SEGMENT 2: Dr. Monica Kraft and Dr. Gary H. Gibbons discuss the microbiome, gut bacteria, and lung diseases.

Dr. Gary H. Gibbons, director, NHLBI:  One of the emerging areas that I am intrigued by is this notion of increasing evidence of host microbe interactions in the microbiome and its potential role in chronic disorders such as obesity, diabetes, indeed, cardiovascular disease. And based on what you have been describing, asthma looks like it could be another potential… may potentially have some of its etiology in the microbiome. 

Could you tell us, though, what’s the state of play in our understanding of the microbiome in asthma?

Dr. Monica Kraft, Duke University:  Absolutely. Very exciting field.  And, as a matter of fact, we had a wonderful Aspen Lung Conference last June on that very topic on microbiome in the lung and Jim Kiley [director of NHLBI’s Division of Lung Diseases] was our summarizer. 

He did a fantastic job and really, I think, well, one, it’s a very young field for the lung. But there’s some incredibly exciting data on early microbial exposures, actually through the gut, and how gut immune development – especially looking at T-cell subsets via Th17 or T regulatory cells – how that really has a profound effect on immune tolerance in the lung and susceptibility to asthma. And to be honest, I actually think that may be where the money is with regards to asthma development, at least in – I can’t say it would be for every patient with asthma but at least a proportion. It’s incredibly exciting data. 

So we heard a lot about that, and also there’s certainly data in older children who live on farms who are exposed to lipopolysaccharide, unpasteurized milk, etc., who have much less asthma. So there’s clinical data to certainly go along with some of the animal work on T cell development.

And then in adults, as part of AsthmaNet, which NHLBI funds – very excited and honored to be part of that network – we are looking at it in adult asthmatics right now, looking at what is the microbiome of the lung in asthma versus non-asthma. And very descriptive but it’s a young field and we need to establish that before we can really move onto the second step of trying to modulate that microbiome. So we’re now looking at it and looking at what therapy does to the microbiome. Because once we have a handle on that, then we can look at a number of factors that could modulate the microbiome and potentially alter chronic inflammation through that avenue. And the AsthmaNet – or actually the previous iteration of AsthmaNet, Asthma Clinical Research Network – published a paper suggesting that the greater diversity of microorganisms in the lung, the less hyperresponsiveness patients would have. So that’s kind of an interesting sort of a relationship between those two, certainly suggesting in chronic disease there is thought to be less diversity of microorganisms and that’s a problem. And so in this case, we show this inverse correlation of hyperresponsiveness and diversity.

So again, early observations but I think they can be, ultimately down the road, I think it’s an incredibly important relationship not only for exacerbations but really for the extensive chronic inflammation and being able to treat it effectively. I think the microbiome is going to be a major player in that arena.

Dr. Gibbons:  Well, that’s fascinating and it’s intriguing that your studies, it sounds like you are going to pursue. It would be interesting to understand the diversity of the microbiome in the lung. But I am also intrigued by your allusion to the fact that actually a lot of the interface with the immune system may actually happen in the gut.

Dr. Kraft:  Right.

Dr. Gibbons:  And so what is the relationship – a naïve question – but what is the relationship between diet and asthma? And do you see another opportunity for some other therapeutic strategies or a way in which, again, diet may affect the immune system and then thereby affect asthma?

Dr. Kraft:  Absolutely. I think as a young child, it’s actually quite significant when you think about breastfeeding. I mean, there are already data that suggest that at least six months of breastfeeding reduces the risk of asthma. Then you also look at exposures to microorganisms that at early life through vaginal delivery versus C-section. So in the setting of C-section, there is increased risk of asthma, for instance; vaginal delivery, less. 

So those early life exposures that really do – those are all determinants, actually, of the gut microbiome, these types of exposures. 

Antibiotics, of course, less diversity. If you are an older sibling, you’re going to have less diversity than your younger sibling. If you go to daycare, you will have more diversity because you are going to have exposure to all those other kids – more infections, less asthma. 

So these are all determinants, actually, of the gut microbiome in early life that then set up the immune system in the lungs. Now, what we don’t often know is exactly how that connection between, once you have established the gut microbiome, what are the mechanisms in the signaling pathways that lead to immune tolerance in the lung? That’s still a little bit of a black box. But certainly, because we see one and then we see the other and now, we’re sort of working out what’s in between.

But it’s incredibly, it’s amazing. I get very excited when I think about it because I think we may be onto something really important and profound about origins of disease now.

Dr. Gibbons:  Yes, yes, very exciting, very provocative.