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The Lung Microbiome: Key to Respiratory Ills?

The Lung Microbiome: Key to Respiratory Ills? The word microbiome has become a catch term only in the past decade, but it refers to something as old as humanity itself: the diverse and unimaginably vast population of microorganisms that share our bodies. These microbiota compose an ecosystem whose constituent cells and genes actually outnumber our own, and without which we would be unable to carry out many functions necessary for life. Medicine has succeeded in mapping much of the gut microbiome, but only recently has advanced technology enabled researchers to identify and study the inhabitants of the human respiratory system and possibly use this information to diagnose and treat respiratory disease. Jack Gilbert, PhD Nancy Wong/University of Chicago Recently, JAMA discussed this research and its potential clinical applications with 2 experts on the front lines, Jack Gilbert, PhD, a microbial ecologist at the University of Chicago and director of its new Microbiome Center—one of many popping up around the country—and Steve White, MD, professor of medicine at the University of Chicago who studies asthma and chronic obstructive pulmonary disease (COPD). The following is an edited version of that conversation. Steve White, MD David Christopher/University of Chicago JAMA:For some time the focus has been on the gut microbiome. When did the realization hit that the lung microbiome is a factor in respiratory pathology? DR WHITE:It was thought some years back that the lung was a sterile organ and that normally there were hardly any bacteria in it, and that only when you have perturbations of the lung as in cystic fibrosis, emphysema, bronchiectasis, or pneumonia would the lungs become infected. More recently it's been recognized that the normal lung has its own microbiome. It's much smaller than the gut microbiome, but it's a unique microbiome that may influence health and disease. JAMA:What might disrupt the airway microbiome leading to illness? You hear the word dysbiosis a lot in reference to such disruption. DR GILBERT:Dysbiosis is a disassociation of the equilibrium in a microbiome. We're really talking about the collapse of an ecosystem. The factors involved might range from antibiotics, which would obviously cause a significant disruption, to immune disorders, since the immune system is the interface between the bacterial populations—the microbiome—and the human body. When the immune system is disrupted it can cause chaos in the microbiome. Diet can affect the microbiome. Differential exposures early in life that could determine what kind of microbes colonize you can affect it, as well as medications and treatments that can have an impact upon the structure and the function of that microbial community. JAMA:What kind of microbes are we talking about? DR WHITE:We have some normal bacteria sitting there, like Veillonella, Prevotella, Neisseria, and Acinetobacter. Some types of Streptococcus are completely normal and sit in our airways all the time. Then there are organisms we think of as being pathogens just by virtue of being there. Like we’ve found that the bacterium Pseuduomonas, which is clearly a pathogen in many contexts, is more prevalent in people who have severe asthma, but we see it hardly at all in normal lungs. DR GILBERT:We also have substantial interactions with fungal organisms. When we talk about the microbiome, we're talking about many different things, not just bacteria. JAMA:Viruses? DR GILBERT:Absolutely. In many airway diseases we’re seeing evidence that bacteriophages—viruses that live inside bacteria—use [these bacteria] to replicate themselves. [They may] hide out inside the genome of a bacterium for many years until they can burst free. Some of these are exacerbated by antibiotic therapy. So if you give someone an antibiotic it will stress the bacteria just enough to cause these viruses to explode out. And then suddenly you have a huge viral burden in the lung. JAMA:What respiratory diseases might be most amenable in the near future to treatment resulting from this new understanding? You mentioned asthma. DR WHITE:We've long thought that asthma is a disease of inflammation, but never understood what initiated it. More and more, we're understanding that certain bacteria, fungi, and viruses have a role. And these [pathogens] can sustain the inflammation in adults. Over time, that's going to cause the airways to become fibrotic and now you not only have the reversible obstruction of airways that you see in early asthma, but this fixed obstruction that occurs later.Right now we're a little stuck at what we can do to help people with asthma. We have inhaled corticosteroids. We have beta-agonist drugs to dilate the airways. We have some very new anticytokine drugs that may help us with inflammation. But after that, we don't know where to go. You can extend this same [situation] to other lung diseases. We know, for example, that in COPD, emphysema, and chronic bronchitis, bacteria have a substantial role in perpetuating the inflammation there that leads to frequent exacerbations that land people in the hospital. So if we understood how the bacteria turned on the parts of host defense that we really don't want turned on, maybe we don't have to go after bacteria A directly, maybe we could change bacteria B or bacteria C, and they would change bacteria A for us, to tell it to be quiet. DR GILBERT:We have 2 ways of using the microbiome most effectively. The first and the easiest is to stratify patients, so we can better predict how they'll respond to a particular therapy. To do that, we build databases [that] link the profile of their microbiome, the profile of their immune system, and their medical history. And we use deep machine learning to map and identify those interactions and determine if they are predictive of health care outcomes. The second is intervention. Utilizing the microbiome, identifying which microbiota are exacerbatory toward disease, which ones could help to suppress disease, and then exploring ways to manipulate them. JAMA:Are both strategies under way? DR GILBERT:The strategy at the moment is to try and identify the playing field—the types of bacteria, the types of fungi, the types of virus interactions [that] can lead to progression of disease and then to identify how they vary across populations. With some of our recent work we've looked at the Hutterites vs the Amish. We can see particular microbiological associations with the Amish and their immune response that appear to be protective against asthma vs the Hutterites who are lacking those microbial signals, leading to the exacerbation of asthma in their population. JAMA:You’re talking about the study published last summer that examined why Amish children have a dramatically lower rate of asthma and allergies than Hutterite kids, even though they belong to communities that are almost exactly alike culturally and genetically? DR WHITE:Yes. In the Amish communities the young children are [fully] exposed to farm life at an early age. To animals and all the dust that goes with that. The Hutterites, for whatever reasons, do not want their young children exposed to the barns and farm life. And so not only are the barns located some distance away from their homes, but the young children weren't going out into the barns to work [as do Amish youngsters]. JAMA:So, exposure to farm pathogens at a very early age seems to train the Amish youngsters’ immune systems, so they don’t develop allergies later on? DR GILBERT:Right. The basic principle is again, that the disruption of microbiota during a critical window in the development of the immune system, say due to antibiotic therapy, leads to a long-term chronic problem. Many specific disease states are being linked to that early window, everything from obesity and metabolic ills to neurological disorders such as autism and these more chronic inflammatory conditions [such as asthma] related to immune function.We see that there are stages in a child's development soon after birth when [microbial] exposure is interrupted [and] can cause a problem. A lot of that work is in the gut microbiome. When we alter that, we affect [immunity] throughout the body. The gut microbiome isn't just affecting the gut. It has very distal effects altering immune responses in other organs, such as the heart, liver, and kidneys. It’s highly likely that the same is true for the lung. DR WHITE:This communication between different microbiomes may well be a 2-way street. We've got some data in animals and a bit in humans suggesting the gut microbiome may influence inflammation in the airways in asthma and cystic fibrosis. An interesting question is whether the airway microbiome then sends signals back to the gut that will be changing the gut over time. JAMA:Do you foresee a time when we will all undergo microbiotic profiling? DR GILBERT:Absolutely. It's one of the key components of stratifying our patient population. We may end up screening every single patient [who] comes into our hospital, maybe even every baby as [it’s] born and in specific stages in its development, 6 months, 18 months, 3 years, 5 years, to build up a strong picture of how they are progressing. You could think about this as microbial GPS [global positioning system]. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA American Medical Association

The Lung Microbiome: Key to Respiratory Ills?

JAMA , Volume 317 (17) – May 2, 2017

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Publisher
American Medical Association
Copyright
Copyright © 2017 American Medical Association. All Rights Reserved.
ISSN
0098-7484
eISSN
1538-3598
DOI
10.1001/jama.2017.3023
pmid
28403451
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Abstract

The word microbiome has become a catch term only in the past decade, but it refers to something as old as humanity itself: the diverse and unimaginably vast population of microorganisms that share our bodies. These microbiota compose an ecosystem whose constituent cells and genes actually outnumber our own, and without which we would be unable to carry out many functions necessary for life. Medicine has succeeded in mapping much of the gut microbiome, but only recently has advanced technology enabled researchers to identify and study the inhabitants of the human respiratory system and possibly use this information to diagnose and treat respiratory disease. Jack Gilbert, PhD Nancy Wong/University of Chicago Recently, JAMA discussed this research and its potential clinical applications with 2 experts on the front lines, Jack Gilbert, PhD, a microbial ecologist at the University of Chicago and director of its new Microbiome Center—one of many popping up around the country—and Steve White, MD, professor of medicine at the University of Chicago who studies asthma and chronic obstructive pulmonary disease (COPD). The following is an edited version of that conversation. Steve White, MD David Christopher/University of Chicago JAMA:For some time the focus has been on the gut microbiome. When did the realization hit that the lung microbiome is a factor in respiratory pathology? DR WHITE:It was thought some years back that the lung was a sterile organ and that normally there were hardly any bacteria in it, and that only when you have perturbations of the lung as in cystic fibrosis, emphysema, bronchiectasis, or pneumonia would the lungs become infected. More recently it's been recognized that the normal lung has its own microbiome. It's much smaller than the gut microbiome, but it's a unique microbiome that may influence health and disease. JAMA:What might disrupt the airway microbiome leading to illness? You hear the word dysbiosis a lot in reference to such disruption. DR GILBERT:Dysbiosis is a disassociation of the equilibrium in a microbiome. We're really talking about the collapse of an ecosystem. The factors involved might range from antibiotics, which would obviously cause a significant disruption, to immune disorders, since the immune system is the interface between the bacterial populations—the microbiome—and the human body. When the immune system is disrupted it can cause chaos in the microbiome. Diet can affect the microbiome. Differential exposures early in life that could determine what kind of microbes colonize you can affect it, as well as medications and treatments that can have an impact upon the structure and the function of that microbial community. JAMA:What kind of microbes are we talking about? DR WHITE:We have some normal bacteria sitting there, like Veillonella, Prevotella, Neisseria, and Acinetobacter. Some types of Streptococcus are completely normal and sit in our airways all the time. Then there are organisms we think of as being pathogens just by virtue of being there. Like we’ve found that the bacterium Pseuduomonas, which is clearly a pathogen in many contexts, is more prevalent in people who have severe asthma, but we see it hardly at all in normal lungs. DR GILBERT:We also have substantial interactions with fungal organisms. When we talk about the microbiome, we're talking about many different things, not just bacteria. JAMA:Viruses? DR GILBERT:Absolutely. In many airway diseases we’re seeing evidence that bacteriophages—viruses that live inside bacteria—use [these bacteria] to replicate themselves. [They may] hide out inside the genome of a bacterium for many years until they can burst free. Some of these are exacerbated by antibiotic therapy. So if you give someone an antibiotic it will stress the bacteria just enough to cause these viruses to explode out. And then suddenly you have a huge viral burden in the lung. JAMA:What respiratory diseases might be most amenable in the near future to treatment resulting from this new understanding? You mentioned asthma. DR WHITE:We've long thought that asthma is a disease of inflammation, but never understood what initiated it. More and more, we're understanding that certain bacteria, fungi, and viruses have a role. And these [pathogens] can sustain the inflammation in adults. Over time, that's going to cause the airways to become fibrotic and now you not only have the reversible obstruction of airways that you see in early asthma, but this fixed obstruction that occurs later.Right now we're a little stuck at what we can do to help people with asthma. We have inhaled corticosteroids. We have beta-agonist drugs to dilate the airways. We have some very new anticytokine drugs that may help us with inflammation. But after that, we don't know where to go. You can extend this same [situation] to other lung diseases. We know, for example, that in COPD, emphysema, and chronic bronchitis, bacteria have a substantial role in perpetuating the inflammation there that leads to frequent exacerbations that land people in the hospital. So if we understood how the bacteria turned on the parts of host defense that we really don't want turned on, maybe we don't have to go after bacteria A directly, maybe we could change bacteria B or bacteria C, and they would change bacteria A for us, to tell it to be quiet. DR GILBERT:We have 2 ways of using the microbiome most effectively. The first and the easiest is to stratify patients, so we can better predict how they'll respond to a particular therapy. To do that, we build databases [that] link the profile of their microbiome, the profile of their immune system, and their medical history. And we use deep machine learning to map and identify those interactions and determine if they are predictive of health care outcomes. The second is intervention. Utilizing the microbiome, identifying which microbiota are exacerbatory toward disease, which ones could help to suppress disease, and then exploring ways to manipulate them. JAMA:Are both strategies under way? DR GILBERT:The strategy at the moment is to try and identify the playing field—the types of bacteria, the types of fungi, the types of virus interactions [that] can lead to progression of disease and then to identify how they vary across populations. With some of our recent work we've looked at the Hutterites vs the Amish. We can see particular microbiological associations with the Amish and their immune response that appear to be protective against asthma vs the Hutterites who are lacking those microbial signals, leading to the exacerbation of asthma in their population. JAMA:You’re talking about the study published last summer that examined why Amish children have a dramatically lower rate of asthma and allergies than Hutterite kids, even though they belong to communities that are almost exactly alike culturally and genetically? DR WHITE:Yes. In the Amish communities the young children are [fully] exposed to farm life at an early age. To animals and all the dust that goes with that. The Hutterites, for whatever reasons, do not want their young children exposed to the barns and farm life. And so not only are the barns located some distance away from their homes, but the young children weren't going out into the barns to work [as do Amish youngsters]. JAMA:So, exposure to farm pathogens at a very early age seems to train the Amish youngsters’ immune systems, so they don’t develop allergies later on? DR GILBERT:Right. The basic principle is again, that the disruption of microbiota during a critical window in the development of the immune system, say due to antibiotic therapy, leads to a long-term chronic problem. Many specific disease states are being linked to that early window, everything from obesity and metabolic ills to neurological disorders such as autism and these more chronic inflammatory conditions [such as asthma] related to immune function.We see that there are stages in a child's development soon after birth when [microbial] exposure is interrupted [and] can cause a problem. A lot of that work is in the gut microbiome. When we alter that, we affect [immunity] throughout the body. The gut microbiome isn't just affecting the gut. It has very distal effects altering immune responses in other organs, such as the heart, liver, and kidneys. It’s highly likely that the same is true for the lung. DR WHITE:This communication between different microbiomes may well be a 2-way street. We've got some data in animals and a bit in humans suggesting the gut microbiome may influence inflammation in the airways in asthma and cystic fibrosis. An interesting question is whether the airway microbiome then sends signals back to the gut that will be changing the gut over time. JAMA:Do you foresee a time when we will all undergo microbiotic profiling? DR GILBERT:Absolutely. It's one of the key components of stratifying our patient population. We may end up screening every single patient [who] comes into our hospital, maybe even every baby as [it’s] born and in specific stages in its development, 6 months, 18 months, 3 years, 5 years, to build up a strong picture of how they are progressing. You could think about this as microbial GPS [global positioning system].

Journal

JAMAAmerican Medical Association

Published: May 2, 2017

Keywords: respiration disorders,asthma

There are no references for this article.