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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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 and welcome to the World Asthma Foundation blog, where we share the latest news and information on asthma and related topics. We are a non-profit organization that pursues our mission and vision with a strategy to support the asthma community with educational resources. Our goal is to foster improved outcomes, better doctor-patient relationships, and support joint decision-making. In this way, asthmatics can take charge of their own health.
One of our main areas of focus is Infectious Asthma, which is a term that describes asthma that is triggered or worsened by infections, such as bacteria, viruses, fungi or parasites. Infectious Asthma can affect anyone, but it is more common and severe in children, elderly, immunocompromised or low-income populations. Infectious Asthma can cause more frequent and severe asthma attacks, lung damage, chronic sinusitis, nasal polyps and other complications.
In this article, we will review the current knowledge on one of the most common and potentially harmful triggers of Infectious Asthma: Staphylococcus aureus (S. aureus), a bacterium that can colonize the skin and mucous membranes of humans. S. aureus can produce various toxins, such as staphylococcal enterotoxins (SE), that can act as superantigens and induce an intense immune response in the airways. This can result in increased production of immunoglobulin E (IgE), a type of antibody that mediates allergic reactions, and activation of eosinophils, a type of white blood cell that causes inflammation and tissue damage.
We will also discuss how measuring SE specific IgE (SE-IgE) may help to identify a subgroup of patients with severe asthma who may benefit from specific interventions. Finally, we will provide some key takeaways and recommendations for asthmatics and clinicians.
We hope that this article will be informative and helpful for you. If you have any questions or comments, please feel free to contact us. Thank you for reading.
Summary
In this article, we have reviewed the current knowledge on the role of S. aureus and its enterotoxins in asthma, especially severe asthma. We have summarized the main findings from five recent studies that have investigated the association between SE sensitization and asthma severity, phenotype and inflammation. We have also discussed how measuring SE-IgE may help to phenotype asthmatics and guide treatment decisions. We have provided some key takeaways and recommendations for asthmatics and clinicians. Here are the main points:
• S. aureus and its enterotoxins are important factors in the pathogenesis of asthma, especially severe asthma.
• SE can act as superantigens and induce an intense T cell activation causing local production of polyclonal IgE and resultant eosinophil activation.
• SE can also manipulate the airway mucosal immunology at various levels via other proteins, such as serine-protease-like proteins (Spls) or protein A (SpA), and trigger the release of IL-33, type 2 cytokines, mast cell mediators and eosinophil extracellular traps.
• SE sensitization is associated with increased risk of asthma, more asthma exacerbations, nasal polyps, chronic sinusitis, lower lung function and more intense type-2 inflammation.
• SE sensitization is also linked to allergic poly-sensitization and allergic multimorbidity, such as rhinitis, eczema and food allergy, indicating a possible role of S. aureus in the development of allergic diseases.
• Measuring SE-IgE may help to identify a subgroup of patients with severe asthma who may benefit from specific interventions, such as anti-IgE therapy or antibiotics.
Key Takeaways
• Asthmatics should be aware of the potential role of S. aureus and its enterotoxins in triggering and worsening their asthma symptoms and seek medical advice if they suspect an infection or colonization.
• Asthmatics should avoid contact with S. aureus carriers or sources of contamination, such as contaminated food or water, and practice good hygiene and wound care to prevent infection or colonization.
• Asthmatics should ask their doctors about testing for SE-IgE as part of their asthma phenotyping and management, as it may help to identify a subgroup of patients with severe asthma who may benefit from specific interventions.
• Clinicians should consider measuring SE-IgE in asthmatics, especially those with severe asthma, nasal polyps, chronic sinusitis or allergic multimorbidity, as it may provide valuable information on the underlying mechanisms and phenotypes of asthma and suggest novel therapeutic targets and strategies.
• Clinicians should also monitor the SE-IgE levels and response to treatment in asthmatics who are receiving anti-IgE therapy or antibiotics, as it may help to evaluate the efficacy and safety of these interventions.
Conclusion
Asthma is a complex and heterogeneous disease that can be influenced by various factors, such as allergens, irritants, infections and stress. Among these factors, S. aureus and its enterotoxins have emerged as important triggers and modulators of asthma, especially severe asthma. SE can act as superantigens and induce an intense immune response in the airways, resulting in increased production of IgE and activation of eosinophils. SE can also manipulate the airway mucosal immunology at various levels via other proteins, such as Spls or SpA, and trigger the release of IL-33, type 2 cytokines, mast cell mediators and eosinophil extracellular traps. These mechanisms can lead to more severe asthma phenotype and type-2 inflammation.
SE sensitization is associated with increased risk of asthma, more asthma exacerbations, nasal polyps, chronic sinusitis, lower lung function and more intense type-2 inflammation. SE sensitization is also linked to allergic poly-sensitization and allergic multimorbidity, such as rhinitis, eczema and food allergy, indicating a possible role of S. aureus in the development of allergic diseases. Measuring SE-IgE may help to identify a subgroup of patients with severe asthma who may benefit from specific interventions, such as anti-IgE therapy or antibiotics.
In this article, we have reviewed the current knowledge on the role of S. aureus and its enterotoxins in asthma, especially severe asthma. We have summarized the main findings from five recent studies that have investigated the association between SE sensitization and asthma severity, phenotype and inflammation. We have also discussed how measuring SE-IgE may help to phenotype asthmatics and guide treatment decisions. We have provided some key takeaways and recommendations for asthmatics and clinicians.
We hope that this article has been informative and helpful for you. If you have any questions or comments, please feel free to contact us. Thank you for reading.
References
: Bachert C., Humbert M., Hanania N.A., Zhang N., Holgate S., Buhl R., Bröker B.M. Staphylococcus aureus and its IgE-inducing enterotoxins in asthma: current knowledge. Eur Respir J. 2020;55(4):1901592. doi: 10.1183/13993003.01592-2019.
: Kanemitsu Y., Taniguchi M., Nagano H., Matsumoto T., Kobayashi Y., Itoh H. Specific IgE against Staphylococcus aureus enterotoxins: an independent risk factor for asthma. J Allergy Clin Immunol. 2012;130(2):376–382.e3. doi: 10.1016/j.jaci.2012.04.027.
: Soh J.Y., Lee B.W., Goh A. Staphylococcal enterotoxin specific IgE and asthma: a systematic review and meta-analysis. Pediatr Allergy Immunol. 2013;24(3):270–279.e1-4. doi: 10.1111/pai.12056.
: Schleich F., Brusselle G.G., Louis R., Vandenplas O., Michils A., Van den Brande P., Lefebvre W.A., Pilette C., Gangl M., Cataldo D.D., et al. Asthmatics only sensitized to Staphylococcus aureus enterotoxins have more exacerbations, airflow limitation, and higher levels of sputum IL-5 and IgE. J Allergy Clin Immunol Pract. 2023;11(5):1658–1666.e4. doi: 10.1016/j.jaip.2023.01.021.
: James A., Gyllfors P., Henriksson E.L., Lundahl J., Nilsson G., Alving K., Nordvall L.S., van Hage M., Cardell L.O. Staphylococcus aureus enterotoxin sensitization is associated with allergic poly-sensitization and allergic multimorbidity in adolescents. Clin Exp Allergy. 2015;45(6):1099–1107. doi: 10.1111/cea.12519.
Sidebar: What is Staphylococcus aureus?
Staphylococcus aureus is a type of bacteria that can cause various infections in humans and animals. It is found in the environment and also in the normal flora of the skin and mucous membranes of most healthy individuals. It can colonize the anterior nares (the front part of the nose), the throat, the skin, and the gastrointestinal tract. It is estimated that up to half of all adults are colonized by S. aureus, and approximately 15% of them persistently carry it in their noses.
S. aureus can cause infections when it breaches the skin or mucosal barriers and enters the bloodstream or internal tissues. These infections can range from mild skin infections, such as boils or impetigo, to more serious infections, such as pneumonia, endocarditis, osteomyelitis, septic arthritis, or sepsis. S. aureus can also produce toxins that can cause food poisoning, toxic shock syndrome, or scalded skin syndrome.
S. aureus is a very adaptable and versatile bacterium that can acquire resistance to various antibiotics. The most notorious example is methicillin-resistant S. aureus (MRSA), which is resistant to most beta-lactam antibiotics, such as penicillins and cephalosporins. MRSA can cause infections both in community-acquired and hospital-acquired settings and poses a major public health challenge.
S. aureus is believed to have originated in Central Europe in the mid-19th century and has since evolved and diversified into many different strains or clones. Some of these strains are more virulent or resistant than others and have spread globally through human migration and travel. One of these strains is ST8, which includes the USA300 clone that is responsible for most community-acquired MRSA infections in the United States.
S. aureus is one of the most common and potentially harmful triggers of Infectious Asthma, especially severe asthma. It can produce various toxins, such as staphylococcal enterotoxins (SE), that can act as superantigens and induce an intense immune response in the airways. This can result in increased production of immunoglobulin E (IgE), a type of antibody that mediates allergic reactions, and activation of eosinophils, a type of white blood cell that causes inflammation and tissue damage.
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.
In this fifth in a series of interviews with Rodney Dietert PhD, he talks about communication between the gut and lung. Dr. Dietert is Cornell University Professor Emeritus, Health Scientist Head of Translational Science + Education for SEED and the Author of the Human Super-Organism How the Microbiome is Revolutionizing the Pursuit of a Healthy Life we learn about:
* The Gut and lung communication and its relationship to Asthma
World Asthma Foundation “Defeating Asthma Series uncovers New Hope for Asthma Managementant
Asthmatics: Our understanding of Asthma and the way we treat it may soon be radically different from what currently exists, due to new research on the human microbiome and how the microbiome affects asthma.
Interview
World Asthma Foundation: Research into the Microbiome and its relationship to health has improved significantly in the last few years. For example, we now know about the relationship between the gut and health. We’ve also learned about communication between the gut and the lung and the impact on Asthma. Dr. Dietert, so there’s some crosstalk, right?
Video interview: Asthma Connection to Gut and Lung Cross Talk – Rodney Dietert, PhD
Dr. Dietert: Tremendous crosstalk, absolutely tremendous. You’re correct that if you’re looking at endpoints, something like risk of asthma or management of asthma, then you really, at a minimum, are going to focus both on the respiratory system microbiome and the gut microbiome. That’s not necessarily the exclusion of others but those two are really important. Just like the gut microbiome can affect the brain, it can affect behavior, mood. You don’t need lots of hardcore meds as an antidepressant when you’ve got the solution sitting right in your gut in terms of the microbiome.
With the respiratory system, you’ve got both the local microbes being extremely important but you have crosstalk, you have chemical interactions that are originating in the gut that are affecting the respiratory system as well.
World Asthma Foundation: Dr. Dietert, we certainly thank you for your time, all that you do for the microbiome and the community. Good afternoon, and thanks again.
Dr. Dietert: Well, and thank you for all you do with the World Asthma foundation, Bill. Pleasure.
Defeating Asthma Series uncovers New Hope for Asthma Management
In this third interview with Martin J Blaser MD, Director of the Center for Advanced Biotechnology and Medicine at Rutgers Biomedical and Health Sciences and the Henry Rutgers Chair of the Human Microbiome and Professor of Medicine and Microbiology at the Rutgers Robert Wood Johnson Medical School in New Jersey and the Author of the “Missing Microbes – How the Overuse of Antibiotics is Fueling Our Modern Plagues.” we learn:
About the H. pylori and Asthma connection
Additional reserach looking into the connection between H. pylori and Asthma
Whether the Microbes can reintroduced
Video: Missing Microbes and Asthma Link Say Multiple Studies – Martin J Blaser MD
Asthma Foundation: Dr. Blaser, we’ve talked about the asthma connection and the H. pylori topic. Can you identify these missing microbes also with tests?
Dr. Blaser: Yes. The paper with Jakob Stokholm in Nature Communications looked at this– We saw that there was a difference in the microbiome in the kids that were one year old. That was the age at which their microbiome made a difference, whether they’d have a risk of asthma or not. Then we asked, “Okay, what’s the difference in the specific microbes at age one between the positives and the negatives?” We identified about 20 microbes that were significantly different, mostly lost, mostly missing.
What was interesting is that a group from British Columbia, led by Dr. Brett Finlay and colleagues had published about this also. They had found, I think, four or five organisms and we matched on four of the five. Again, two independent studies finding the same relationship makes it stronger
World Asthma Foundation: If I understand correctly, your research is determining whether or not you can repopulate the H. pylori. Is that independent of the intestinal microbes?
Dr. Blaser: In theory, yes. What’s interesting is that people have been interested in microbes and asthma for quite some time, and most of the concentration was in the large intestine, in the colon. We were interested in the stomach first, but then we got more involved in the colon also. I think that both compartments in the body are important. Both of them are important. They’re both subject to this terrible pressure of the disappearance of microbes because of such things as antibiotics and cesarean sections and the like. They’re both. All of these microbes are potentially replaceable. That’s the hope.
World Asthma Foundation: Fantastic, that’s the hope.
Among this panel of relatively moderate to severe asthmatics, the respiratory irritants produced by several domestic combustion sources were associated with increased morbidity.
Although there is abundant clinical evidence of asthmatic responses to indoor aeroallergens, the symptomatic impacts of other common indoor air pollutants from gas stoves, fireplaces, and environmental tobacco smoke have been less well characterized. These combustion sources produce a complex mixture of pollutants, many of which are respiratory irritants.
Results of an analysis of associations between indoor pollution and several outcomes of respiratory morbidity in a population of adult asthmatics residing in the U.S. Denver, Colorado, metropolitan area. A panel of 164 asthmatics recorded in a daily diary the occurrence of several respiratory symptoms, nocturnal asthma, medication use, and restrictions in activity, as well as the use of gas stoves, wood stoves, or fireplaces, and exposure to environmental tobacco smoke.
Multiple logistic regression analysis suggests that the indoor sources of combustion have a statistically significant association with exacerbations of asthma. For example, after correcting for repeated measures and autocorrelation, the reported use of a gas stove was associated with moderate or worse shortness of breath (OR, 1.60; 95% CI, 1.11-2.32), moderate or worse cough (OR, 1.71; 95% CI, 0.97-3.01), nocturnal asthma (OR, 1.01; 95% CI, 0.91-1.13), and restrictions in activity (OR, 1.47; 95% CI, 1.0-2.16
The WAF Editorial Board wishes to thank and acknowledge B D Ostro 1 , M J Lipsett, J K Mann, M B Wiener, J Selner
California Environmental Protection Agency, Berkeley for their contribution to Asthma education and research.
Asthma does not appear to increase the risk or influence its severity, according to University study
Whats new
Rutgers researchers say further study is needed but those with the chronic respiratory disease don’t appear to be at a higher risk of getting extremely ill or dying from coronavirus.“Older age and conditions such as heart disease, high blood pressure, chronic obstructive pulmonary disease, diabetes and obesity are reported risk factors for the development and progression of COVID-19,” said Reynold A. Panettieri Jr., a pulmonary critical care physician and director of the Rutgers Institute for Translational Medicine and Science and co-author of a paper published in the Journal of Allergy and Clinical Immunology.
“However, people with asthma — even those with diminished lung function who are being treated to manage asthmatic inflammation — seem to be no worse affected by SARS-CoV-2 than a non-asthmatic person. There is limited data as to why this is the case — if it is physiological or a result of the treatment to manage the inflammation.”
Children and young adults with asthma suffer mainly from allergic inflammation, while older adults who experience the same type of airway inflammation can also suffer from eosinophilic asthma — a more severe form. In these cases, people experience abnormally high levels of a type of white blood cell that helps the body fight infection, which can cause inflammation in the airways, sinuses, nasal passages and lower respiratory tract, potentially making them more at risk for a serious case of COVID-19.
Further Study Needed
Panettieri discusses what we know about asthma and inflammation and the important questions that still need to be answered.
How might awareness of SARS-CoV-2 affect the health of people with asthma?
Since the news has focused our attention on the effects of COVID-19 on people in vulnerable populations, those with asthma may become hyper-vigilant about personal hygiene and social distancing. Social distancing could improve asthma control since people who are self-quarantined are also not as exposed to seasonal triggers that include allergens or respiratory viruses. There is also evidence that people are being more attentive to taking their asthma medication during the pandemic, which can contribute to overall health.
What effect might inhaled steroids have on COVID-19 outcomes?
Inhaled corticosteroids, which are commonly used to protect against asthma attacks, also may reduce the virus’s ability to establish an infection. However, studies have shown that steroids may decrease the body’s immune response and worsen the inflammatory response. Steroids also have been shown to delay the clearing of the SARS and MERS virus — similar to SARS-CoV-2 — from the respiratory tract and thus may worsen COVID-19 outcomes. Future studies should address whether inhaled steroids in patients with asthma or allergies increase or decrease the risks of SARS-CoV-2 infection, and whether these effects are different depending on the steroid type.
In what way does age play a role in how asthma patients react to exposure to the virus?
A person’s susceptibility to and severity of COVID-19 infection increases with age. However, since asthma sufferers tend to be younger than those with reported high-risk conditions, age-adjusted studies could help us better understand if age is a factor in explaining why asthma patients may not be at greater risk for infection.
Children and young adults with asthma suffer mainly from allergic inflammation, while older adults who experience the same type of airway inflammation can also suffer from eosinophilic asthma — a more severe form. In these cases, people experience abnormally high levels of a type of white blood cell that helps the body fight infection, which can cause inflammation in the airways, sinuses, nasal passages and lower respiratory tract, potentially making them more at risk for a serious case of COVID-19.
In addition, an enzyme attached to the cell membranes in the lungs, arteries, heart, kidney and intestines that has been shown to be an entry point for SARS-CoV-2 into cells is increased in response to the virus. This enzyme is also thought to be beneficial in clearing other respiratory viruses, especially in children. How this enzyme affects the ability of SARS-CoV-2 to infect people with asthma is still unclear.
How might conditions in addition to asthma affect a person’s risk of infection?
Asthma tends to be associated with far fewer other conditions than chronic obstructive pulmonary disease or cardiovascular disease. If SARS-CoV-2 is a disease that causes dysfunction in the cells that line blood vessels throughout the body, then diabetes, heart disease, obesity and other diseases associated with this condition may make people more susceptible to the virus than those who are asthmatic.
Important to know
However, older people with asthma who also have high blood pressure, diabetes or heart disease may have similar instances of COVID-19 as non-asthmatics with those conditions.
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.
Although non-eosinophilic asthma (NEA) is not the best known and most prevalent asthma phenotype, its importance cannot be underestimated. NEA is characterized by airway inflammation with the absence of eosinophils, subsequent to activation of non-predominant type 2 immunologic pathways. This phenotype, which possibly includes several not well-defined subphenotypes, is defined by an eosinophil count <2% in sputum. NEA has been associated with environmental and/or host factors, such as smoking cigarettes, pollution, work-related agents, infections, and obesity. These risk factors, alone or in conjunction, can activate specific cellular and molecular pathways leading to non-type 2 inflammation.
Note from the WAF: We wish to acknowledge and thank Darío Antolín-Amérigo, Javier Domínguez-Ortega,3,4 and Santiago Quirce Department of Allergy, Hospital General de Villalba, Madrid, Spain, for their contribution to Asthma education and research.
The most relevant clinical trait of NEA is its poor response to standard asthma treatments, especially to inhaled corticosteroids, leading to a higher severity of disease and to difficult-to-control asthma. Indeed, NEA constitutes about 50% of severe asthma cases. Since most current and forthcoming biologic therapies specifically target type 2 asthma phenotypes, such as uncontrolled severe eosinophilic or allergic asthma, there is a dramatic lack of effective treatments for uncontrolled non-type 2 asthma. Research efforts are now focusing on elucidating the phenotypes underlying the non-type 2 asthma, and several studies are being conducted with new drugs and biologics aiming to develop effective strategies for this type of asthma, and various immunologic pathways are being scrutinized to optimize efficacy and to abolish possible adverse effects.
