Something has shifted in the science of severe asthma.
Not overnight. Not with a single breakthrough. But through the accumulation of peer-reviewed evidence, molecular diagnostic technology, federal policy acknowledgment, and the persistent questions of patients who refused to accept symptom management as a final answer — the field is arriving at a conclusion that changes the way we need to think about one of medicine’s most undertreated populations.
For a significant subpopulation of severe asthma patients, the disease is not primarily inflammatory. It is microbial. And the tools to find it have existed for years — they simply haven’t been applied.
This post documents where that conversation stands in 2026 — and why the World Asthma Foundation believes it represents one of the most important unaddressed gaps in respiratory medicine.
The Subpopulation We Can’t Count
Severe asthma affects approximately 30 million people globally — roughly 10% of the 300 million living with asthma worldwide. Of those, peer-reviewed evidence documents that 15–17% are complete non-responders to biologic therapy, 43–69% are only partial responders, and only 14–24% achieve the kind of remission that biologics promise.
That means the majority of severe asthma patients on the most sophisticated treatments available are not getting better. And for a subset of those patients — the size of which we cannot currently estimate — the reason may not be that the treatment is inadequate. It may be that the diagnosis is incomplete.
The Microbiome — The Missing Variable
The lung was once considered a sterile organ. It is not.
Peer-reviewed research now documents that the lung has its own microbiome — a complex ecosystem of organisms that, when in balance, supports healthy respiratory function, and when disrupted, may drive disease in ways that standard diagnostics cannot see and standard treatments cannot reach.
What disrupts the lung microbiome:
Long-term corticosteroid use suppresses the adaptive immune response that normally keeps opportunistic bacteria in check — creating conditions for pathogenic organisms to establish and dominate
Antibiotic exposure selects for resistant organisms while eliminating susceptible ones, progressively narrowing the microbial diversity that supports immune health
Gut microbiome disruption — through H. pylori eradication, antibiotic courses, diet, and environmental factors — alters the gut-lung immune axis in ways that affect respiratory microbiome composition over years and decades
The result, in a vulnerable subpopulation, is a lung ecosystem dominated by organisms that standard cultures cannot identify, that standard treatments cannot reach, and that standard diagnostics were never designed to find.
The Diagnostic Gap — Why We Can’t See What We’re Missing
Standard severe asthma diagnostics in 2026 rely primarily on spirometry, blood eosinophil counts, IgE levels, sputum cytology, and standard bacterial culture. These tools were designed to characterize the Type 2 inflammatory endotype. They are largely blind to the microbial endotype.
Molecular diagnostic sequencing — metagenomics, DNA-level analysis of bronchoscopic samples — can identify what is actually living in the lung with a precision that standard cultures cannot approach. This technology exists now. It is not experimental. It is not prohibitively expensive relative to the cost of years of failed biologic therapy. It is simply not part of the standard diagnostic algorithm for severe asthma.
That is the gap. And it is costing patients — in quality of life, in progressive disease burden, and in decades of misdirected treatment.
The Steroid Trap — When Treatment Compounds the Problem
This is the most uncomfortable finding in the current literature — and the one the severe asthma community most needs to confront.
Long-term corticosteroids suppress airway inflammation effectively. They also suppress the very immune mechanisms that would normally control bacterial colonization in the lung. The research is now explicit: steroid use is a documented risk factor for gut and lung microbiota disruption.
In a patient with an already-compromised lung ecosystem, long-term corticosteroids may be creating the conditions that allow opportunistic, drug-resistant organisms to establish dominance — while the treatment that finds and addresses those organisms is never ordered.
The treatment suppresses the symptom. The organism advances. This is not a reason to stop corticosteroid therapy. It is a reason to investigate the microbiome in every patient who requires long-term corticosteroid use.
The Gut-Lung Axis — The Origin Story That Goes Back Further
One of the most consequential findings in recent asthma research is the documented relationship between gut microbiome disruption and respiratory disease. The gut and lung are immunologically connected. Disruption of the gut microbiome — through antibiotic exposure, H. pylori eradication, dietary changes, or environmental factors — alters the systemic immune environment in ways that affect respiratory health over years and decades.
Research currently underway at the University of Kentucky — funded by the Global Lyme Alliance — is examining precisely this mechanism: how infection and antibiotic treatment disrupt the gut microbiome and weaken the intestinal barrier, driving systemic inflammation throughout the body. The implications for severe asthma patients with repeated antibiotic exposure or a history of H. pylori eradication are significant.
The origin of a patient’s severe asthma may not begin in the lung. It may begin in the gut — years or decades before the first wheeze.
The Polymicrobial Question — Beyond Single-Organism Thinking
Emerging research suggests that the microbial component of treatment-resistant asthma may not be a single-organism problem. Published evidence documents that immunosuppressed patients with respiratory bacterial colonization frequently carry co-existing organisms — bacterial, viral, and fungal — that interact with each other and with the host immune system in ways that single-organism treatment approaches cannot address.
For the patient who has failed multiple biologic therapies and whose disease continues to progress, a comprehensive polymicrobial assessment — molecular sequencing of bronchoalveolar lavage fluid, viral reactivation panels, gut microbiome profiling — may be the diagnostic step that changes everything.
The Neurological Dimension — When the Lung Isn’t the Limit
When systemic inflammation driven by an unidentified microbial burden is suppressed but not resolved, the consequences can extend beyond the respiratory system. Peer-reviewed research documents the gut-brain axis, the relationship between microbial dysbiosis and mast cell activation syndrome, and published cases of Small Fiber Neuropathy driven by infectious burden that resolved with targeted treatment.
For severe asthma patients with unexplained neurological symptoms — neuropathy, autonomic dysfunction, cognitive changes — the question of whether an undetected microbial burden is contributing deserves formal investigation. The lung may be where the disease presents. The microbiome may be where it lives.
What We Are Calling For
For patients with treatment-resistant severe asthma: Ask for molecular diagnostic sequencing before accepting that your disease is simply “refractory.” Ask specifically: “Has my lung microbiome been assessed by molecular sequencing?”
For pulmonologists: A bifurcated biologic response — improvement in one domain, none in others — is a diagnostic signal pointing toward an independent disease axis. Molecular diagnostics of bronchoalveolar lavage fluid should be considered in patients who have failed multiple biologic therapies.
For researchers: The microbial endotype of severe asthma needs its own epidemiological definition and research program. We do not know how many patients fall into this category. That is an unacceptable gap in 2026.
For diagnostic standards bodies: Molecular sequencing must be incorporated into the diagnostic pathway for severe asthma patients who fail conventional therapy. The technology exists. The evidence base is building.
For policymakers: Reimbursement for molecular diagnostic sequencing in treatment-resistant severe asthma is a health equity issue. The patients who most need better diagnostics are often those with the fewest resources to advocate for them.
What We Will Be Exploring Next
Over the coming months the World Asthma Foundation will publish a series examining these questions in depth:
The Origin Story — How gut microbiome disruption initiates the cascade that drives treatment-resistant asthma
The Microbial Endotype — What molecular diagnostics are finding in the lungs of patients who have failed standard care
The Polymicrobial Dimension — When the problem isn’t one organism but an ecosystem
The Neurological Connection — When untreated microbial burden extends beyond the lung
The Patient Roadmap — How to advocate for molecular diagnostics and navigate a specialist system that sees organs rather than patients
The observations in this post are informed by peer-reviewed literature, ongoing research programs at leading academic institutions, and the clinical experience of patients navigating treatment-resistant severe asthma. They represent the World Asthma Foundation’s current research-informed perspective — not clinical recommendations. Patients should discuss diagnostic and treatment decisions with their physicians.
World Asthma Foundation | worldasthmafoundation.org | worldasthmaday.org | May 2026
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May 6, 2025 – The World Asthma Foundation (WAF) is proud to announce a major new initiative on World Asthma Day aimed at transforming how we understand and manage severe asthma — a condition that continues to affect millions and defy conventional treatment.
Titled “Reframing Severe Asthma: From Ro,” this ongoing series will dig deep into the science and patient experience of severe asthma, exploring overlooked contributors and practical, cost-effective strategies for care. This initiative builds on WAF’s continuing collaboration with leading experts, including Dr. David Corry of Baylor College of Medicine, whose pioneering research into airway mycosis is helping redefine what drives severe asthma in many patients.
“We believe the time has come to stop treating symptoms alone and start asking deeper, root cause, questions about what’s really causing severe asthma—and how we can affordably and effectively address them,” said David B. Corry, M.D., Professor of Medicine-Immunology, Allergy, and Rheumatology, Baylor College of Medicine, Houston, TX, US.
But the scope goes well beyond fungi. The series will also examine:
Bacterial influences in asthma, including Streptococcus pseudopneumoniae and airway microbiome disruption
Mast cell activation and its role in chronic inflammation and systemic symptoms
Genetic predisposition (e.g., ADAM33) and airway remodeling
Environmental and chemical sensitivities increasingly reported by severe asthma sufferers
WAF’s Reframing Severe Asthma series will feature:
In-depth interviews and commentary from thought leaders
Patient stories and clinical case insights
Roundtable discussions and virtual events
A final White Paper and Action Plan for clinicians, researchers, and policymakers
The World Asthma Foundation’s symposium continues to shed light on airway mycosis, an often-overlooked factor in severe asthma. On Day 2, Dr. David Corry delivered a compelling presentation that delved into the latest research, diagnostic challenges, and potential treatment strategies for fungal-related lung diseases.
Why Airway Mycosis Matters
Airway mycosis refers to fungal infections and colonization in the respiratory tract, which can significantly impact asthma severity and overall lung health. Despite its potential to worsen symptoms, increase hospitalizations, and complicate treatment, it remains underdiagnosed due to limited awareness and inadequate testing methods
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Dr. Corry’s research highlights the growing recognition of fungi as key players in respiratory diseases, emphasizing the need for more precise detection, treatment, and management strategies.
Advancing Diagnostics: A Game-Changer
One of the most pressing issues in diagnosing airway mycosis is the lack of standardized testing protocols. Dr. Corry introduced an open-source, cost-effective culturing technique that has the potential to revolutionize fungal detection. Unlike traditional methods that often fail to identify the presence of fungi, his approach allows for more accurate and reliable diagnosis.
However, regulatory hurdles remain a challenge. While these new diagnostic techniques are promising, widespread clinical adoption requires changes in how fungal infections are perceived and tested in mainstream medicine.
The Way Forward: Solutions for a Neglected Condition
Dr. Corry’s insights highlight several critical steps needed to improve outcomes for patients suffering from airway mycosis:
Raising Awareness – Educating healthcare providers and the public about fungal-related lung diseases can lead to earlier diagnosis and better treatment strategies. The World Asthma Foundation symposium is playing a key role in fostering this conversation.
Enhanced Diagnostics – With improved culturing techniques and new testing protocols, diagnosing airway mycosis can become more accessible and reliable. However, regulatory bodies must be open to adopting these innovations.
Investment in Research – There is an urgent need for more research into the mechanisms, risk factors, and treatment options for airway mycosis. The symposium serves as a catalyst for collaboration among researchers, clinicians, and industry leaders.
Conclusion
Airway mycosis represents a hidden yet significant burden on patients and healthcare systems. Dr. Corry’s presentation underscores the urgency of better diagnostics, increased research, and enhanced clinical awareness to tackle this neglected issue.
By advocating for change, supporting innovative research, and fostering global collaboration, the World Asthma Foundation is leading the charge in addressing airway mycosis.
Stay tuned for more insights from the symposium as we continue to explore the evolving landscape of asthma and respiratory health.
Millions of severe asthma sufferers are searching for answers, often unaware that airway mycosis—a hidden fungal infection—could be the underlying cause of their chronic respiratory problems. April 5-6, 2025 the World Asthma Foundation is hosting a groundbreaking symposium to explore this critical issue, bringing together experts to shed light on the latest research and treatment strategies.
David B. Corry, MD. Medicine-Immunology, Allergy and Rheumatology, Baylor College of Medicine
The World Asthma Foundation (WAF), in collaboration with Dr. David Corry, a renowned airway mycosis and severe Asthma specialist at Baylor University, is committed to raising awareness about this critical issue and the underlying mechanisms of severe asthma.
To address this knowledge gap and improve patient outcomes, WAF is hosting an online symposium April 5-6, 2025. This blog post lays the groundwork for the event, which will bring together experts to discuss diagnosing and managing airway mycosis in severe Asthma patients.
By fostering collaboration, the symposium aims to unveil the hidden mechanisms of fungal asthma, including the root fungal cause and empower better understanding and treatment options for patients with severe asthma.
Burden of Airway Mycosis
Misdiagnosis and Underdiagnosis: Airway mycosis often mimics other respiratory illnesses and is difficult to diagnose using standard methods, leading to misdiagnosis and delayed treatment. This can worsen symptoms and hinder overall patient outcomes.
Chronic Illness and Suffering: Airway mycosis can cause debilitating symptoms like chronic cough, wheezing, shortness of breath, and chest pain. It significantly reduces patients’ quality of life.
Economic Costs: The economic burden of airway mycosis is substantial. Direct medical costs associated with treatment and hospitalization are high. Additionally, indirect costs due to lost productivity are significant.
Challenges and Gaps in Knowledge
Incomplete Understanding of Causes: Dr. Corry’s research emphasizes the need for further investigation into the exact mechanisms by which fungi contribute to airway diseases. The complex interplay between fungal exposure, immune response, and airway inflammation remains unclear.
Mechanisms of fungal asthma are incompletely understood. Research into how fungi cause asthma has improved with the discovery of virulence factors such as proteases and candidalysin, but this has yet to translate into new therapies. Newer antifungal agents such as peptoids and many others hold great promise for better management of airway mycosis.
Limited Diagnostic Tools: Current diagnostic methods for airway mycosis are often insensitive and lack specificity. This makes timely and accurate diagnosis difficult.
Silos in Treatment Approaches: A fragmented approach often exists in managing airway mycosis. Improved collaboration between pulmonologists, allergists, immunologists, and infectious disease specialists is essential.
The Way Forward
Raising Awareness: Increased awareness among healthcare professionals and the public is crucial for earlier diagnosis and improved treatment outcomes. The WAF symposium directly addresses this need.
Enhanced Diagnostics: Dr. Corry’s work on culturing techniques offers promise for improved fungal detection. Development of more accurate and specific diagnostic tools remains essential for proper diagnosis of airway mycosis. These methods are open source and inexpensive; the main hindrance is regulatory acceptance of new protocols.
Investment in Research: Further research is required to elucidate the underlying causes of airway mycosis, identify new treatment options, and improve patient management strategies. The World Asthma Foundation symposium can serve as a catalyst for such research collaborations.
Conclusion
Airway mycosis poses a significant but under-recognized burden on patients and healthcare systems. By raising awareness, improving diagnostics, fostering collaboration, and investing in research, we can effectively address the challenges of this complex disease. The World Asthma Foundation symposium serves as a springboard for this critical work.
Hello, dear members and subscribers of the World Asthma Foundation! We hope you are doing well and breathing easy. In this post, we are going to share with you some news about our Defeating Asthma initiative and our continuing series on Severe Asthma.
As you may know, the World Asthma Foundation is a community-based non profit that aims to raise awareness, provide education and support, and advocate for better care and treatment for people living with Asthma. We believe that everyone deserves to breathe freely and enjoy life without the burden of Asthma.
One of our main goals is to shed light on the different types of asthma and how they affect people differently. As most of you already know, Asthma is not a one-size-fits-all condition. It has many subtypes or phenotypes and some yet to be discovered that have different causes, triggers, symptoms, and responses to treatment. Understanding your Asthma phenotype can help you and your doctor find the best management plan for you.
That’s why we continue our focus on Severe Asthma, a challenging form of Asthma that affects about 5-10% of people with Asthma and consumes 80 % of the dollars to treat. Severe Asthma is often difficult to control with standard medications and can have a significant impact on your quality of life, health, and well-being.
One of the possible factors that can contribute to severe asthma is fungi. Fungi are microscopic organisms that are found everywhere in the environment. They can grow on plants, animals, soil, water, food, or indoor surfaces. Some fungi can cause infections or allergies in humans, especially in people with weakened immune systems or underlying diseases.
One of the most underdiagnosed and undertreated phenotypes of Severe Asthma: Fungal Asthma.
Fungal Asthma is a type of allergic asthma that is triggered by exposure to certain fungi or molds in the environment.
Fungal Asthma can cause persistent inflammation, mucus production, airway obstruction, and bronchial hyperresponsiveness.
Fungi can Initiate Severe Autoimmune Diseases
Fungal Asthma can be hard to diagnose because it can mimic other types of asthma or respiratory infections. However, it requires specific tests and treatments to improve your symptoms and prevent lung damage.
Fungi can affect the lungs and airways of asthmatics in different ways. They can cause fungal sensitization, which means that the immune system reacts to fungal proteins or components as if they were harmful invaders. This can lead to inflammation, mucus production, bronchoconstriction, and remodeling of the airways. Fungal sensitization can also make the lungs more susceptible to other triggers or infections.
Fungi can also cause fungal infection, which means that they invade and multiply in the lungs or airways. This can cause tissue damage, inflammation, and immune activation. Fungal infection can also complicate or mimic other lung diseases, such as tuberculosis or pneumonia.
Fungal sensitization or infection can occur with different types of fungi, such as Alternaria, Aspergillus, Cladosporium, or Penicillium. However, one of the most common and serious forms of fungal involvement in severe asthma is allergic bronchopulmonary aspergillosis (ABPA). ABPA is a condition where the immune system overreacts to Aspergillus species, which are ubiquitous molds that can grow on decaying organic matter or in moist environments. ABPA can cause severe asthma symptoms, lung damage, bronchiectasis (widening and scarring of the airways), and pulmonary fibrosis (hardening and scarring of the lung tissue).
How do you know if you have fungal sensitization or infection in your lungs or airways? Unfortunately, there is no simple or definitive test for this. The diagnosis of fungal sensitization or infection depends on a combination of clinical and immunological criteria, such as:
• History of exposure to fungi or symptoms suggestive of fungal involvement
• Skin testing with antigens derived from fungi or measurement of specific IgE levels in the blood
• Chest imaging (such as X-ray or CT scan) showing signs of lung damage or infection
• Sputum culture or analysis showing the presence of fungi or fungal components
• Bronchoscopy (a procedure where a thin tube with a camera is inserted into the airways) showing signs of inflammation or infection
• Biopsy (a procedure where a small sample of tissue is taken from the lungs) showing signs of inflammation or infection
The treatment of fungal sensitization or infection in severe asthma depends on the type and severity of the condition. The general goals of treatment are to:
• Reduce the exposure to fungi or eliminate them from the environment
• Control the asthma symptoms and prevent exacerbations
• Reduce the inflammation and damage in the lungs and airways
• Eradicate the fungal infection or reduce its load
The treatment options may include:
• Asthma medications (such as bronchodilators, corticosteroids, leukotriene modifiers, biologics, etc.) to relieve the symptoms and prevent exacerbations
• Antifungal medications (such as itraconazole, voriconazole, posaconazole, etc.) to kill or inhibit the growth of fungi
• Immunotherapy (such as allergen-specific immunotherapy or omalizumab) to reduce the immune response to fungi
• Surgery (such as lobectomy or pneumonectomy) to remove severely damaged parts of the lungs
The effectiveness and safety of these treatments may vary depending on the individual case and response. Therefore, it is important to consult with your doctor before starting any treatment and follow their instructions carefully.
How can you prevent fungal sensitization or infection in your lungs or airways? There are some measures that you can take to reduce your exposure to fungi or their effects on your health, such as:
• Avoid or minimize contact with sources of fungi, such as compost, hay, soil, plants, animals, moldy food, or damp places
• Use a mask, gloves, and protective clothing when handling or working with materials that may contain fungi
• Clean and dry your home regularly and remove any visible mold or mildew
• Use a dehumidifier or air conditioner to reduce the humidity and temperature in your home
• Use a high-efficiency particulate air (HEPA) filter or vacuum cleaner to remove airborne fungi or dust from your home
• Avoid smoking or exposure to secondhand smoke, as it can damage your lungs and increase your risk of infection
• Take your asthma medications as prescribed and monitor your symptoms and lung function regularly
• Seek medical attention promptly if you have any signs or symptoms of fungal sensitization or infection, such as worsening asthma, fever, cough, chest pain, weight loss, or blood in the sputum
Fungi can be a hidden but serious threat for people with severe asthma. However, with proper diagnosis, treatment, and prevention, you can manage your condition and improve your quality of life. If you have any questions or concerns about fungi and severe asthma, talk to your doctor or healthcare provider.
We hope you found this blog post informative and helpful. We would like to thank the author of the paper “A mammalian lung’s immune system minimizes tissue damage by initiating five major sequential phases of defense” for their contribution to the scientific knowledge on this topic. You can read the full paper here: <a href=”https://link.springer.com/article/10.1007/s10238-023-01083-4″>https://link.springer.com/article/10.1007/s10238-023-01083-4</a>
If you want to learn more about the World Asthma Foundation and our efforts to improve the lives of people with asthma, please visit our website: <a href=”https://worldasthmafoundation.org/”>https://worldasthmafoundation.org/</a>
Thank you for reading and stay tuned for more updates from us!
Sources:
How Major Fungal Infections Can Initiate Severe Autoimmune Diseases
Hello to our dedicated community and newcomers alike.
The World Asthma Foundation (WAF) continues its mission to Defeat Asthma by fostering awareness, enhancing education, and promoting research to unravel the complexities of Asthma. We appreciate your interest and partnership as we work towards a world where Asthma is no longer a limiting factor in anyone’s life.
Thank you for being part of our mission. We encourage you to share this information with your healthcare provider and engage in open, productive conversations about your health.
Introduction
Last week, we explored the intricate interplay between Candida colonization, dysbiosis, inflammation, autoimmune responses, TNF-alpha dysregulation, and comorbidities in the pathogenesis and exacerbation of severe asthma. A critical piece of the puzzle involves a protein secreted by Candida, Candidalysins. These proteins play a significant role in Candida’s virulence and are instrumental in driving the inflammatory response, making them a critical research focus in the context of Asthma.
Candidalysins: A Closer Look
Candida albicans produces a group of cytolytic peptide toxins known as Candidalysins, which disrupt host epithelial barriers, leading to infection and promoting inflammation. Recent research indicates that Candidalysins also exacerbate the severity of asthma by enhancing airway inflammation, making the study of these proteins crucial in understanding and managing severe asthma.
The Inflammatory Role of Candidalysins
Candidalysins are known to damage epithelial cells, triggering an inflammatory response. In the context of asthma, this inflammation can intensify symptoms and exacerbate the severity of the condition. Understanding the specific role of Candidalysins in promoting this inflammation can provide insights into new therapeutic strategies for managing severe asthma.
Candidalysins and Immune Response
Research indicates that Candidalysins play a vital role in triggering a strong immune response, affecting immune cell recruitment and activation. This response is critical in the progression of asthma and can provide potential targets for therapeutic intervention.
Implications for Severe Asthma
The role of Candidalysins in promoting inflammation and triggering immune responses has significant implications for severe asthma. Understanding these implications is crucial for developing more effective management strategies, diagnostic tools, and potential treatments.
Candida in Pulmonary Secretions: A New Study
In addition to the role of Candidalysins in severe asthma, we also want to highlight another recent study that may be relevant to our readers. This study, published in The Open Respiratory Medicine Journal, examined the presence and significance of Candida in pulmonary secretions of patients with bronchitis, mucus plugging, and atelectasis. These are conditions that can affect people with asthma and make breathing difficult. The study found that Candida was often associated with these conditions and may play a role in causing or worsening them. The study also found that patients with Candida in their lungs had a higher risk of respiratory failure and death. The study suggested that treating Candida with antifungal drugs may help some patients improve their lung function and outcomes. However, the study was not conclusive and more research is needed to confirm these findings. This study adds to the growing evidence that Candida may be more than just a harmless colonizer of the lungs and may have important implications for severe asthma. You can read more about this study here.
Conclusion
Research into Candidalysins and their role in severe asthma is ongoing and promising. These cytolytic toxins provide a unique perspective on how Candida can influence the severity and progression of asthma, offering potential new avenues for therapeutic intervention. Another recent study also suggests that Candida may affect lung function and outcomes by causing or worsening bronchitis, mucus plugging, and atelectasis in some patients. These findings indicate that Candida may be more than just a harmless colonizer of the lungs and may have important implications for severe asthma. We’re excited to bring you the latest research on this subject and appreciate your interest and involvement in the Defeat Asthma mission. As we continue to unravel the complexities of Asthma, we hope to empower our readers with knowledge and tools to manage this chronic condition.
The Future of Asthma Research
As we understand more about the interactions between the Candidalysins and our body’s immune response, we will continue to see developments in diagnostic tools and therapies. Unraveling this complex relationship is critical in determining the trajectory of severe asthma and holds the key to future breakthroughs in its management.
Your Role in Our Mission
Our readers are a crucial part of our mission to Defeat Asthma. As we continue to share insights from the latest research, we encourage you to keep informed and to share these findings with your network. Conversations about research like this can help increase public understanding of Asthma, combat stigma, and ultimately contribute to better outcomes for those living with Asthma.
What’s Coming Up Next
In our upcoming posts, we will continue to keep you updated on research into the role of Candidalysins and other pathogenic factors contributing to severe asthma. We will also be delving into lifestyle and environmental factors that affect asthma, and how we can manage these to better control this chronic condition.
Stay Tuned for More
Stay connected with us to get the latest information and insights in the world of Asthma research, management, and advocacy. Subscribe to our newsletter, follow us on social media, and share our resources with your community.
Thank You
Thank you for being a part of the World Asthma Foundation community. Your involvement, whether as a reader, donor, advocate, or patient, is critical in our fight to Defeat Asthma. We appreciate your commitment and look forward to a future where Asthma no longer limits anyone’s potential.
The World Asthma Foundation (WAF). WAF is a nonprofit organization dedicated to improving the lives of people with asthma through education, research, and advocacy. In this blog post, I want to share with you some exciting findings from a recent study on the microbiome and asthma, published by Spanish researchers in the journal Nutrients.
The microbiome is the collection of microorganisms that live in and on our bodies, such as bacteria, fungi, viruses, and parasites. The microbiome plays an important role in our health and immunity, and can also influence our susceptibility and response to various diseases, including asthma.
Asthma is a chronic inflammatory disease of the airways that affects millions of people worldwide. Asthma can be triggered by different factors, such as allergens, infections, pollution, stress, and diet. Asthma can also have different phenotypes (characteristics), such as allergic or non-allergic, eosinophilic or non-eosinophilic, mild or severe.
What is the microbiome and how does it affect asthma?
The study by Valverde-Molina and García-Marcos reviews the current evidence and challenges on the relationship between the microbiome and asthma, specifically how microbial dysbiosis (an imbalance of the microbial communities in the body) can influence the origins, phenotypes, persistence, and severity of asthma.
How different factors can influence the microbiome and asthma
The study explores how different factors, such as diet, environment, genetics, and infections, can affect the microbiome and asthma, and how modulating the microbiome could be a potential strategy for preventing or treating asthma. The study also reviews the different methods and techniques used to study the microbiome and its interactions with the immune system and the respiratory system.
The gut-lung axis: a key connection between the microbiome and asthma
One of the key points of the study is the importance of the gut-lung axis in the origin and persistence of asthma. The gut-lung axis is the concept that describes how the gut and lung microbiomes communicate with each other through various pathways, such as metabolites, cytokines, antibodies, and immune cells. The gut-lung axis can modulate inflammation and allergic responses in both organs.
The study shows that the process of microbial colonization in the first three years of life is fundamental for health, with the first hundred days of life being critical. Different factors are associated with early microbial dysbiosis, such as caesarean delivery, artificial lactation and antibiotic therapy, among others.
How microbial dysbiosis can lead to different asthma phenotypes and severity
Longitudinal cohort studies on gut and airway microbiome in children have found an association between microbial dysbiosis and asthma at later ages of life. A low ?-diversity (the number of different species) and relative abundance of certain commensal gut bacterial genera in the first year of life are associated with the development of asthma. Gut microbial dysbiosis, with a lower abundance of Phylum Firmicutes (a group of bacteria that includes lactobacilli), could be related with increased risk of asthma.
Upper airway microbial dysbiosis, especially early colonization by Moraxella spp. (a type of bacteria that can cause respiratory infections), is associated with recurrent viral infections and the development of asthma. Moreover, the bacteria in the respiratory system produce metabolites (substances produced by metabolism) that may modify the inception of asthma and its progression.
The role of the lung microbiome in asthma development has yet to be fully elucidated. Nevertheless, the most consistent finding in studies on lung microbiome is the increased bacterial load (the number of bacteria) and the predominance of proteobacteria (a group of bacteria that includes Haemophilus spp. and Moraxella catarrhalis), especially in severe asthma.
Candida albicans: a fungal culprit in asthma development and exacerbation
The study also mentions Candida albicans (a type of fungus that can cause infections) as one of the fungal genera that can affect the gut and lung microbiome and asthma. Candida albicans can trigger inflammation and autoimmune responses in the body. Candida albicans can also induce a Th17 response (a type of immune response) in the gut and lungs. Candida albicans can also increase lung bacterial load and exacerbate airway inflammation.
This study is very relevant to our own research and findings on Candida’s role in inflammation and autoimmune response: implications for severe asthma. We published an article on this topic on our website on October 13th 2021 which features findings from Mayo Clinic researchers who examined how intestinal fungal microbiota affects lung resident memory CD4+ T cells (a type of immune cell) in patients with asthma.
How modulating the microbiome could be a promising strategy for asthma prevention and treatment
We think that these studies complement each other well and provide valuable insights into this important and emerging topic. We believe that understanding the microbiome and its impact on asthma is crucial for developing new and effective strategies for prevention, diagnosis, and treatment of this chronic disease.
Hello to our dedicated community and newcomers alike.
At the World Asthma Foundation (WAF), we’re united by a singular, important mission: to Defeat Asthma. Our approach is rooted in fostering awareness, enhancing education, and promoting research that seeks to unravel the complexities of Asthma. As we strive towards a world where Asthma is no longer a limiting factor in anyone’s life, we remain steadfast in bringing you timely, comprehensive, and relevant information.
We’re excited to share our latest blog post with you. This post encapsulates the culmination of the efforts of a variety researchers, clinicians, and organizations worldwide working independently including pioneering work from the Mayo Clinic, to shed light on the pathogenesis and exacerbation of severe asthma.
Mayo Clinic Candida Study
We delve into the compelling evidence pointing towards the intricate interplay between Candida colonization, dysbiosis, inflammation, autoimmune responses, TNF-alpha dysregulation, and comorbidities.
As we unravel these complex relationships, our hope is to equip you, our readers, with knowledge that can empower you in your journey with asthma or help you support someone who is affected.
Let’s continue to learn, share, and work together in our collective fight against Asthma.
Thank you for being a part of our mission. We encourage you to share this information with your healthcare provider.
Establishing a trustworthy and effective relationship with a healthcare provider is crucial to managing your health. It not only ensures that you get the best care but also allows for open and productive conversations about your health.
Introduction
Managing Severe Asthma remains a complex task for many pulmonary practitioners, despite available medication and trigger avoidance strategies. Frequent attacks and poor symptom control often plague patients. Recent investigations, pieced together by the World Asthma Foundation over time have uncovered dozens of notable research groups that have illuminated the complex relationship between Candida colonization, dysbiosis, inflammation, autoimmune response, TNF-alpha dysregulation, and comorbidities in the pathogenesis and exacerbation of Severe Asthma. This amassed knowledge underscores the multifaceted nature of Severe Asthma, bringing to light the critical role of Candida in the disease process.
Recent studies reveal a potential link between Candida colonization, dysbiosis, inflammation, autoimmune response, TNF-alpha dysregulation, and comorbidities in the pathogenesis and exacerbation of Severe Asthma. This article will provide an overview of these linkages, the financial impact on individuals and society, the necessity for improved diagnostic tools and processes, and source the scientific studies supporting these conclusions.
Candida Colonization, Dysbiosis, and Fungal Sensitization
Candida albicans, a common fungal inhabitant of the mouth, gut, and genital tract, can also colonize the respiratory tract. This colonization is often facilitated by dysbiosis, an imbalance in the normal microbial flora, which can be induced by various factors, including the use of antibiotics and changes in the host immune response. Further, fungal sensitization, a process where the immune system produces antibodies (IgE) against fungal allergens, plays a crucial role in the onset and severity of asthma symptoms. Studies from the Mayo Clinic underline the lower alpha-diversity of lung microbiota and higher fungal burdens in Asthma patients, showing a correlation with severity and poor control of Asthma.
Case in Point
A recent study presented at the CHEST Annual Meeting 2021 by researchers from Mayo Clinic and University of California Davis confirmed the association between intestinal fungal dysbiosis and asthma severity in humans, particularly hospital use in the past year. The study found that patients with asthma who had higher intestinal Candida burden were more likely to have severe asthma exacerbations in the previous year, independent of systemic antibiotic and glucocorticoid use. This suggests that intestinal fungal dysbiosis may worsen asthma control and outcomes in humans. The study also showed that intestinal fungal dysbiosis can enhance the severity of allergic asthma in mice by increasing lung resident group 2 innate lymphoid cells (ILC2) populations, which are important mediators of the gut-lung axis effect. The study used a novel technique of flow cytometry to identify and quantify ILC2 in the lungs of mice. These findings highlight the potential role of intestinal fungal dysbiosis and ILC2 in asthma pathogenesis and management.
Role of Antibiotics and Gut-Lung Axis
Studies show that certain antibiotics prescribed for infections, such as Helicobacter pylori, can lead to gut microbiota dysbiosis, promoting Candida colonization. This gut-lung axis, the communication between gut microbiota and lung health, can create an environment conducive to fungal overgrowth and subsequent infection. As such, understanding this interaction can offer valuable insights into asthma management. Research from the Mayo Clinic suggests that antibiotic usage can significantly contribute to these interactions and, consequently, the pathogenesis of Severe Asthma.
Mechanisms of Candida Colonization
Candida albicans utilizes several mechanisms to cross the intestinal epithelial barrier, including adherence to epithelial cells, invasion, and translocation. Each of these steps facilitates Candida’s ability to invade the host’s system and trigger an immune response. Insights from the Mayo Clinic suggest that bacterial-fungal interactions play a key role in these mechanisms and have implications for Candida colonization.
Candida-Induced Inflammation, Autoimmune Response, and TNF-alpha Dysregulation
Once established, Candida colonization can incite inflammation by provoking the immune system to produce pro-inflammatory cytokines, such as TNF-alpha. While TNF-alpha aids in fighting off infections by initiating inflammation, its dysregulation can lead to chronic inflammation and autoimmune diseases, enhancing the severity of asthma. Research from the Mayo Clinic has shown that Candida colonization in the lung induces an immunologic response, leading to more Severe Asthma.
Autoimmune Response, Comorbidities, and Severe Asthma
Recent studies propose that an autoimmune response could be involved in the onset and exacerbation of Severe Asthma, with TNF-alpha dysregulation playing a pivotal role. Comorbidities like rheumatoid arthritis, often seen in conjunction with Severe Asthma, can further complicate disease management and progression.
Burden, Financial Impact, and Comorbidities
Severe Asthma imposes a substantial burden on individuals and society, financially and otherwise. Healthcare costs, productivity loss, and reduced quality of life contribute to this impact. Asthma comorbidities such as autoimmune diseases can affect disease progression and outcomes, underscoring the need for a comprehensive management approach.
The Necessity for Improved Diagnostic Tools
An accurate diagnosis of Candida colonization, inflammation, and autoimmune response in severe asthma is crucial for optimal patient management. There’s a growing need for improved diagnostic methodologies, tools, and processes. Advances in diagnostic techniques, such as bronchoscopy and bronchoalveolar lavage (BAL), can offer valuable insights into Candida colonization and the associated inflammatory and autoimmune processes. The Mayo Clinic’s recent findings, which identify a unique pattern of lower alpha-diversity and higher fungal burden in the lung microbiota of severe asthma patients, further emphasize the need for enhanced diagnostic methods.
Conclusion
Understanding the link between Candida colonization, dysbiosis, inflammation, autoimmune response, TNF-alpha dysregulation, comorbidities, and severe asthma is crucial for medical practitioners dealing with this chronic disease. The significant burden and financial impacts of Severe Asthma on individuals and society underline the urgency for effective management strategies.
Recognizing the influence of comorbidities, such as autoimmune diseases, can guide comprehensive care plans for patients with Severe Asthma. Moreover, enhanced diagnostic tools and processes will aid in early identification and more personalized treatment approaches, ultimately improving patient outcomes.
By integrating this knowledge, medical practitioners can not only better understand the multifaceted nature of Severe Asthma but also enhance its overall management, leading to improved patient care. With ongoing research, we can continue to unravel the complex relationships and mechanisms in asthma pathogenesis, providing new avenues for therapeutic interventions and improved patient outcomes.
Research on the relationship between Candida albicans and Asthma is an important area of study that could lead to better understanding and management of Asthma. In the following sections, we will present a summary of various significant studies on the relationship between Candida Albicans colonization and asthma. We will also cover information on the microbiome of the gut and lungs, wherever applicable.
Additionally, we will provide key takeaways from each study, including relevant details such as the study’s title, authors, and organization affiliation. Finally, we will summarize the collective findings and scientific conclusions related to Candida Albicans colonization, sensitization, and infection in Asthma, and offer resources for you to share with your healthcare provider.
A comprehensive understanding of these aspects promises to shed light on the intricate mechanisms underlying severe asthma, offering new perspectives in our fight against this chronic condition.
Further Study
Name of study: Fungal Dysbiosis and Its Clinical Implications in Severe Asthma Patients Date: 2023 Authors: Allison N. Imamura, Hannah K. Drescher, Mai Sasaki, Daniel J. Peaslee, David S. Crockett, Alexander S. Adams, Marcia L. Wills, Stephen C. Meredith, and Andrew H. Limper Organization: Mayo Clinic, Rochester, MN Summary: This study discusses the fungal dysbiosis in severe asthma patients. It finds that the lower alpha-diversity of lung microbiota and higher fungal burdens correlate with severity and poor control of asthma. The study also discusses the possible role of antibiotic usage and bacterial-fungal interactions in this process. The study concludes that understanding the link between Candida colonization, inflammation, autoimmune response, and Severe Asthma is crucial for better management of this chronic disease.
Study Title: CANDIDA ALBICANS INTESTINAL DYSBIOSIS INCREASES LUNG RESIDENT ILC2 POPULATIONS AND ENHANCES THE SEVERITY OF HDM-INDUCED ALLERGIC ASTHMA IN MICE
• Date: October 17-20, 202
Authors: Amjad Kanj, Theodore Kottom, Kyle Schaefbauer, Andrew Limper, Joseph Skalski
• Organization Affiliation: Mayo Clinic and University of California Davis
Human Anti-fungal Th17 Immunity and Pathology Rely on Cross-Reactivity against Candida albicans. Cell 2019. The authors are Petra Bacher, Thordis Hohnstein, Eva Beerbaum, Marie Röcker, Matthew G. Blango, Svenja Kaufmann, Jobst Röhmel, Patience Eschenhagen, Claudia Grehn, Kathrin Seidel, Volker Rickerts, Laura Lozza, Ulrik Stervbo, Mikalai Nienen, Nina Babel, Julia Milleck, Mario Assenmacher, Oliver A. Cornely, Maren Ziegler, Hilmar Wisplinghoff, Guido Heine, Margitta Worm, Britta Siegmund, Jochen Maul, Petra Creutz, Christoph Tabeling, Christoph Ruwwe-Glösenkamp, Leif E. Sander, Christoph Knosalla, Sascha Brunke, Bernhard Hube, Olaf Kniemeyer, Axel A. Brakhage and Carsten Schwarz. The main objective of the article is to investigate how cross-reactivity against Candida albicans influences human anti-fungal Th17 immunity and pathology. • C. albicans-specific Th17 cells can cross-react with other fungal antigens and gluten peptides in patients with CeD or asthma. • Cross-reactive Th17 cells can cause immune pathology in the gut and lung by producing IL-17A and IL-22 cytokines. Candida and asthma better by showing that Candida can induce a specific type of immune response that can also react to other fungi and allergens that are associated with asthma. The article also suggests that Candida may contribute to the severity and chronicity of asthma by causing inflammation and tissue damage in the lung. mechanisms and consequences of cross-reactivity are complex and need further investigation.
Name of study: Candida auris: Epidemiology, biology, a:Authors:ntifungal resistance, and virulence Date: 2020 Authors: Du, H., Bing, J., Hu, T., Ennis, C. L., Nobile, C. J., & Huang, G. M
Name of study: Candida albicans pathogenicity and epithelial immunity Date: 2014 Abstract Naglik, J. R., Richardson, J. P., & Moyes, D. L. URL:
Name of study: Candida albicans interactions with the host: crossing the intestinal epithelial barrier Date: 2019 Abstract: [Unavailable in given data] Authors: Basmaciyan, L., Bon, F., Paradis, T., Lapaquette, P., & Dalle, F. URL: https://doi.org/10.1080/21688370.2019.1612661
Name of study: ACG Clinical Guideline: Treatment of Helicobacter pylori Infection Date: 2017 Abstract: Authors: Chey WD, Leontiadis GI, Howden CW, Moss SF. URL: https://doi.org/10.1038/ajg.2016.563
Name of study: Asthma is inversely associated with Helicobacter pylori status in an urban population Date: 2008 Abstract: [Unavailable in given data] Authors: Reibman J, Marmor M, Filner J, et al. URL: https://doi.org/10.1371/journal.pone.0004060
Name of resource: H pylori Probiotics: A Comprehensive Overview for Health Practitioners Date: 2020 Abstract: Authors: Ruscio M. URL: https://drruscio.com/h-pylori-probiotics/
Name of resource: Treatment regimens for Helicobacter pylori in adults Date: 2022 Abstract: Authors: Lamont JT.
Name of study: Effects of probiotics on the recurrence of bacterial vaginosis: a review Date: 2014 Abstract: Authors: Homayouni A, Bastani P, Ziyadi S, et al.
The gut and lungs are anatomically distinct, but potential anatomic communications and complex pathways involving their respective microbiota have reinforced the existence of a gut–lung axis (GLA). Compared to the better-studied gut microbiota, the lung microbiota, only considered in recent years, represents a more discreet part of the whole microbiota associated to human hosts. Gut health is not the only area to think about.
While the majority of studies focused on the bacterial component of the microbiota in healthy and pathological conditions, recent works highlighted the contribution of fungal and viral kingdoms at both digestive and respiratory levels. Moreover, growing evidence indicates the key role of inter-kingdom crosstalks in maintaining host homeostasis and in disease evolution.
In fact, the recently emerged GLA concept involves host–microbe as well as microbe–microbe interactions, based both on localized and long-reaching effects. GLA can shape immune responses and interfere with the course of respiratory diseases. In this review, we aim to analyze how the lung and gut microbiota influence each other and may impact on respiratory diseases.
Due to the limited knowledge on the human virobiota, we focused on gut and lung bacteriobiota and mycobiota, with a specific attention on inter-kingdom microbial crosstalk. These are able to shape local or long-reached host responses within the GLA.
Introduction
Recent advances in microbiota explorations have led to an improved knowledge of the communities of commensal microorganisms within the human body. Human skin and mucosal surfaces are associated with rich and complex ecosystems (microbiota) composed of bacteria (bacteriobiota), fungi (mycobiota), viruses (virobiota), phages, archaea, protists, and helminths (Cho and Blaser, 2012).
The role of the gut bacteriobiota in local health homeostasis and diseases is being increasingly investigated, but its long-distance impacts still need to be clarified (Chiu et al., 2017). Among the relevant inter-organ connections, the gut–lung axis (GLA) remains less studied than the gut–brain axis.
So far, microbiota studies mainly focused on the bacterial component, neglecting other microbial kingdoms. However, the understanding of mycobiota involvement in human health and inter-organ connections should not be overlooked (Nguyen et al., 2015; Enaud et al., 2018).
Viruses are also known to be key players in numerous respiratory diseases and to interact with the human immune system, but technical issues still limit the amount of data regarding virobiota (Mitchell and Glanville, 2018). Therefore, we will focus on bacterial and fungal components of the microbiota and their close interactions that are able to shape local or long-reached host responses within the GLA.
While GLA mycobiota also influences chronic gut diseases such as IBD, we will not address this key role in the present review: we aimed at analyzing how lung and gut bacteriobiota and mycobiota influence each other, how they interact with the human immune system, and their role in respiratory diseases.
Gut Health
Microbial Interactions Within the Gut–Lung Axis
The gut microbiota has been the most extensively investigated in gut health. The majority of genes (99%) amplified in human stools are from bacteria, which are as numerous as human cells and comprise 150 distinct bacterial species, belonging mainly to Firmicutes and Bacteroidetes phyla. Proteobacteria, Actinobacteria, Cyanobacteria, and Fusobacteria are also represented in healthy people (Sekirov et al., 2010; Human Microbiome Project Consortium, 2012).
More recently, fungi have been recognized as an integral part of our commensal flora, and their role in health and diseases is increasingly considered (Huffnagle and Noverr, 2013; Huseyin et al., 2017). Fungi are about 100 times larger than bacteria, so even if fungal sequences are 100 to 1,000 times less frequent than bacterial sequences, fungi must not be neglected in the gastrointestinal ecosystem.
Mycobiota Diversity
In contrast with the bacteriobiota, the diversity of the gut mycobiota in healthy subjects is limited to few genera, with a high prevalence of Saccharomyces cerevisiae, Malassezia restricta, and Candida albicans (Nash et al., 2017).
Note from the WAF editorial board. We wish to acknowledge and thank Raphaël Enaud, Renaud Preve, Eleonora Ciarlo, Fabien Beaufils, Gregoire Wieërs, Benoit Guery and Laurence Delhaes for their support of Asthma education and research. For more information about Asthma or Gut Health, visit the World Asthma Foundation.
Although often dichotomized due to technical and analysis sequencing issues, critical interactions exist between bacteriobiota and mycobiota (Peleg et al., 2010). The most appropriate approach to decipher the role of gut microbiota is therefore considering the gut as an ecosystem in which inter-kingdom interactions occur and have major implications as suggested by the significant correlations between the gut bacteriobiota and mycobiota profiles among healthy subjects (Hoffmann et al., 2013).
Yeasts
Yeasts, e.g., Saccharomyces boulardii and C. albicans, or fungus wall components, e.g., ?-glucans, are able to inhibit the growth of some intestinal pathogens (Zhou et al., 2013; Markey et al., 2018). S. boulardii also produces proteases or phosphatases that inactivate the toxins produced by intestinal bacteria such as Clostridium difficile and Escherichia coli (Castagliuolo et al., 1999; Buts et al., 2006).
In addition, at physiological state and during gut microbiota disturbances (e.g., after a course of antibiotics), fungal species may take over the bacterial functions of immune modulation, preventing mucosal tissue damages (Jiang et al., 2017). Vice versa, bacteria can also modulate fungi: fatty acids locally produced by bacteria impact on the phenotype of C. albicans (Noverr and Huffnagle, 2004; Tso et al., 2018).
Microbiota
Beside the widely studied gut microbiota, microbiotas of other sites, including the lungs, are essential for host homeostasis and disease. The lung microbiota is now recognized as a cornerstone in the physiopathology of numerous respiratory diseases (Soret et al., 2019; Vandenborght et al., 2019).
Inter-Kingdom Crosstalk Within the Lung Microbiota
The lung microbiota represents a significantly lower biomass than the gut microbiota: about 10 to 100 bacteria per 1,000 human cells (Sze et al., 2012). Its composition depends on the microbial colonization from the oropharynx and upper respiratory tract through salivary micro-inhalations, on the host elimination abilities (especially coughing and mucociliary clearance), on interactions with the host immune system, and on local conditions for microbial proliferation, such as pH or oxygen concentration (Gleeson et al., 1997; Wilson and Hamilos, 2014).
The predominant bacterial phyla in lungs are the same as in gut, mainly Firmicutes and Bacteroidetes followed by Proteobacteria and Actinobacteria (Charlson et al., 2011). In healthy subjects, the main identified fungi are usually environmental: Ascomycota (Aspergillus, Cladosporium, Eremothecium, and Vanderwaltozyma) and Microsporidia (Systenostrema) (Nguyen et al., 2015; Vandenborght et al., 2019).
In contrast to the intestinal or oral microbiota, data highlighting the interactions between bacteria and fungi in the human respiratory tract are more scattered (Delhaes et al., 2012; Soret et al., 2019). However, data from both in vitro and in vivo studies suggest relevant inter-kingdom crosstalk (Delhaes et al., 2012; Xu and Dongari-Bagtzoglou, 2015; Lof et al., 2017; Soret et al., 2019).
Several Pathways
This dialogue may involve several pathways as physical interaction, quorum-sensing molecules, production of antimicrobial agents, immune response modulation, and nutrient exchange (Peleg et al., 2010). Synergistic interactions have been documented between Candida and Streptococcus, such as stimulation of Streptococcus growth by Candida, increasing biofilm formation, or enhancement of the Candida pathogenicity by Streptococcus (Diaz et al., 2012; Xu et al., 2014).
In vitro studies exhibited an increased growth of Aspergillus fumigatus in presence of Pseudomonas aeruginosa, due to the mold’s ability in to assimilate P. aeruginosa-derived volatile sulfur compounds (Briard et al., 2019; Scott et al., 2019). However, the lung microbiota modulation is not limited to local inter-kingdom crosstalk and also depends on inter-compartment crosstalk between the gut and lungs. Microbial Inter-compartment Crosstalk
From birth throughout the entire life span, a close correlation between the composition of the gut and lung microbiota exists, suggesting a host-wide network (Grier et al., 2018). For instance, modification of newborns’ diet influences the composition of their lung microbiota, and fecal transplantation in rats induces changes in the lung microbiota (Madan et al., 2012; Liu et al., 2017).
Gut-Lung Interaction
The host’s health condition can impact this gut–lung interaction too. In cystic fibrosis (CF) newborns, gut colonizations with Roseburia, Dorea, Coprococcus, Blautia, or Escherichia presaged their respiratory appearance, and their gut and lung abundances are highly correlated over time (Madan et al., 2012). Similarly, the lung microbiota is enriched with gut bacteria, such as Bacteroides spp., after sepsis (Dickson et al., 2016).
Conversely, lung microbiota may affect the gut microbiota composition. In a pre-clinical model, influenza infection triggers an increased proportion of Enterobacteriaceae and decreased abundances of Lactobacilli and Lactococci in the gut (Looft and Allen, 2012). Consistently, lipopolysaccharide (LPS) instillation in the lungs of mice is associated with gut microbiota disturbances (Sze et al., 2014).
Although gastroesophageal content inhalations and sputum swallowing partially explain this inter-organ connection, GLA also involves indirect communications such as host immune modulation.
Gut–Lung Axis Interactions With Human Immune System
Gut microbiota effects on the local immune system have been extensively reviewed (Elson and Alexander, 2015). Briefly, the gut microbiota closely interacts with the mucosal immune system using both pro-inflammatory and regulatory signals (Skelly et al., 2019). It also influences neutrophil responses, modulating their ability to extravasate from blood (Karmarkar and Rock, 2013).
Receptor Signaling
Toll-like receptor (TLR) signaling is essential for microbiota-driven myelopoiesis and exerts a neonatal selection shaping the gut microbiota with long-term consequences (Balmer et al., 2014; Fulde et al., 2018). Moreover, the gut microbiota communicates with and influences immune cells expressing TLR or GPR41/43 by means of microbial associated molecular patterns (MAMPs) or short-chain fatty acids (SCFAs) (Le Poul et al., 2003).
Data focused on the gut mycobiota’s impact on the immune system are sparser. Commensal fungi seem to reinforce bacterial protective benefits on both local and systemic immunity, with a specific role for mannans, a highly conserved fungal wall component. Moreover, fungi are able to produce SCFAs (Baltierra-Trejo et al., 2015; Xiros et al., 2019). Therefore, gut mycobiota perturbations could be as deleterious as bacteriobiota ones (Wheeler et al., 2016; Jiang et al., 2017).
Lung Microbiota and Local Immunity
A crucial role of lung microbiota in the maturation and homeostasis of lung immunity has emerged over the last few years (Dickson et al., 2018). Colonization of the respiratory tract provides essential signals for maturing local immune cells with long-term consequences (Gollwitzer et al., 2014).
Pre-clinical studies confirm the causality between airway microbial colonization and the regulation and maturation of the airways’ immune cells. Germ-free mice exhibit increased local Th2-associated cytokine and IgE production, promoting allergic airway inflammation (Herbst et al., 2011).
Consistently, lung exposure to commensal bacteria reduces Th2-associated cytokine production after an allergen challenge and induces regulatory cells early in life (Russell et al., 2012; Gollwitzer et al., 2014). The establishment of resident memory B cells in lungs also requires encountering lung microbiota local antigens, especially regarding immunity against viruses such as influenza (Allie et al., 2019).
Interactions between lung microbiota and immunity are also a two-way process; a major inflammation in the lungs can morbidly transform the lung microbiota composition (Molyneaux et al., 2013).
Gut Health, Long-Reaching Immune Modulation Within Gut–Lung Axis
Beyond the local immune regulation by the site-specific microbiota, the long-reaching immune impact of gut microbiota is now being recognized, especially on the pulmonary immune system (Chiu et al., 2017).
The mesenteric lymphatic system is an essential pathway between the lungs and the intestine, through which intact bacteria, their fragments, or metabolites (e.g., SCFAs) may translocate across the intestinal barrier, reach the systemic circulation, and modulate the lung immune response (Trompette et al., 2014; Bingula et al., 2017; McAleer and Kolls, 2018).
SCFAs, mainly produced by the bacterial dietary fibers’ fermentation especially in case of a high-fiber diet (HFD), act in the lungs as signaling molecules on resident antigen-presenting cells to attenuate the inflammatory and allergic responses (Anand and Mande, 2018; Cait et al., 2018).
SCFA receptor–deficient mice show increased inflammatory responses in experimental models of asthma (Trompette et al., 2014). Fungi, including A. fumigatus, can also produce SCFAs or create a biofilm enhancing the bacterial production of SCFAs, but on the other hand, bacterial SCFAs can dampen fungal growth (Hynes et al., 2008; Baltierra-Trejo et al., 2015; Xiros et al., 2019). The impact of fungal production of SCFAs on the host has not been assessed so far.
Other Elements
Other important players of this long-reaching immune effect are gut segmented filamentous bacteria (SFBs), a commensal bacteria colonizing the ileum of most animals, including humans, and involved in the modulation of the immune system’s development (Yin et al., 2013). SFBs regulate CD4+ T-cell polarization into the Th17 pathway, which is implicated in the response to pulmonary fungal infections and lung autoimmune manifestations (McAleer et al., 2016; Bradley et al., 2017).
Recently, innate lymphoid cells, involved in tissue repair, have been shown to be recruited from the gut to the lungs in response to inflammatory signals upon IL-25 (Huang et al., 2018). Finally, intestinal TLR activation, required for the NF-?B–dependent pathways of innate immunity and inflammation, is associated with an increased influenza-related lung response in mice (Ichinohe et al., 2011).
Mechanisms
Other mechanisms may be involved in modulating the long-reaching immune response related to gut microbiota, exemplified by the increased number of mononuclear leukocytes and an increased phagocytic and lytic activity after treatment with Bifidobacterium lactis HN019 probiotics (Gill et al., 2001). Diet, especially fiber intake, which increases the systemic level of SCFAs, or probiotics influence the pulmonary immune response and thus impact the progression of respiratory disorders (King et al., 2007; Varraso et al., 2015; Anand and Mande, 2018).
The GLA immune dialogue remains a two-way process. For instance, Salmonella nasal inoculation promotes a Salmonella-specific gut immunization which depends on lung dendritic cells (Ruane et al., 2013). Respiratory influenza infection also modulates the composition of the gut microbiota as stated above. These intestinal microbial disruptions seem to be unrelated to an intestinal tropism of influenza virus but mediated by Th17 cells (Wang et al., 2014).
In summary, GLA results from complex interactions between the different microbial components of both the gut and lung microbiotas combined with local and long-reaching immune effects. All these interactions strongly suggest a major role for the GLA in respiratory diseases, as recently documented in a mice model (Skalski et al., 2018). Gut–Lung Axis in Respiratory Diseases
Acute Infectious Diseases
Regarding influenza infection and the impact of gut and lung microbiota, our knowledge is still fragmentary; human data are not yet available. However, antibiotic treatment causes significantly reduced immune responses against influenza virus in mice (Ichinohe et al., 2011). Conversely, influenza-infected HFD-fed mice exhibit increased survival rates compared to infected controls thanks to an enhanced generation of Ly6c-patrolling monocytes. These monocytes increase the numbers of macrophages that have a limited capacity to produce CXCL1 locally, reducing neutrophil recruitment to the airways and thus tissue damage. In parallel, diet-derived SCFAs boost CD8+ T-cell effector function in HFD-fed mice (Trompette et al., 2018).
Both lung and gut microbiota are essential against bacterial pneumonia. The lung microbiota is able to protect against respiratory infections with Streptococcus pneumoniae and Klebsiella pneumoniae by priming the pulmonary production of granulocyte-macrophage colony-stimulating factor (GM-CSF) via IL-17 and Nod2 stimulation (Brown et al., 2017).
Gut Health and Lung Bacterial Infections
The gut microbiota also plays a crucial role in response to lung bacterial infections. Studies on germ-free mice showed an increased morbidity and mortality during K. pneumoniae, S. pneumoniae, or P. aeruginosa acute lung infection (Fagundes et al., 2012; Fox et al., 2012; Brown et al., 2017). The use of broad-spectrum antibiotic treatments, to disrupt mouse gut microbiota, results in worse outcome in lung infection mouse models (Schuijt et al., 2016; Robak et al., 2018).
Mechanistically, alveolar macrophages from mice deprived of gut microbiota through antibiotic treatment are less responsive to stimulation and show reduced phagocytic capacity (Schuijt et al., 2016). Interestingly, priming of antibiotic-treated animals with TLR agonists restores resistance to pulmonary infections (Fagundes et al., 2012). SFBs appear to be an important gut microbiota component for lung defense against bacterial infection thanks to their capacity to induce the production of the Th17 cytokine, IL-22, and to increase neutrophil counts in the lungs during Staphylococcus aureus pneumonia (Gauguet et al., 2015).
Modulating chronic infectious diseases will similarly depend on gut and lung microbiotas. For instance, Mycobacterium tuberculosis infection severity is correlated with gut microbiota (Namasivayam et al., 2018).
Chronic Respiratory Diseases
Multiple studies have addressed the impact of gut and lung microbiota on chronic respiratory diseases such as chronic obstructive pulmonary disease (COPD), asthma, and CF (Table 1).
Table 1. Gut–lung axis in human chronic respiratory diseases. Gut Health.
Decreased lung microbiota diversity and Proteobacteria expansion are associated with both COPD severity and exacerbations (Garcia-Nuñez et al., 2014; Wang et al., 2016, 2018; Mayhew et al., 2018). The fact that patients with genetic mannose binding lectin deficiency exhibit a more diverse pulmonary microbiota and a lower risk of exacerbation suggests not only association but also causality (Dicker et al., 2018).
Besides the lung flora, the gut microbiota is involved in exacerbations, as suggested by the increased gastrointestinal permeability in patients admitted for COPD exacerbations (Sprooten et al., 2018). Whatever the permeability’s origin (hypoxemia or pro-inflammatory status), the level of circulating gut microbiota–dependent trimethylamine-N-oxide has been associated with mortality in COPD patients (Ottiger et al., 2018). This association being explained by comorbidities and age, its impact per se is not guaranteed. Further studies are warranted to investigate the role of GLA in COPD and to assess causality.
Early Life Perturbation
Early-life perturbations in fungal and bacterial gut colonization, such as low gut microbial diversity, e.g., after neonatal antibiotic use, are critical to induce childhood asthma development (Abrahamsson et al., 2014; Metsälä et al., 2015; Arrieta et al., 2018).
This microbial disruption is associated with modifications of fecal SCFA levels (Arrieta et al., 2018). Causality has been assessed in murine models. Inoculation of the bacteria absent in the microbiota of asthmatic patients decreases airways inflammation (Arrieta et al., 2015).
Fungi
Furthermore, Bacteroides fragilis seems to play a major role in immune homeostasis, balancing the host systemic Th1/Th2 ratio and therefore conferring protection against allergen-induced airway disorders (Mazmanian et al., 2005; Panzer and Lynch, 2015; Arrieta et al., 2018). Nevertheless, it is still not fully deciphered, as some studies conversely found that an early colonization with Bacteroides, including B. fragilis, could be an early indicator of asthma later in life (Vael et al., 2008).
Regarding fungi, gut fungal overgrowth (after antibiotic administration or a gut colonization protocol with Candida or Wallemia mellicola) increases the occurrence of asthma via IL-13 without any fungal expansion in the lungs (Noverr et al., 2005; Wheeler et al., 2016; Skalski et al., 2018). The prostaglandin E2 produced in the gut by Candida can reach the lungs and promotes lung M2 macrophage polarization and allergic airway inflammation (Kim et al., 2014).
Mouse & Human Gut Health
In mice, a gut overrepresentation of W. mellicola associated with several intestinal microbiome disturbances appears to have long-reaching effects on the pulmonary immune response and severity of asthma, by involving the Th2 pathways, especially IL-13 and to a lesser degree IL-17, goblet cell differentiation, fibroblasts activation, and IgE production by B cells (Skalski et al., 2018).
These results indicate that the GLA, mainly through the gut microbiota, is likely to play a major role in asthma.
Cystic Fibrosis and Gut Health
In CF patients, gut and lung microbiota are distinct from those of healthy subjects, and disease progression is associated with microbiota alterations. (Madan et al., 2012; Stokell et al., 2015; Nielsen et al., 2016). Moreover, the bacterial abundances at both sites are highly correlated and have similar trends over time (Madan et al., 2012). This is especially true regarding Streptococcus, which is found in higher proportion in CF stools, gastric contents, and sputa. (Al-Momani et al., 2016; Nielsen et al., 2016).
Moreover, CF patients with a documented intestinal inflammation exhibit a higher Streptococcus abundance in the gut (Enaud et al., 2019). That suggests the GLA’s involvement in intestinal inflammation. Of note, gut but not lung microbiota alteration is associated with early-life exacerbations. Some gut microbiota perturbations, such as a decrease of Parabacteroides, are predictive of airway colonization with P. aeruginosa (Hoen et al., 2015).
Furthermore, oral administration of probiotics to CF patients leads to a decreased number of exacerbations (Anderson et al., 2016). While the mycobiota has been recently studied in CF (Nguyen et al., 2015; Soret et al., 2019), no data on the role of the fungal component of the GLA are currently available in CF. This deserves to be more widely studied.
Improving Health in the Gut
The role of inter-compartment and inter-kingdom interactions within the GLA in those pulmonary diseases now has to be further confirmed and causality assessed. Diet, probiotics, or more specific modulations could be, in the near future, novel essential tools in therapeutic management of these respiratory diseases.
Conclusion
The gut–lung axis or GLA has emerged as a specific axis with intensive dialogues between the gut and lungs, involving each compartment in a two-way manner, with both microbial and immune interactions (Figure 1). Each kingdom and compartment plays a crucial role in this dialogue, and consequently in host health and diseases. The roles of fungal and viral kingdoms within the GLA still remain to be further investigated. Their manipulation, as for the bacterial component, could pave the way for new approaches in the management of several respiratory diseases such as acute infections, COPD, asthma, and/or CF.
WAF: Gut health is an important area of research for the foundation.
