Defeating Asthma Series uncovers New Hope for Asthma Management
In this second 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 connection between Asthma and the Microbiome
About research and studies that predict Asthma in childhood
About bacteria not just in the stomach but in the colon
About C-sections and the likelihood to develop asthma
About the Mayo Clinic study on Asthma and antibiotics useage
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.
World Asthma Foundation: Dr. Blaser, can you help us connect Asthma and the Microbiome?
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Dr. Blaser: I’ve gotten very involved in studying the human microbiome in general, not just in the stomach, but in the colon. We and others are working on the relationship of the bacteria (microbiome) in the colon and asthma.
Again, there’s a paper that’s published. A young doctor from Denmark, Dr. Jakob Stokholm, came to work in my lab. This happened after Missing Microbes was published, so it’s not in the book. He’s part of a study in Copenhagen called the COPSAC study, the Copenhagen Open Study of Asthma in Children. They have cohorts of moms whose kids are going to have high risk of asthma, either because they have asthma or they already have a child who has asthma.
In 2010, if I remember correctly, they enrolled 750 moms with this high risk. They obtained fecal samples from the moms. They also got samples from the kids at one week, one month, and one year of life. Then they followed these kids until they were about six. The question was, is there anything that might predict who was going to get asthma at the age of six? We did a lot of work studying the microbiome in their fecal specimens, and what we found is consistent with what other people found: that the microbiome matures over time between one week and one month, and one year. It shows a pattern of maturation, but in some kids, their microbiome doesn’t mature in the normal way.
Then we made a very important observation. In those kids whose microbiome didn’t mature normally when you compare them to kids who did have normal maturation, the odds ratio, the chances that they were going to get asthma when they were six was 3, (300%) meaning a rate three times normal. Then we divided those kids by whether their mother previously had asthma or not. If their mother didn’t have asthma, the maturation pattern did not make a difference, but if their mother did have asthma, the odds ratio was 13.
We’re getting in the range of the association between smoking and lung cancer. That’s how strong that is. That was published about two years ago in Nature Communications. We have a new paper that now is in press. It is about cesarean sections. It’s known that kids born by C-section have a higher risk of developing asthma. The question is why?
From this study, again with the children in the Copenhagen study, we confirmed that kids born by C-section are more likely to develop asthma than those who didn’t. In those kids who had C-section, on average, their microbiome early was abnormal compared to those who were born vaginally. But by a year, in many of them, their microbiome had matured normally, but if it didn’t mature normally, those kids had a very high rate of getting asthma. Again, a high risk. That’s going to be published within a month or two because it’s been accepted already.
Now, what I will tell you is that with Dr. Müeller and with a graduate student in my lab, Tim Borbet, we’ve been doing a lot of mouse-asthma studies where we can experimentally give a mouse asthma or allergy. We already can show that if we perturb the microbiome early in life with antibiotics, they’re going to get more allergy and more asthma. That’s interesting because a paper was just published from British Columbia, showing that they had a really good program to diminish antibiotic use across the whole province. They showed that with diminishing antibiotic use, asthma rates are going down, so it’s all connected.
Furthermore, I’m part of another study that’s also in press. It’s going to be published probably in a month or two with scientists at the Mayo Clinic. I visited there a few years ago. The Mayo clinic is located in Olmsted County, Minnesota. It’s a pretty isolated place. In general, people don’t come, people don’t go, they stay there. It’s a very good stable population to study. I suggested to my colleagues there, why don’t you look at the effects of antibiotics in early life for certain marker diseases, including asthma and food allergy, and atopic dermatitis and allergic rhinitis. All these diseases go together. The group there is very active and outstanding, and they studied about 14,000 kids who were born in Olmsted County, and they were followed up to the time that they were 15 or 14. They had a lot of information from their health records because most of their medical care there is through the Mayo Clinic.
The bottom line is that if they received antibiotics in the first two years of life, their odds ratio of getting asthma was 2. They were twice as likely as kids who did not receive early-life antibiotics. Lots of things are pointing to the importance of the early life microbiome and the importance of when its being perturbed by antibiotics, that there’s increased risk. The relationship with moms, that’s this kind of transgenerational thing that each generation is stepping down.
World Asthma Foundation: A lot of these antibiotics are not only prescribed, but they’re ubiquitous in our diet and our food supply right?.
Dr. Blaser: Yes. Well, I’m very interested in that as well, although the prescribed antibiotic is more important because it’s higher dose. In mice, when we give low doses of antibiotics, it perturbs the immune system but not so much. When we give them the same kind of doses that kids get to treat their ear infections or their throat infections, it really perturbs their immune system and puts it on a different path. That’s also published.
Defeating Asthma Series uncovers New Hope for Asthma Management
In this 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
That H. pylori was disappearing with modernization
Can we identify these missing microbes
Can we replace them?
Can we repopulate these missing microbes?
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.
Dr. Blaser: These are good questions.
World Asthma Foundation: Great. Thank you for the support.
Dr. Blaser: Fine. That’s good. I’m happy to help you because this is what I really believe.
World Asthma Foundation: Doctor Blaser, what prompted your interest in this area?
Dr. Blaser: Well, it all starts with H. pylori. We did a lot of work on H. pylori. Some of this is in the book, but we developed the first really good blood test to tell if a person had H. pylori or not, and that opened a lot of doors for us.
We made the association between H. pylori and stomach cancer, and brought depth to the association with ulcers. We’ve discovered a form of H. pylori that has a gene called CagA.
We discovered that actually using my own serum and tests, and so we could distinguish between two different subtypes of H. pylori, one which is more interactive with people, and the other is less interactive. The more interactive is called the CagA-positive strain.
And we learned that H. pylori was disappearing with modernization. To many doctors, that was good news because of the linkage with stomach cancer and ulcers, but I was not certain.
I’m not a gastroenterologist, my specialty is infectious diseases, but I had a lot of gastroenterologists working with me. One day I said to one of the gastroenterologists, Dr. Richard Peek, “I’ve heard a lot about this disease called reflux or GERD. Why don’t we see whether there’s an association with H. pylori or not? I’m thinking that there might be because GERD is a disease that is increasing in incidence.”
It was a disease that wasn’t recognized until the 1930s, it wasn’t in the medical literature until the 1930s.
We did the study, it’s recounted in Missing Microbes. He came back to me and said, “This is funny. There’s an inverse association. People who have GERD less often have H. pylori than others.”
Then it occurred to me that maybe H. pylori is protective against GERD, and maybe the reason that GERD is going up is because H. pylori is disappearing.
We conducted about 10 other studies on GERD, on Barrett’s esophagus, on adenocarcinoma of the esophagus, all of these showed an inverse association. It became clear to me that helicobacter is bad for your stomach but good for your esophagus.
Because I’m a medical doctor, I knew that there’s a relationship between reflux and asthma. There are people who start wheezing and their doctor treats them with a medicine to suppress gastric acidity and their asthma gets better. That’s well-known to physicians, and in adult-onset asthma, that might be 10% of the cases. It’s not rare.
I thought, “Well, if helicobacter protects against reflux, maybe it protects against asthma.” Of course, I knew that asthma was one of these increasing diseases, increasing as H. pylori was going away, so it was a reasonable hypothesis.
At that point, I was at Vanderbilt University. I tried to get the pulmonary people interested in this idea to test it. There was some interest but nobody had the time to test it, and then I moved to NYU, and I became the chair of medicine at NYU. The people at NYU were more responsive.
There was one physician there who had a big asthma clinic, and I said, “Let’s do this test. You give me serum from people who have asthma and controls who do not have asthma, send it to us blindly, and we will see, is there any relationship with H. pylori.”
They did that, and actually I recount this in the book Missing Microbes because it’s one of the more dramatic moments in my career.
My colleague Joan Reibman writes to me, and she says, “You’re right. There’s an inverse association between H. pylori and asthma.” She said, “The results aren’t that great. Maybe we should discuss it.”
They come to my office, she and a couple of other colleagues, and she starts showing me the data. I said, “Oh, that’s it.” The odds ratio was 0.7, I remember it, which is an inverse association. It was statistically significant because there were several hundred people. The study had about 500 people.
I said, “Oh, that’s nice. Well, what about CagA?” She said, “Oh, we didn’t run CagA. We didn’t analyze it.” I said, “Oh, CagA is the most important because that’s the one that’s the most interactive, and what we found with esophageal disease is that CagA strains are the most protective strains.
They are the ones most associated with stomach cancer and ulcers (and thus most bad), but for esophageal disease, they’re the most beneficial strains. They’re the ones that are most protective.
How’s that possible that they are both most good and most bad? It’s because they’re the most interactive. The other ones are not nearly as interactive. And good or bad depends on context, the disease in which you are studying.
I said to her, “Well, what about the CagA strains in asthma?” One of the people on her team was a statistician, he had his laptop, and he said, “Oh, I can just calculate this right now.” He taps a couple of keys in his computer. He says, “Odds ratio of 0.6.” It was even stronger. This was a blinded study.
That was the first study to show an inverse association of H. pylori and asthma. Then about a couple of weeks later, a new epidemiologist came to NYU, Dr. Yu Chen, and she said, “I’ve been told to look you up because you were doing interesting work.” And I said, “Well, I’m really interested in asthma.”
There’s a series of big national studies called the NHANES studies. I suggested to her that we should look at asthma in NHANES because we had a contract some years earlier and we ran H. pylori serology on 11,000 people as part of NHANES.
“So why don’t you go to the NHANES database and find those 11,000 people and see if there’s any relationship with H. pylori?” She did it, and what she found is yes, same thing, inverse relationship with asthma, almost exactly the results from New York.
So we have two independent blinded studies, one with 500 people and one with 11,000 people, both show the same thing.
What was interesting is that we could divide asthma into two classes: childhood-onset asthma, and adult-onset asthma. The association is that in general, the correlation was not with adult-onset asthma, it was only with childhood-onset asthma.
There were several NHANES studies and they had conducted H. pylori serology in another one. We performed that study as well, and we’ve found almost the same results.
Three large independent blinded studies all show the same thing. What was clear is the lack of H. pylori is a marker for risk of asthma for childhood-onset, really clear. Others have been working on this, but I think these were the three most definitive studies.
Then a very good scientist in Zurich, Anne Müeller began doing mouse experiments. There’s a way that you can provoke asthma in mice. There are different mouse models of asthma in mice.
She asked, what if she gives H. pylori to these mice, can she protect them against asthma? And she could.
Then she worked out many of the details of the mechanism, how H. pylori is involved in a lot of the regulation of immunity in the model that I just mentioned. The mechanism is there.
In the meantime, I’ve been working extensively with Dr. Müller for the last four or five years to continue this work. We’ve got a couple of papers already published, and we have more papers that we’re working on and about to submit about the microbiome and about H. pylori. Some of the effect of microbes in asthma is H. pylori.
Defeating Asthma Series uncovers New Hope for Asthma Management
In this interview with Rodney Dietert, PhD 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 that we’re a superorganism and we are, by several measures, primarily microbial, living on a microbial planet.
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: What prompted your interest in this area?
Dr. Dietert: It was literally the result of a dream. Woke up in the middle of the night, I had been struggling to write a new paper. The paper was supposed to identify the single, most important thing that you could measure in a newborn baby that would be the best predictor of whether that baby’s life was filled with health or filled with disease. That’s a challenging but a worthwhile idea. What could you measure in a newborn baby? I was pretty sure I had the answer because I’d been working for decades on the developing immune system and it was something surrounding that.
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Dr. Dietert: I started to write the paper and it was a very frustrating, terrible effort. Got a couple of paragraphs down and very unconvincing and uninspired and so I went to bed and woke up in the middle of the night and had a magnificent dream, which I don’t really remember the details of but it’s like, “Wow, have I been dreaming? Wow, do I have this idea?” The idea was the best measurement you could have at that point in time with a newborn is the extent to which the baby has self-completed. By self-completed, I mean acquired a full microbiome from mom, dad, and the environment and that is critical. That’s what we’re supposed to be.
We’re a superorganism and we are, by several measures, primarily microbial, living on a microbial planet. The major life form on the planet are bacteria. Really anything that disrupts that completion, in my mind, is viewed as a type of birth defect. It’s a correctable birth defect but nevertheless, it’s like missing a limb or missing a different organ. To miss the seeding events, to miss the microbiome the baby is intended to have is an incredibly serious biological effect that has really serious health ramifications.
My wife helped me put together the scrambled ideas coming off a dream. We wrote the paper and that wound up really turning my career in a whole different direction because it was seen by some filmmakers who were making a wonderful documentary called Microbirth, and it won the Life Science Film Festival Award for 2014. In that documentary, I was able to explain this concept and why it was so critical for preventing essentially diseases like asthma or really reducing the risk dramatically.
That we had control of these risks, the risk for diabetes, for asthma, for psoriasis, for inflammatory bowel, for a whole host of diseases that were to some extent under more control to a greater degree than we had ever envisioned. The reason we had that opportunity was because there was a new biology that we as humans were not what we had been taught or at least what I was taught decades ago in school and what I taught at Cornell for a number of years. That we were quite different.
Once we’ve recognize that difference, then it changes everything. It changes how you approach diet, how you approach what a healthy life looks like, how you approach medicine, therapeutics, drug development, environmental chemicals. Everything changes. Really that’s been my path, to try and help chart and provide useful information on how we, as a superorganism, can lead a healthier life.
World Asthma Foundation: With that, Dr. Dietert, we certainly thank you for your time, all that you do for the microbiome, and the patient population in the community. With that, 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 interview with Justin L. Sonnenburg PhD, Associate Professor of Microbiology and Immunology at Stanford University, we learn diseases largely driven by inflammation and an altered immune system may benefit from taking our microbiome into account.
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.
“Diseases largely driven by inflammation and an altered immune system. If we start to take our gut microbiota into account, as we live our life, as we make medical decisions, eat different foods and potentially even eventually reintroduce some of these lost microbes, how profound can the impact be on our health?” Justin L. Sonnenburg Ph.D
Interview
World Asthma Foundation: Dr. Justin L. Sonnenburg Associate Professor of Microbiology and Immunology at Stanford University, well known author, sought after speaker and an infectious disease investigator.
Dr. Sonnenburg’s interest includes the basic principles that govern interactions within the intestinal microbiota and between the microbiota and the host. To pursue these aims, they colonize germ-free (gnotobiotic) mice with simplified, model microbial communities, apply systems approaches (e.g. functional genomics), and use genetic tools for the host and microbes to gain mechanistic insight into emergent properties of the host-microbial super-organism.
World Asthma Foundation: Good afternoon, Dr. Sonnenburg, and thanks for agreeing to the interview.
Dr. Justin L. Sonnenburg: Great to be with you.
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World Asthma Foundation: Super. Asthmatics want to know some things you’ve written about the gut. We know for example that we need more fiber. We also know that we need to eat healthier, but for some of us, unfortunately, the gut for a variety of reasons is out of whack or disrupted. Some suggested the potential of Missing Microbes. The gut is a delicate ecosystem. The question that I have for you today is can we get some of those microbes back?
Dr. Justin L. Sonnenburg: I think that’s a key question. It’s very clear that we’ve done things during the process of industrialization and things that are associated with our modernized lifestyle now, antibiotics, highly processed food, C-sections, baby formula. There are a lot of things that have been associated with microbiome deterioration.
The question is when we lose microbes or change this malleable component of our biology, our gut microbiota, how meaningful is that for our biology? I think what’s really interesting and notable is that at the same time that our microbiome has been changing, we’ve seen this incredible rise in what we call Western diseases or non-communicable chronic diseases.
Diseases largely driven by inflammation and an altered immune system. I think that a big question is if we start to take our gut microbiota into account, as we live our life, as we make medical decisions, eat different foods and potentially even eventually reintroduce some of these lost microbes, how profound can the impact be on our health?
Can we greatly improve the status of our immune system? Potentially both preventing the onset of chronic diseases and maybe even helping to treat or reduce the severity of some of these diseases.
New Hope for Asthma Management – World Asthma Foundation Announces The Microbiome Podcast Series
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. The Microbiome Podcast Series – New Hope for Asthma Management commences with interviews and reports with leading Microbiome researchers providing new hope for asthma management.
Why this matters
300 million people around the world have asthma, and while there are treatments to mitigate its effects, there is no definitive understanding of the root causes. Research into the microbiome is now piecing together new understanding of how the microbiome may be closely connected to causing asthma and other diseases.
The microbiome is the genetic material of microbes – bacteria, fungi, protozoa and viruses – that live on and inside the human body.
“The World Asthma Foundation podcast series allows researchers to discuss what they have learned, so people with asthma can learn about some of the advances and connections they are making” – Alan Gray, Director, World Asthma Foundation.
“A growing body of evidence implicates the human microbiome as a potentially influential player actively engaged in shaping the pathogenetic processes underlying the endotypes and phenotypes of chronic respiratory diseases, particularly of the airways.” Lung Microbiome in Asthma: Current Perspectives 2019
Rodney Dietert, Ph.D., Cornell University Professor Emeritus, Health Scientist Head of Translational Science + Education for SEED. Author of Human Super-Organism How the Microbiome is Revolutionizing the Pursuit of a Healthy Life. For full interview with Rodney Dietert, PhD on the Microbiome click here.
Justin L. Sonnenburg. Ph.D., Associate Professor of Microbiology and Immunology at Stanford University, well known author, sought after speaker and an infectious disease investigator. Co-author of the Good Gut. Taking Control of Your Weight, Your Mood, and Your Long Term Health. For full interview with Justin L. Sonnenburg PhD on the Microbiome click here.
“In this new era of the Microbiome, there is a massive gap between what we know about human biology and how human health is managed in westernized medicine. That gap needs to be closed soon so medicine can look more like the ecological management of a coral reef than something akin to smothering a forest fire with a small blanket.” Rodney Dietert, Ph.D, Cornell University Professor Emeritus
Respiratory infections can cause wheezing episodes in children and can influence the onset and severity of asthma via complex and intersecting mechanisms. Infections can trigger atopic asthma, and atopy can cause wheezing during airway infections and modify the course of airway infections. Mycoplasma pneumoniae (M. pneumoniae), primarily recognized as a causative agent of community-acquired pneumonia, has recently been linked to asthma. Infections with M. pneumoniae can precede the onset of asthma, exacerbate asthmatic symptoms, and cause difficulties with asthma management.1
The clinical association between M. pneumoniae infection and exacerbation of asthma symptoms has been suspected for longer than two decades; however, the nature of the correlation is still far from clear. In 1970, Berkovich et al.2 provided the first prospective study showing serological evidence of infection with either M. pneumoniae or a respiratory virus in 27 of 84 (32%) asthma patients. Huhti et al.3 analyzed 63 patients after severe episodes of acute asthma and found that 19% had associated viral or mycoplasma infections. Biscardi et al.4 reported that 20% (24/119) of the patients with previously diagnosed asthma had simultaneous acute M. pneumoniae infection and asthma exacerbation; of 51 patients experiencing their first episode, acute infection with M. pneumoniae was identified in 26 (50%) of the patients. Therefore, based on the current literature, M. pneumoniae appears to be an important trigger for the acute exacerbation of asthma, accounting for 3.3%-50% of exacerbations.
Several recent studies have implicated M. pneumoniae infection in the pathophysiology of asthma in subsets of patients. In two of the most influential studies, Kraft et al.5 and Martin et al.6 used polymerase chain reactions (PCRs) to detect M. pneumoniae in the lower pulmonary airways in 25 of 55 (45%) adult patients with chronic stable asthma, compared with 1 of 11 (9%) controls. Using serology and PCR, Esposito et al.7 found M. pneumoniae significantly more often in children with acute episodes of wheezing than in controls, and infection was significantly associated with a history of recurrent wheezing. Lieberman et al.8 showed in a prospective study using serological detection that M. pneumoniae infection was significantly associated with acute exacerbation of bronchial asthma. Furthermore, treatment with antibiotics against M. pneumoniae significantly improved pulmonary function in asthmatics with M. pneumoniae infection, suggesting a role for infection in chronic asthmatics.9
Although the evidence linking M. pneumoniae infection with exacerbation and chronic asthma is convincing, the role of M. pneumoniae as the cause of the initial onset of asthma remains unclear. In 1994, Yano et al.10 was first to describe a patient in whom a previous acute mycoplasmal respiratory infection led to an initial onset of bronchial asthma. In a follow-up study in 50 children, Mok et al.11 reported that five children (10%) with M. pneumoniae respiratory illness developed clinical signs of asthma. All five children, however, had a family and personal history of atopy. It seems that acute infection with M. pneumoniae can initiate asthma in some previously asymptomatic patients and in some individuals with atopy. However, regarding a quantitative role of these bacteria or a direct cause-and-effect association as asthma initiators, additional large population-based prospective or cohort studies are necessary before definitive conclusions can be drawn.
The WAF would like to acknowledge and thank Soo-Jong Hong corresponding author at The Korean Academy of Asthma, Allergy and Clinical Immunology • The Korean Academy of Pediatric Allergy and Respiratory Disease for contribution to Astma education and research.
The mechanisms of M. pneumoniae interactions with human airways are complex and multifactorial. Underlying mechanisms of M. pneumoniae infection-induced or exacerbated asthma may involve the stimulation of predisposing immune responses. Factors involved in these immune responses may include the induction of Th2 cytokines, immune cells, and IgE production; physiological changes such as bronchial obstruction, angiogenesis, edema, and cell wall thickening; and even neural mechanisms.5,6,10-12 Further elucidation of these mechanisms may enable the development of novel therapeutic strategies for the prevention and treatment of infection-induced asthma. The immune cells of bronchoalveolar lavage fluid in children with M. pneumoniae pneumonia were found to comprise high percentages of neutrophils and lymphocytes.12 Thus, the exacerbation of asthma may be related to neutrophil cytokine signaling and degranulation, and cell lysis at the respiratory epithelial cell surface.13,14 In addition, asthmatics with infection had a significantly greater number of mast cells than asthma patients without infection.6 These observations suggest that M. pneumoniae infections, particularly in children, may result in a dominant Th2 response that induces increased IgE release, thereby predisposing patients to atopy.
Increased airway wall thickness has been observed in several different studies in asthma patients. Continued function requires extensive microvascular systems, and adding thickness to the airway wall further reduces airway conductance.15 Angiogenesis and edema have been associated with airway remodeling in asthma. These responses to M. pneumoniae infection of the airways may induce chronic asthma.16 However, studies about how this feature of asthma is affected during bacterial infection and the impact on treatment of the disease have only recently commenced.
Animal models of chronic airway infection with M. pulmonis (the murine equivalent of human M. pneumoniae) have been used to describe the mechanisms underlying angiogenesis, vascular remodeling, and airway wall thickening observed in asthma.15 Airway remodeling results from inflammatory responses that allow the movement of leukocytes and plasma proteins into the airway epithelium. This vascular leakage is promoted by vascular endothelial growth factor (VEGF).15
As presented in this issue of Allergy, Asthma & Immunology Research, Jeong et al.17 investigated the changes in VEGF and interleukin-5 (IL-5) serum levels in atopic children with M. pneumoniae pneumonia. The authors showed that the serum levels of VEGF and IL-5 were increased in atopic children with mycoplasma pneumonia compared with levels in other groups. Furthermore, the serum levels of VEGF and IL-5 were increased at the recovery phase compared with the admission phase. These results suggest an association between M. pneumoniae infection and VEGF or IL-5 in the pathogenesis of atopic asthma in children. A limitation to this study was the reliance on the past and family history of allergic diseases and IgE concentration to define atopy. Future studies will require a more definitive definition of atopy in study subjects. In addition, a long-term follow-up study examining the development of asthma in non-atopic individuals with mycoplasma infection would be interesting. Further research will be required to demonstrate a link between the development of hypersensitivity and M. pneumoniae infection.
Despite recent advances in diagnostic technology and the development of animal models representative of human disease, well-designed and controlled human clinical studies and experimentation with animal models are needed to elucidate the role of M. pneumoniae infection in the predisposition for or protection from asthma. Future large, general population-based prospective studies will be necessary to investigate the development of asthma induced by M. pneumoniae infection in humans.
Allergic disorders pose a growing challenge to medicine and our society. Therefore, novel approaches to prevention and therapy are needed. Recent progress in studies on bacterial viruses (phages) has provided new data indicating that they have significant immunomodulating activities. We show how those activities could be translated into beneficial effects in allergic disorders and present initial clinical data that support this hope. Phage therapy is a potential weapon to combat microbial resistance.
Allergic disorders pose a growing challenge to medicine and our society, so new approaches to prevention and therapy are urgently needed. Our article summarizes progress that has been recently made and presents a shift in our understanding of the immunobiological significance of bacterial viruses (phages). Currently, phages may be considered not only as mere “bacteria eaters” but also as regulators of immunity. The new understanding of phages as important factors in maintenance of immune homeostasis opens completely new perspectives for their use in controlling aberrant immune responses. It is likely that this new knowledge could be translated into novel means of immunotherapy of allergic disorders.
Introduction
The allergy epidemic has become a great challenge to medicine and society. While currently available therapies provide some relief and benefit, all those treatments have significant drawbacks, and therefore novel approaches are urgently needed.1 Bacterial viruses (phages) have recently gained greatly increased attention in view of their ability to kill bacteria, including antibiotic-resistant strains.
Consequently, phage therapy (PT) has remained of interest as a potential weapon to combat the microbial resistance believed today to be a grave challenge to medicine and civilization. While available data indicate high safety and strongly suggest efficacy of PT, it is expected that ongoing clinical trials will provide awaited proof of efficacy in accordance with the requirements of evidence-based medicine.
The WAF Editorial board would like to acknowledge and thank Andrzej Górski, Ewa Joczyk-Matysiak, Marzanna usiak-Szelachowska, Ryszard Midzybrodzki, Beata Weber-Dbrowska, and Jan Borysowski at the Society for Experimental Biology and Medicine for their contributions to education and research.
Growing Interest in Phage Therapy
The growing interest in PT is paralleled by better understanding of the actual significance and role of phages, especially as potential regulators of immunity. Initially considered as mere “bacteria killers,” today phages are recognized as an important part of the mammalian immune system.
Phages present in mammalian organisms (endogenous phages, e.g. in the intestines) may exert immunomodulating action similar to probiotics and, by their ability to translocate from the gut to other tissues, they can mediate such activities, locally contributing to maintenance of immune homeostasis.
Interestingly, phages have been shown to cause strong anti-inflammatory effects reducing levels of C-reactive protein and other indices of inflammation in patients receiving PT even though the infection has not been eliminated, thus suggesting that some phage effects are at least partly independent from their direct antibacterial action.
Possible Phage Mechanisms
The possible mechanisms of immunomodulating and anti-inflammatory activities of phages have recently been discussed in detail. Those observations have been confirmed and extended by other authors. Of particular interest are the recent data of van Belleghem et al., who studied the effect of purified phages on immune responses of human peripheral blood mononuclear cells and showed that their prevailing effect is anti-inflammatory.
Thus, phages were shown to induce the anti-inflammatory IL-1 receptor antagonist (IL-1RA) and strong upregulation of IL-10. This cytokine has been recognized as having anti-inflammatory properties blocking the expression of pro-inflammatory cytokines and inhibiting the activities of Th1 cells, NK cells and macrophages.
Similar data were obtained by Sun and Feng, who showed that phage films downregulate the inflammatory response and induce high IL-10 expression. Van Belleghem’s group also showed a marked reduction of TLR4 expression on human mononuclears; TLR4 is known to induce pro-inflammatory cytokines and chemokines.10 Also of interest are data indicating that phages do not induce degranulation of human granulocytes and markedly decrease inflammation caused by the autoimmune reaction.
Phage Therapy Summit
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Evidence has accumulated that IL-10, a cytokine which is upregulated by phages, is a strong inhibitor of allergen-induced inflammation and airways hyper-responsiveness.
Administration of IL-10 reduces the number of eosinophils and mast cells alleviating nasal inflammation, thus showing potential as an inhibitor of allergic rhinitis. Moreover, IL-10 was shown to stabilize mast cells, protecting against degranulation. CD5?+?B cells suppress IgE- and antigen-mediated activation of mast cells in vitro and allergic responses in mice in an IL-10-dependent manner.16
Also, IL-10 production by T cells coincided with inhibition of eosinophilic airways inflammation and epithelial mucus plugging.17 What is more, specific immunotherapy causes increased IL-10 production and resulting anergy of T cells and switching of specific IgE towards normal IgG4-related immunity. Similar allergy-attenuating effects have been described for IL-1RA.
Thus, an adenovirus expressing IL-1RA was observed to attenuate allergic airways inflammation in a mouse model of asthma.The ability of IL-1RA to reduce allergen-induced airway inflammation and mucus secretion in mice has also been reported by Gurusamy et al. IL-1RA has also been shown to prevent experimentally induced allergic eye disease in mice by downregulation of the recruitment of eosinophils and other inflammatory cells.
Phage Therapy and Allergies
There is ample evidence that allergic disorders such as asthma, rhinitis and atopic dermatitis may be mediated by oxidative stress.22 Endogenous and exogenous reactive oxygen species (ROS) have been shown to be responsible for the airway inflammation in allergic asthma. In animal models, excessive ROS production may cause airway inflammation and hyper-responsiveness, tissue injury, and remodeling.23 In this regard, it is noteworthy that phages – in contrast to pathogenic viruses and bacteria – do not induce ROS24 and inhibit ROS production by phagocytes.25,26
TLR4 antagonist has been shown to reduce asthma features provoked by an allergen.27 Therefore, phage ability to downregulate its expression might cause similar effects. Recent data suggest that the microbiomes of the lung and gut contribute to the pathogenesis of asthma and allergy.28 Allergic children harbor higher counts of coliforms and Staphylococcus aureus.29 It is also well known that local allergic reactions can be induced and aggravated by microorganisms.30
As phages usually have very narrow spectra, in contrast to antibiotics (whose use is believed to be associated with the rising prevalence of allergies), phage application could thus selectively eliminate those bacterial pathogens and perhaps alleviate or even prevent symptoms of allergy. Table 1 briefly summarizes what is known about phage activities in vitro and in vivo and how those findings can be translated into beneficial effects in allergic disorders. Table 1.
Phages in Vitro
Phage activities in vitro and in vivo which may be beneficial in allergic disorders.
In vitro In vivo Reactive oxygen species ?(26) Circulating eosinophils – IL-10 ? (10,11) C-reactive protein? IL-1 receptor antagonist ? Erythrocyte sedimentation rate ? TLR4?(10) Leukocytosis?
Degranulation of granulocytes – Autoimmune reaction ? Inflammatory infiltration of skin and lung? Local reactions to phage administered subcutaneously –
Note: Relevant references are given in parentheses.
References
? downregulation, ? upregulation, – no effect. Interestingly, in >150 patients who received PT significant side-effects including some signs of allergic reactions occurred in only 1.4% of cases. What is more, eosinophil counts remained within a normal range in all of them.31 A search of the non-English literature from Eastern Europe has revealed publications reporting lack of local reactions to phage preparations in patients.34 Intravenous phage phi X174 has been used to study immunocompetence in patients with the hyper-IgE syndrome and in children with steroid-dependent asthma.
The above data suggest that phage administration in humans rarely induces allergic reactions. Moreover, there are some data claiming efficacy of PT in allergic patients. Sakandelidze et al., reported success in “infectious allergoses.” Similarly, good results were reported in patients with allergy to antibiotics. American physicians as long ago as in the 1950s and 1960s suggested that PT may be helpful in controlling allergy and asthma. Recently, successful PT of a boy with Netherton syndrome with atopic diathesis was reported. By the seventh day of the therapy, a significant improvement including a marked reduction of skin involvement was noted. No allergic reactions to the phage were observed.
Conclusions
Phages exert anti-inflammatory action in vitro and in vivo and can downregulate aberrant immune reactions. Initial observations in patients receiving PT suggest that allergic reactions to phage administration are rare; furthermore, PT may be useful in specific cases of allergic disorders. Further studies and clinical trials of phage efficacy in those disorders are warranted.
bacteriophage phage therapy, Image by neo tam from Pixabay
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.
