A discovery by an international research team led by Greek scientist Stavros Garantziotis may pave the way for a targeted therapy for idiopathic pulmonary fibrosis, a progressive lung disease for which transplantation remains the only potentially curative option.
The team found that Toll-like receptor 5, known as TLR5, helps protect the lungs by controlling their microbial environment. When the receptor does not function properly, harmful changes can develop in the lung microbiome, potentially increasing inflammation and tissue scarring.
Moreover, the researchers showed that activating TLR5 with a synthetic compound protected mice from experimental pulmonary fibrosis. Although the findings remain preclinical, they identify a promising biological pathway that could guide future drug development.
A progressive disease with no cure
Idiopathic pulmonary fibrosis, or IPF, causes scar tissue to accumulate deep inside the lungs. Over time, the tissue becomes thick and stiff, making it increasingly difficult for oxygen to pass into the bloodstream.
Patients often experience shortness of breath, a persistent dry cough, fatigue and a gradual decline in their ability to perform everyday activities. Because these symptoms can resemble those of other respiratory or cardiovascular conditions, diagnosis may be delayed.
The word “idiopathic” means that the precise cause of the disease remains unknown. Nevertheless, age, genetic predisposition, cigarette smoking and certain environmental exposures have been associated with an increased risk.
Available antifibrotic medications can slow the disease’s progression in some patients. However, they cannot reverse the scarring that has already developed. At present, lung transplantation remains the only potentially curative option for eligible patients with advanced disease.
Consequently, researchers have continued to search for the biological mechanisms that initiate or accelerate lung fibrosis.
The lung microbiome’s role in disease
For many years, scientists assumed that healthy lungs were sterile. Advances in genetic sequencing have since shown that the respiratory system contains a diverse community of microorganisms known as the lung microbiome.
Under normal circumstances, immune defenses help maintain a stable microbial balance. However, smoking, air pollution, infections and other forms of lung injury can disrupt this environment.
This imbalance, known as dysbiosis, may allow certain microorganisms to multiply or trigger an excessive immune response. As a result, prolonged inflammation can damage lung tissue and contribute to fibrosis.
Garantziotis and his colleagues investigated whether dysbiosis merely accompanies pulmonary fibrosis or actively contributes to the disease’s development.
Their findings suggest that the lung microbiome plays a direct role. In particular, TLR5 appears to act as a protective regulator that helps prevent harmful microbial changes following lung injury.
An immune receptor with a protective role
TLR5 forms part of the innate immune system, the body’s first line of defense against infection. The receptor recognizes flagellin, a protein found in the structures that some bacteria use for movement. Once activated, TLR5 stimulates the production of antimicrobial substances that help control bacterial populations.
The researchers found that TLR5 deficiency was associated with idiopathic pulmonary fibrosis in humans. In laboratory experiments, mice without functioning TLR5 receptors also showed greater susceptibility to chemically induced pulmonary fibrosis. Furthermore, TLR5 deficiency in both mice and patients with IPF was linked to microbial imbalance in the lungs.
By contrast, when the researchers activated TLR5 in lung epithelial cells with a synthetic flagellin-based compound, antimicrobial gene activity increased. The treatment improved microbial balance and protected the animals from experimental fibrosis. These findings indicate that TLR5 may help shield the lungs from scarring by controlling microbial populations after an injury.
Greek scientist’s lung disease experiments confirm the microbiome connection
The researchers conducted additional experiments to determine whether the protective effect depended on the lung microbiome. When antibiotics were used to eliminate the microbiome in mice, TLR5 activation no longer provided the same protection against fibrosis. This result suggested that the receptor’s effectiveness depended on its interaction with microbial communities.
The scientists then restored the animals’ microbiome through microbiota transplantation. Following this procedure, the protective effect reappeared. Together, the experiments strengthened the evidence that TLR5 influences pulmonary fibrosis by regulating the microbiome rather than acting solely through a general anti-inflammatory mechanism.
Greek scientist identifies a potential target for future lung disease therapies
The discovery raises the possibility of developing treatments that activate TLR5 and reinforce the lungs’ natural antimicrobial defenses. Such an approach would differ from existing antifibrotic drugs, which primarily aim to slow the formation of scar tissue. Instead, a TLR5-based treatment could target an earlier biological mechanism linked to microbial imbalance and immune dysfunction.
The findings may also help researchers identify patients who are more likely to benefit from microbiome-focused treatments. For example, some individuals with TLR5 deficiency or a specific form of lung dysbiosis could potentially respond to carefully selected antimicrobial therapies.
However, the researchers have not established that antibiotics can treat IPF. Broad or unnecessary antibiotic use can disrupt beneficial microbial communities and contribute to antimicrobial resistance. Therefore, any microbiome-based therapy would require extensive clinical testing and precise patient selection.
Likewise, the compound used to activate TLR5 has so far been tested only in experimental models. Human trials will be needed to determine whether this strategy is safe and effective for patients.
Possible implications for COPD
The biological pathway may also have implications for chronic obstructive pulmonary disease, commonly known as COPD.
In related research described by Garantziotis, higher levels of TLR5 expression in the lungs of patients with COPD were associated with lower levels of inflammatory markers in their blood. Researchers also observed that cigarette smoke reduced TLR5 expression in airway cells.
These observations could help explain how smoking weakens the lungs’ natural defenses and promotes persistent inflammation. Nevertheless, the COPD findings are separate from the published IPF study and will require further scientific evaluation.
From Athens to US medical research
Garantziotis was born and raised in Athens before studying medicine at Albert Ludwig University in Germany. He later completed his medical training in the United States.
After specializing in internal medicine at Albert Einstein College of Medicine in New York, he pursued further training in pulmonary and critical care medicine at Duke University in North Carolina.
His research at the National Institute of Environmental Health Sciences has examined how environmental exposures, immune responses and the lung microbiome contribute to chronic respiratory disease.
He also served for approximately 15 years as director of the institute’s Clinical Research Unit, where researchers investigate the effects of environmental factors on human health.
Greek scientist’s promising finding for deadly lung disease, not yet a cure
The latest discovery does not provide an immediate cure for idiopathic pulmonary fibrosis. However, it identifies a previously underexplored mechanism connecting immune function, microbial balance and lung scarring. Importantly, the study also offers researchers a defined target for future therapies.
The next stages will involve determining whether TLR5 activation can safely produce similar protective effects in humans and identifying which patients would be most likely to benefit. Although that process may take years, the findings offer new hope that scientists can eventually move beyond slowing pulmonary fibrosis and begin targeting one of the mechanisms that drives it.
The study was published in the peer-reviewed journal Science Translational Medicine.
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