THE MICROBIOME SUMMIT : The New Path to Health

Looking at Microbes Outside the Gut

Dr. Curtis Huttonhower, PhD

dr-curtis-huttenhower-phd

Dr. Curtis Huttenhower, PhD

Harvard T.H. Chan School of Public Health

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Overview

At the T.H. Chan School of Public Health at Harvard University, Dr. Curtis Huttenhower is using data to better understand the human microbiome so that more effective diagnostic tools and therapies can be developed. Although the “ideal” human microbiome has not yet been identified, Dr. Huttenhower is asking questions like – can being in the right microbial state before treatment influence the outcome of the treatment? In this interview, you will learn about a recent study that Dr. Huttenhower was involved in, where the state of the microbiome pre-cancer treatment determined whether patients would have success in chemotherapy treatment in melanoma.

Transcript

  • TRACEY:
  • Hi, Curtis. Thank you for joining me here today.
  • CURTIS:
  • Likewise. Thank you so much.
  • TRACEY:
  • Your lab is doing some interesting work. Specifically, you were looking at how gut microbes can travel to different sites of the body. Can you explain to us a little bit about that?
  • CURTIS:
  • Most of the recent work in gut microbial involvement in systemic conditions throughout the body that we’ve been involved with has been in immune conditions such as rheumatoid arthritis, for example, where there’s immune development in the gut but the effects are felt elsewhere, or in other areas where we don’t work as much. For example, the gut-brain axis or in lung microbiomes. There are other cases, such as cancer, where there are some unexpected gut systemic interactions, either through colo-rectal cancer where it’s really gut microbial involvement at the site of cancer development or in other cases like melanoma. Skin cancer is a great example where the gut microbiome has been implicated in how the patient might respond to treatment even for a cancer that’s well outside of the gut.
  • TRACEY:
  • Would you mind just telling us a little bit more about what you discovered?
  • CURTIS:
  • So there are two areas, I’d say, in cancer specifically where that gut microbiome has been suggested to be involved outside of the gut. One is in direct translocation either through immune compromise or other effects of cancer treatment that can erode the normal barrier between gut microbes and the rest of the body, typical healthy microbes can escape and in the worst cases cause infections outside of the gut, in tissues, the bloodstream, at the site of the cancer itself. Cases such as melanoma are a second type of gut microbial involvement in which direct effects on therapeutic treatment can change the course of the therapy, hopefully for the better in the sense of having the right gut microbiome and the right gut microbial state at the time of therapy can improve the body’s response to therapy even for a skin cancer that’s not directly involved with the gut at all.
  • TRACEY:
  • You were involved in a study that was very interesting. It was specifically looking at melanoma and whether or not the treatment that’s known to cause colitis could be changed at all by addressing the microbiome. Would you mind elaborating on that?
  • CURTIS:
  • Sure. It’s an interesting example of a case where the diagnostic and therapeutic aspects of the microbiome really intersect. There’s a general principle that I’m interested in of, sort of, being in the right microbial state before a therapeutic intervention. Some of the earliest, really good work in the area came from Eric Pamer’s group, who is also the leader of that study, who established that being in the right microbial state before bone marrow transplant surgery can greatly improve outcome. His group’s gone on to do some great work understanding what the right state is and how it can be controlled, mainly through the appropriate use of antibiotics prior to bone marrow transplant in that case. The melanoma study assures that property in that having the right microbiome prior to Ipilimumab therapy, which is a cancer immunotherapy agent for melanoma, so skin cancer again far outside of the gut, being in the right microbiome state and having the right immune priming will influence how the body responds to the chemotherapy and whether the immune system then correctly attacks the cancer itself. Defining the right state in the case of melanoma is a little trickier and there’s still work going on to follow up that study, for example, and understand which specific microbes and what specific molecules that they’re generating and how they’re interacting with the immune system puts it in the right state to be receptive to immunotherapy in that case.
  • TRACEY:
  • That leads us to the billion dollar question. What is a healthy microbiome? What is the right microbial environment?
  • CURTIS:
  • It’s a great question and interesting inasmuch as it addresses the surprising personalization of our microbiome. I’ve been personally shocked at the degree to which, even in the absence of disease, the absence of drugs, of chemical exposures, at a baseline of normal health, individuals’ microbes differ strikingly. An oft-quoted statistic at this point is our DNA is 99.9 percent plus the same but our microbes in the gut or elsewhere can differ by 80, 90 or more percent. So, even without perturbations, immunotherapy, our typical gut residents are quite different. When we zoom in, those individual microbes are themselves very different. So, at the very precise, strain level even if we both have the same microbe that microbe might differ in important ways in terms of its metabolic capability, how it responds to chemical exposures, even though it’s superficially the same. So, the degree of personalization and the effect that can have on microbial chemical activity and health outcomes is really surprising.
  • TRACEY:
  • Yeah. It’s so fascinating to me because it seems like we’re never going to be able to answer that question. There could be many different ways that a healthy microbiome could exist.
  • CURTIS:
  • That’s part of why it’s been so difficult to define even what a healthy microbiome is, given five to 10 years now with very precise tools to investigate it, a simple definition of what a healthy microbiome is still quite challenging.
  • TRACEY:
  • Right. And then this pulls in the whole idea that it depends on where you live, too. What your definition of a healthy microbiome is. So, we’re learning that in different parts of the world there’s different dynamic environments of the microbiome that exists.
  • CURTIS:
  • I would phrase it as, there are many different ways to be healthy as an ecosystem. So, if you think about the gut as a constrained microbial habitat, there are many different ways to put microbes in that habitat that will support each other and support you. An example might be a forest. There are many different ways around the globe to assemble healthy forests. If you go to any one of them, they’ll have different types of trees. Even if they have the same trees they’ll have different, individual trees. Everything about those ecosystems will be surprisingly different but taking a step back you can still look at them from the outside and say this is a healthy forest or perhaps it’s not. So, there are aspects that that complex ecosystem assembly that apply to the human microbiome as well.
  • TRACEY:
  • Right. I’m sitting here asking myself the question, okay let’s say, going back to your melanoma paper, if I’m diagnosed with melanoma and I know that having the right microbial healthy environment is important, what would be your top things that you would advise me to do.
  • CURTIS:
  • That’s a tough one. At this stage of the research, there are few cases where the answer is really …. Eric Pamer’s group and Marcel van den Brink have really been in leaders in identifying a couple of cases like melanoma therapy and graft-versus-host disease in bone marrow transplant where there are actionable differences in health outcomes and some knowledge of how to promote the good ones and avoid the bad ones. In more complex, chronic or longer-term conditions like inflammatory bowel disease it’s definitely not clear yet. We can see clinical heterogeneity that some individuals will do well with simple therapies and some individuals will not. We can see microbial heterogeneity if we look from person to person within inflammatory bowel disease, microbial communities are different. But whether, or how, those two things relate to each other in that particular disease is not yet understood.
  • TRACEY:
  • Right. I think that’s a very fair assessment. Such fascinating work that’s happening at your lab.
  • CURTIS:
  • And many other places. It’s a great area to be working in.
  • TRACEY:
  • Thank you so much, Curtis.
  • CURTIS:
  • Likewise. Thanks again.