THE MICROBIOME SUMMIT : The New Path to Health

The Microbiome’s Potential for Diagnosis & Treatment

Dr. Curtis Huttenhower, PhD

dr-curtis-huttenhower-phd

Dr. Curtis Huttenhower, PhD

Harvard T.H. Chan School of Public Health

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Overview

Dr. Curtis Huttenhower and his lab at the T.H. Chan School of Public Health at Harvard University are looking at microbes and disease – through data. This work is helping researchers identify and better understand the microbes that are present or absent in various disease states, particularly with autoimmune conditions, such as type 1 diabetes and inflammatory bowel disease. In this interview, Dr. Huttenhower discusses the microbiome and its relationship to the future of personalized medicine – in the future, it may be possible for doctors to make a diagnosis or tailor therapy to a patient based on their microbiome.

Transcript

  • TRACEY:
  • Hi, Curtis. Thank you for joining me here today.
  • CURTIS:
  • Hi there. Likewise. Thank you.
  • TRACEY:
  • Your lab is doing some interesting work. Can you explain to us how the human microbiome is now being studied as a means of diagnosing chronic disease, but also as a means of therapeutic intervention?
  • CURTIS:
  • Sure. So, we’ve been working on the human microbiome in public health for a while now. It’s interesting and one of the reasons I’m particularly interested in it, for exactly those two reasons, that in the past 10 or 20 years now I’ve seen a lot of progress in personalized medicine using different types of molecular or cellular or very detailed mechanistic read outs to understand the course of each individual’s personalized health. The microbiome provides a new opportunity to do this by providing a type of read out that we didn’t have before. This speaks particularly to diagnosis or prognosis, figuring out what’s going on in a particular individual. But relative to, say, genetics, which have also seen progress in exactly the same area, the microbiome is plastic, it’s modifiable. And, while 99 percent of the time we don’t necessarily know the right modifications to make yet to improve health, or how to make those modifications, it provides opportunities for changing health outcomes that are very difficult, say, with human genetics.
  • TRACEY:
  • What kinds of chronic diseases might we see through the diagnosis through the microbiome?
  • CURTIS:
  • Some of the most active work in the microbiome right now, both for us and for others, is in chronic autoimmune-link disease. Conditions like inflammatory bowel disease, type 1 diabetes, even metabolic syndrome, type 2 diabetes, or systemic conditions outside of the gut like rheumatoid arthritis – all of these are conditions in which normal immune environments or immune microbes interactions are disrupted somehow in different ways for different conditions in which there’s a complex genetic background as well. So, not necessarily a single human genetic locus or a single causal microbe or single pathogen to which the disease can be pinned. Complex, chronic, long-term conditions with no single microbial or genetic cause.
  • TRACEY:
  • I see. So, it’s more that we’re looking at the ecosystem itself and how it is interacting with the host, being the human being?
  • CURTIS:
  • Exactly. And that tends to be true in these conditions for the ecosystem of microbes, the ecosystem, so to speak, of their interaction with their immune system and then, again, the ecosystem of a complex interacting system at the cellular or molecular level, the specific mechanisms by which our microbes or bugs and our immune systems interact.
  • TRACEY:
  • Right. So, what do you think it will look like in the future for somebody to get a diagnosis through their microbiome?
  • CURTIS:
  • I like to draw a parallel to the past, say, decades worth of advancement in cancer molecular therapies. For some cancers now, we’re able to target very specifically the genetic and molecular activity disruptions that are present in a particular individual’s tumour and very specifically understand the prognosis of the disease based on that read-out and, in some cases, target treatments to fix exactly what’s broken in that specific environment. I’d like to get to the same sort of place for the microbiome, to be able to understand the disruptions in a particular individual’s microbial ecosystem in these complex, long-term conditions and make exactly the right changes in that ecosystem to fix that condition as well.
  • TRACEY:
  • Just to go back a bit, the diseases that we think we’re going to be able to use the microbiome as a means of diagnosis are, you know, the gut, inflammatory bowel diseases, autoimmune diseases, anything else I’ve missed?
  • CURTIS:
  • Those are the areas, I’d say, that are under closest study right now because they have the most immediate connection to the gut microbiome in particular. There are other conditions, either in the gut like colo-rectal cancer, or systemically where there are either immune interactions or distal microbial interactions or chemical interactions that can link the microbiome either elsewhere in the body or in the gut to, again, health systemically..
  • TRACEY:
  • Interesting. So, right now we don’t have any tools – like a patient cannot go into their clinician’s office and say, you know, here’s my poop sample, you know, and can you diagnose me?
  • CURTIS:
  • They can, but we can’t do much about it yet. So, there’s been a lot of interest in a few conditions in the past few years where there are good microbial therapeutic treatments such as Clostridium difficile infection where there’s, surprisingly, not a great understanding of the therapeutic mechanism yet. But there are good therapeutic options. But that’s one of very, very few examples where there are safe, well-understood therapies extant already.
  • TRACEY:
  • That makes sense. Let’s move on and talk about some of the therapeutic interventions that are available right now. Can you describe …. I think of there being, you know, about four different modalities that we could use. Do you want to speak to, maybe, start with probiotics?
  • CURTIS:
  • Sure. So, the microbiome is, again, interesting as a therapeutic target because it is in principle modifiable and there’s a lot of ongoing work to figure out what the right modifications to take are, and how to make them. But there are many possible mechanisms by which a microbial community and the gut or elsewhere can, in principle, be modified. Probiotics or live-cell therapies are a great option because there is such an awareness already of probiotics already in the sense of fermented foods. These tend to be microbes that have been bred, so to speak, over thousands of years to process foods that often have well-supported health benefits in the gut which are not necessarily microbes that would typically colonize us. So, if you think of something like yogurt, it’s made by microbes that colonize dairy products and they tend to do some good things while they’re in our gut but they’re not going to colonize and stay there and change our community permanently, typically. Extending that concept, though, one can imagine probiotics that are more targeted to a particular ecosystem or which chooses microbes that will specifically modify an environment such as the gut to improve long-term health. So, the promise is there. Again, the challenge right now is figuring out when and how to do that and how to do it safely or in the long term in humans.
  • TRACEY:
  • I think you said something really important that a lot of people have maybe some confusion around. That probiotics are not going in there and staying and colonizing.
  • CURTIS:
  • If you watch at the molecular level, most food product made of probiotics tend to pass through the gut environment. Again, they’re made to colonize milk rather than a gut. The beneficial effects they have on the way through are more in the kinds of metabolism they perform or the kinds of regulation that they change – and other microbes while they’re there. It’s challenging for something that likes to grow in milk to colonize a human gut instead, just as an example.
  • TRACEY:
  • So, with respect to probiotics are we at the stage yet of recommending a specific strain? Like, a patient can walk into a pharmacy and say, “I have this. What probiotic should I take?”
  • CURTIS:
  • I should have touched on that earlier and that’s a great question. We’re nearing that point for the opposite, for disease causing gut microbial residents. There are examples like E. coli that are fairly well-understood and very strain specific, that 99.9 percent of the time you can carry a completely harmless strain of E. coli but small changes in individual strains cause things like the German outbreak or other infectious E. coli outbreaks that you hear about in the news. Probiotics could well work in exactly the same way. We need to have exactly the right beneficial microbe in exactly the right environment to confer a health benefit. That’s where the link to personalized medicine comes up again. Understanding exactly which bug to introduce in a particular individual for their particular ecology will take a lot of work. I think about it very much like an ecological intervention, like reintroducing wolves to Yellowstone, just adding a particular organism in the middle of a complex ecology may or may not work at all and it may or may not change the environment in a way that benefits the whole community. So, that’s where we need to get to to really understand how to make that kind of targeted change.
  • TRACEY:
  • I like that metaphor that you used. That’s a really good one. It’s a good way to think about how to use probiotics.
  • CURTIS:
  • It’s easier to see wolves than it is to see bacteria.
  • TRACEY:
  • And, the pharmacists, can try to use examples like that try to explain to patients, we aren’t there yet, we don’t really have, I don’t really know what your specific, personalized microbiome looks like.
  • CURTIS:
  • Cancer therapies are another case where it can currently be very challenging since there are particular cancers where if you have that cancer and the correct sub-type of that cancer there exists exactly the right molecule to treat it. But if you have a very slightly molecular sub-type, the treatment might not work as effectively or at all. That took, again, 10 or 20 years to get there for a few types of cancer. We’ve got a lot of work cut out for that, the microbiome, as well.
  • TRACEY:
  • Can you elaborate more on the diet, specifically as a therapeutic intervention?
  • CURTIS:
  • Diet is a tricky one inasmuch as if there were silver bullets we’d probably know. There’ve been, literally, hundreds of thousands of years of human evolution with our microbes in our diet and decades now of dietary epidemiology research. So, if there were particular dietary changes that would improve health, regardless of the microbiome, we’d probably already have run into them. There are cases like prebiotics, for example, specific dietary compounds that are metabolized by microbes that can, sort of, encourage the good ones to grow rather than adding new live cells that a probiotic would. Those can be fairly specific compounds. They’re sort of between a dietary compound and a drug or pharmaceutical and I do think there’s a lot of opportunity there, especially in extreme cases like inflammatory bowel disease, for example, where there’s a clear microbial dysbiosis. And targeting specific microbes, good or bad, with specific dietary compounds can have a more pronounced effect.
  • TRACEY:
  • Right. And when you’re speaking about prebiotics, you’re referring to, like, garlic, onion, leeks, bananas?
  • CURTIS:
  • Even more specific. Prebiotics in our context usually means specific dietary compounds that are metabolized by microbes. So, inulin or fructooligosaccharides, or specific types of fibre that are thought of as prebiotics because they’re specifically used by our gut microbes. And in those cases, the typical good ones to produce short-change fatty acids or other types of healthy gut metabolism.
  • TRACEY:
  • Right. Okay, that’s helpful. We know that drugs can have a certain effect on the microbiome. Can you speak to drugs as, perhaps, a therapeutic intervention?
  • CURTIS:
  • The interaction between pharmaceuticals and the microbiome, I think, has some of the biggest promise. It’s one of the more challenging areas to develop but there are great examples already of current drugs that interact with gut microbes, that are metabolized differently in different individuals, for example, to have a more or less beneficial effect depending on which bugs you happen to be carrying. So, this provides one aspect of drug development or therapy through the microbiome, better understanding the interactions of bugs with current drugs. Another opportunity is the development of compounds that specifically target the microbiome. So, you can think of of targeted antibiotics as an extreme example, in the sense of targeting by killing in that case. So, current antibiotics tend to wipe out large swaths of our typical gut residents – the good guys as well as the bad guys. A very targeted antibiotic might remove just the bad guys and you can imagine other types of targeted pharmaceuticals to specific microbes or specific types of molecular activity in individual microbes, very much like we currently design human targeted drugs just to hit just that right molecular activity to improve something that’s broken. So, we could in principle expand drug discovery or drug activity to include our microbes and our microbial communities in much the same way that drug development currently targets human cells and human molecular activity.
  • TRACEY:
  • Are there drug classes that specifically are going to be used to target the microbiome?
  • CURTIS:
  • It’s definitely early days. There are extreme examples, like antibiotics, that can either be broadly targeted right now based on available classes of antibiotics or hopefully developed to be even more precise in the future. There are anecdotal examples that are known where – they’re sort of point examples like acetaminophen or digoxin. Both have known microbial interactions but exactly how to respond to that or how to deal with that in a particular individual is not yet clear. Some of the more promising examples are, again, extreme cases. In particular, cancer immunotherapies have been looked at very closely over even just the past year now as a case in which, again, the condition can be very personalized, both in terms of a particular cancer and a particular individual’s resident microbes and those resident microbes can change how the immune system responds to the same immunotherapy drug. So, that’s maybe the single area that’s moving the most in the short term. Some of the more chemically-focused changes, even antibiotics, will take some more development to really be precisely targetable.
  • TRACEY:
  • Right. And your lab is focusing on some of that work right now?
  • CURTIS:
  • We do a lot of what I would think of as microbiome epidemiology. So, watching how large populations either in particular diseases like inflammatory bowel disease or, in a general observational population, watching how they respond to chronic disease over time and how that interacts with the resident microbes or how they respond or interact with environmental exposures including things like pharmaceuticals.
  • TRACEY:
  • Are there known environmental exposures that have an effect in the microbiome that you can explain to us about?
  • CURTIS:
  • That’s a good related question to pharmaceutical exposures inasmuch as, again, they’re both types of xenobiotics or chemicals that aren’t typically encountered in the body or often even biologically synthesized. And in the built environment, which can include, say, architectural environments or even other types of microbe environmental interaction such as, say, environmental pollutant chemicals, those are areas where’s there’s a lot of active research to understand how these new kinds of chemicals might interact with microbes. Since we evolved with the latter again but not necessarily with the former, so both pharmaceuticals on the good side and, say, environmental glutens on the bad side are types of chemicals that we did not necessarily evolve with, neither us nor our microbes, and so their impact on, say, microbial metabolism is difficult to understand.
  • TRACEY:
  • Can you speak a little on the importance of early life exposures to the development of our microbiome, especially in terms of the built environment?
  • CURTIS:
  • That’s a great example where environmental exposures seem to really matter and microbial development in general. There’s quite a bit of good evidence now that the first few years of life are special in terms of immune development and microbial exposure. The microbiome itself behaves very differently during those first couple of years as infants are colonized. There’s a lot more chaos, probably in life in general for infants, but also for microbial and immune development. And then things settle down in terms of how the microbiome looks and how the immune system responds after the first few years. So, things like the hygiene hypothesis or the old friends hypothesis have, for many years now, considered that early microbial exposures are important for later immune health. So, studying the microbiome gives a much more precise lens through which the mechanisms of those exposures can be identified.
  • TRACEY:
  • Right. As well as the lack of microbial exposure, I mean, if we are constantly living our lives in the built environment in these sealed buildings and very minimal exposure to the outside environment in terms of nature, the lack of microbial exposure could also have an influence on the microbiome.
  • CURTIS:
  • That’s also been an area where there’s been great research lately. Much like chronic disease, it’s difficult to study because it’s a long-term, gradual exposure. But you can easily imagine that types of human associated microbes and the types of environmentally associated microbes that we encounter if we’re in an office all day, or even in an urban environment all day, versus a rural or a green environment are quite different. There have been some really interesting studies recently on the effects of early light exposure to green spaces and to animals like livestock. Since that might be much more similar to what our immune system and our microbial interactions evolved with than, say, an office environment.
    TRACY:Right. Exactly. And you mentioned we may be looking at the whole field of architecture in a whole different way from now on. How can we make our buildings more microbial?
  • CURTIS:
  • There’s been great work there on infectious disease, control and transmission and understanding how our built spaces interact with pathogens. It’s been interesting to see that extended into, the good guys, into the rest of our microbial communities over the past few years.
  • TRACEY:
  • Are there specific drugs that you might want to elaborate on to maybe exercise caution in taking, just to give our listeners an idea of what they should be careful of?
  • CURTIS:
  • Many of the best understood examples at this point are very specific. Things like cancer immunotherapies that are important for a very small group of people. But some of the more widespread compounds that will obviously affect the microbiome are antibiotics. There is some attention here in the US recently when the FDA recommended not to use triclosan, for example, as a topical antibiotic. There’s no need to continually disinfect surfaces when we don’t necessarily know what long-term effect that’s going to have on good microbes as well as the bad guys. In general, as far as oral antibiotics, in, for example, the epidemiology work that we do that is consistently one of the largest effects on the microbiome. If we think about xenobiotics again or compounds that our microbes did not evolve with in high concentrations in large exposures, antibiotics are a great example. And so on one hand they’re extremely important when used in a targeted, correct way but widespread use has good evidence now it can gradually degrade a normal or healthy microbiome and long-term exposure over the course of, say, many generations of this exposure is not really well understood yet.
  • TRACEY:
  • That’s good information. So, should I then not be using hand sanitizer?
  • CURTIS:
  • If you’re a healthcare professional, for example, if you’re in an environment where that’s important, if you’re a food handler, then it can be very important. On a day-to-day basis in your home that’s a whole different ballgame. As with any antibiotics, the important part I would say for microbial health is being as targeted as possible and as context appropriate as possible.
  • TRACEY:
  • Thank you so much, Curtis. You provided us with so much great information today. Thank you for joining me.
  • CURTIS:
  • Great. Likewise. It’s been a lot of fun and I look forward to seeing the rest of the project.
  • TRACEY:
  • Thank you.