study Adds Another Layer

A 2026 translational study investigated Toll-like receptor 5 in pulmonary fibrosis.

TLR5 deficiency was associated with lung dysbiosis and greater susceptibility to experimental fibrosis.

Activation of epithelial TLR5 improved lung microbial balance and protected against fibrosis.

When the microbiome was removed using antibiotics, this protective effect disappeared.

Reconstitution through fecal microbiota transplantation restored the phenotype. (PubMed⁠)

This provides additional evidence that microbial ecosystems participate actively in experimental fibrosis biology.

Importantly, this study focused substantially on the lung microbiome, illustrating that FMT experiments can affect complex systemic microbial-immune networks.

Does This Mean FMT Should Be Used for IPF?

No.

There are currently no adequate human clinical trials demonstrating that FMT treats idiopathic pulmonary fibrosis.

FMT should be considered experimental in this context.

Human and Mouse Evidence Are Fundamentally Different

Experimental pulmonary fibrosis allows investigators to:

• induce injury at a known time

• manipulate microbiota before and after injury

• use germ-free animals

• transfer complete microbial communities

• control diet and environment

Human IPF develops over years.

By the time IPF is diagnosed, established fibrosis may already be present.

This is a fundamentally different biological scenario.

Donor Selection Is a Major Challenge

There may not be a universal “healthy microbiome.”

Microbiota vary according to:

• geography

• diet

• age

• genetics

• medications

• environment

The ideal microbiome for one recipient may not be ideal for another.

This makes donor standardization difficult.

Infection Risk

FMT involves transfer of biological material containing microorganisms.

Rigorous donor screening is essential.

Potential risks include transmission of:

• infectious organisms

• antibiotic-resistant bacteria

• viruses

• unrecognized pathogens

This is particularly relevant in autoimmune patients receiving immunosuppression.

Could FMT Transfer Unwanted Metabolic Traits?

Potentially.

The microbiome influences:

• energy metabolism

• bile acids

• drug metabolism

• immune signaling

Transferring an entire ecosystem is inherently less precise than administering a defined metabolite or microbial consortium.

This is one reason future therapy may move away from conventional donor-stool FMT.

Next-Generation Microbiome Therapy

Future alternatives may include:

• defined bacterial consortia

• cultured microbial communities

• precision probiotics

• postbiotics

• microbial metabolites

• engineered microorganisms

These approaches could provide greater reproducibility than traditional stool transfer.

ACHIM itself represents an attempt to use a standardized cultured microbiome rather than uncontrolled donor stool.

Functional and Integrative Medicine Perspective

FMT is a good example of why microbiome therapy requires evidence rather than enthusiasm.

The conceptual rationale is strong.

The experimental data can be impressive.

But the larger human SSc trial did not confirm the benefit suggested by the initial pilot. (PubMed⁠)

Therefore, routine FMT should not currently be recommended as treatment for:

• systemic sclerosis

• SSc-ILD

• IPF

• pulmonary fibrosis

outside established indications or appropriate clinical research.

What We Know About FMT in SSc

We know that:

• gut dysbiosis occurs in systemic sclerosis

• a small randomized pilot suggested GI symptom improvement

• microbiome composition could be modified

• the larger phase 2 ReSScue trial did not show significant improvement in its primary endpoint

(PubMed⁠)

What We Know About FMT in Pulmonary Fibrosis

We know that:

• fecal microbiota can alter fibrosis severity in mice

• microbiota from severe-fibrosis environments can transmit greater fibrosis

• microbiota from selected treated animals can transmit partial protection

• FMT effects are inconsistent between models

(PubMed⁠)

What We Do Not Know

We do not know:

• whether FMT improves human IPF

• whether FMT improves SSc-ILD

• which microbial community would be therapeutic

• optimal timing

• optimal delivery route

• long-term safety

• whether defined metabolites would be safer and more effective

Frequently Asked Questions

Has FMT been studied in systemic sclerosis?

Yes. It has been evaluated in randomized controlled human studies.

Did it work?

The 2020 pilot showed encouraging signals, but the larger phase 2 trial did not demonstrate significant improvement in the primary GI outcome.

Has FMT been studied in pulmonary fibrosis?

Yes, mainly in animal models.

Can FMT reverse lung fibrosis?

There is no evidence that it reverses human pulmonary fibrosis.

Is FMT approved for systemic sclerosis?

No.

Conclusion

FMT represents one of the most direct ways to test whether changing the intestinal microbiome can change disease.

In systemic sclerosis, the evidence has progressed further than in most autoimmune diseases.

A small 2020 randomized pilot suggested improvement in gastrointestinal symptoms after ACHIM microbiota transfer. (PubMed⁠)

But the larger 67-person phase 2 ReSScue trial did not demonstrate significant improvement in the primary gastrointestinal endpoint. (PubMed⁠)

This negative trial is clinically important and should prevent premature claims that FMT is an established treatment for systemic sclerosis.

For pulmonary fibrosis, evidence remains preclinical.

Animal experiments demonstrate that gut microbiota can alter fibrosis severity and that fecal transfer can sometimes reproduce protective or harmful phenotypes. (PubMed⁠)

These studies provide biological proof of concept.

They do not establish FMT as a human antifibrotic treatment.

The future may ultimately move beyond traditional FMT toward defined microbial ecosystems or specific microbial metabolites with clearer biological mechanisms and better safety.

For now, FMT in systemic sclerosis and pulmonary fibrosis should remain a research strategy rather than routine integrative treatment.

bout 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, together with expertise in functional and integrative medicine.

Her approach combines evidence-based pulmonary medicine with a broader assessment of factors that may influence a patient’s overall health, including nutrition, gastrointestinal health, the gut microbiome, metabolic health, lifestyle, and relevant environmental exposures.

A particular focus of her work is the emerging field of Integrative and Functional Pulmonology, especially in pulmonary fibrosis and autoimmune-associated interstitial lung disease. Her goal is to bridge conventional respiratory medicine with scientifically grounded integrative strategies, while clearly distinguishing established clinical evidence from promising but still experimental research.

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