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The Effects of Chemicals on Asthma – with Rodney Dietert, Phd

Defeating Asthma Series uncovers New Hope for Asthma Management

In this third 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 about:

* Chemicals and disease such as Asthma

Video: The Effects of Chemicals on Asthma – with Rodney Dietert, Phd

World Asthma Foundation: Can you explain the relationship between chemicals and disease?

Dr. Dietert: We’re under attack really from a variety of chemicals. Research reflects disruption of the microbiome, and we know a lot more today.

World Asthma Foundation: It’s obvious that that phthalates, petrochemicals, cosmetics, pesticides, fungicides that can disrupt the gut, correct?

Dr. Dietert: Absolutely. Look at glyphosate. Glyphosate is an antimicrobial. It has antibacterial properties inherent in it, and we’ve distributed widely across the earth. It’s exposing us through the food systems in soil, plants, our food, animals, and us and yet, it’s essentially an antimicrobial. Knowing what we know now, you wouldn’t do that, would never do that. I think that that’s an example of the kind of changes. Ironically, I once was asked to give an educational lecture at a national conference on bisphenol A and the immune system as the target for bisphenol A, particularly in early development.

I presented evidence and suggested that it was an immunotoxic compound. We now know it operates both directly on the immune system but through the microbiome as well. It was ironic because when I finished, I had a very irate pediatrician who told me I really shouldn’t be saying things that I was saying because someone from The New York Times could be there and they might even write about it. My reaction was, “Oh, wow, would that be wonderful? I hope they are.” He was very irate. He thought I was being very irresponsible. You don’t have to go back very many years to where people were really challenging the risk that was present in certain foods and certain chemicals. There’s a lot of things embedded in processed foods that are absolutely disastrous for the microbiome and that’s a huge problem, obviously to weed those out.

World Asthma Foundation: And a very big list. We don’t know all of them right?

Dr. Dietert: We know some of the important ones that are very prevalent, and we know exactly what they target and exactly what diseases are the likely outcomes of that targeting. That should be sufficient for us to make some changes.

World Asthma Foundation: With that, 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.

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Chemical Compound BPA Affects Lung Development says UC Davis Study

BPA Affects Lung Development
Collaborative efforts add critical information to understanding effects of BPA

BPA (bisphenol A), is used in the manufacturing of various plastics and food packaging, consumer products, some paper receipts, and medical devices. It is controversial because it exerts weak, but detectable, hormone-like properties which can mimic estrogen and may lead to far-ranging negative health effects including increased cardiovascular disease and diabetes in adults, increased cancer rates, including breast cancer, neurological difficulties, and hormonal and reproductive issues in both sexes and at all stages of life.

Recent results from research at the California National Primate Research Center (CNPRC) have shown that fetal BPA exposure during a critical window of susceptibility in the third trimester, at levels similar to those measured in human blood, caused an increase in mucin genes and mucous cell maturation in the lungs (Environmental Health Perspectives, National Institutes of Health).

This is of environmental health importance because increases in airway mucins are hallmarks of a number of childhood lung diseases that may be impacted by BPA exposure. Overly abundant secretion and storage of mucous can cause airway obstruction as found in a number of lung diseases including asthma and bronchitis.

CNPRC scientists Drs. Laura S. Van Winkle, Respiratory Diseases Unit, and Catherine A. VandeVoort, Reproductive Sciences and Regenerative Medicine Unit, along with co-authors Drs. Shannon R. Murphy and Miriam V. Boetticher (UC Davis Center for Health and the Environment), conducted this collaborative study to investigate the effects of BPA on fetal development.

Their data indicate that exposure to environmentally relevant levels of BPA during fetal lung development can alter expression of secretory genes (Muc5B, Clara cell secretory protein (CCSP)) and proteins (Muc5B mucins and CCSP) in the conducting airways. They also found that this increase is most pronounced in the bronchi (proximal conducting airways).

In companion studies conducted at the CNPRC, it has been shown that exposure of pregnant monkeys to BPA disrupts development of fetal ovaries, potentially causing birth defects and reproductive problems that would not emerge for a generation (Link); and that BPA also affects several developmental parameters of the mammary gland of rhesus monkeys, including some that are relevant to breast cancer risk in humans (Link).

The study of BPA in a primate model is critical because the rhesus monkey has estrogen levels as well as reproductive and developmental processes that are similar to humans.

The WAF would like to thank Dr. Van Winkle is a faculty member of the Department of Anatomy, Physiology and Cell Biology at the UC Davis School of Veterinary Medicine, and the UC Davis Center for Health and the Environment, as well as an Affiliate Scientist at the CNPRC for their support of education and research.

Dr. VandeVoort is a faculty member of the Department of Obstetrics and Gynecology, UC Davis School of Medicine, in addition to being a Core Scientist at the CNPRC.

This research was funded by the National Institutes of Health.

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Asthma and the Microbiome – What’s New with Rodney Dietert, Phd

Defeating Asthma Series uncovers New Hope for Asthma Management

In this second 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 about:

* Advances in technology that have supported making the connections between the Microbiome and disease like Asthma

* Some useful things for both preventative medicine and to avoid disease

World Asthma Foundation: What’s new in the world of the microbiome?

Asthma and the Microbiome – What’s New with Rodney Dietert, Phd

Dr. Dietert: I think it’s making the connections. There were a lot of data collected early on and there were different technologies that have enabled us to characterize bacteria viruses, fungi, archaea in different ways and to different details. Now has been the process of figuring out ecosystems of these. Once you have technologies that you feel comfortable with, that you think have utility, then it’s a matter of understanding how these interact because bacteria don’t exist in our gut or in our airways or on the skin in isolation. There are communities and they are interacting not just with the mammalian cells of our body but with each other.

The ways in which they interact with each other to produce little ecological systems filled with different chemicals, different vitamin production, different ways to handle toxic metals are important. Understanding how you approach those communities and how you can do some useful things for both preventative medicine which is ideal, avoid the disease when you can and then more effective therapeutic integrative holistic approaches.

World Asthma Foundation: With that, 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.

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Asthma and the Microbiome – Martin J Blaser MD Interview

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.

Catch the video interview by clicking here .

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Asthma and the Missing Microbes – Martin J Blaser MD Interview

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.

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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.

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Asthma and the Microbiome – Rodney Dietert PhD Interview

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.

World Asthma Foundation: Thank you so much.

 

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Asthma and the Microbiome – Justin L. Sonnenburg PhD Interview

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.

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New Hope for Asthma Management – The Microbiome Podcast Series 

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

Featured guests include:

“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

 

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The Role of Mycoplasma pneumoniae Infection in Asthma

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.

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Phage therapy in allergic disorders?

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.

See the WAF followup interview with Dr. Paul L. Bollyky, Bacteriophages, Asthma, Airway Inflammation and Infection.

Impact statement

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.

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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
bacteriophage phage therapy, Image by neo tam from Pixabay