Interview: The medicine living inside your gut

This blog is part of a series of interviews on our Emerging Technologies 2014.

Can you give an overview of what “microbiome-based” healthcare is?

About seven years ago, the tools that were first used to sequence the human genome were used to begin large-scale sequencing of the microorganisms in our guts and other parts of the body. That work soon indicated intriguing differences between people. For example, the collection of organisms prevalent in the guts of obese people was quite different to that within lean people, though it was not clear what was causal and what was correlative. In the past few years, more specific research has looked at the functional role these organism collections play.

Recent press attention has focused on a medical procedure called fecal microbial transplant (FMT). It has been used to treat infections of Clostridium difficile, which can be acquired through hospitalization and heavy antibiotic use. The procedure, which has been done as a kind of last resort, seems curative. When that was combined with the growing understanding of the organisms in the gut, a hypothesis emerged that organisms from a healthy donor might be able to “reboot” microbes in the gut.

What work is going on now?

Several groups, both in academia and industry, are collecting and combining organisms. Their results are beginning to show that restoring the health of a gut microbiome may well be a viable clinical procedure; not just with fecal transplants, but also more specific microbiome therapeutics.

Treating people with organisms taken from healthy guts is a methodology that is now being considered for several other diseases that appear to involve a disturbed state of the microbiome, such as inflammatory bowel disease. It could even be used to treat other things, which is unprecedented. Currently, there is no healthcare product that involves organism collections.

When we talk about the microbiome, we’re talking about a vast system, aren’t we?

Some people suggest there are at least 10 times more genes in the microbiome than in the human genome. My guess is that the resulting difference is much larger than 10 times, because the diversity in function is not a linear product of the number of genes; it is the product of the interaction of genes. With three genes, you could see all sorts of interactions. If you have 3,000, or 30,000, the potential interactions grow exponentially. It is clear that the metabolic potential – by which I mean the ability to synthesize chemicals in the gut, or degrade chemicals – is really vast, and differs between individuals. The population of genes cohabiting with us is huge, dynamic and diverse.

What we have found out, really only in the past couple of years, is that you can have 100 organisms that, as a group, can have a certain number of reactions. Another person may have a different 100, but they have the same metabolic capability that the gut needs to function. That is useful to know, because it implies there is a minimal kind of viable microbiome. In this way, the microbiome is like any other organ: you need the right functions to be healthy; too much or too few can lead to disease.

Some scientists have suggested recently that antibiotic use could be damaging the microbiome in unknown ways.

We take a lot of antibiotics. There is no doubt that antibiotics can profoundly alter the state of the microbiome. Not necessarily to its detriment, though in some cases certainly to its detriment. How that perturbs the microbiome is still ahead of us.

But what is interesting is the opposite of that: if you could actually restore a minimal microbiome, then it might be possible to accommodate the effects of a short-term exposure to antibiotics with restorative treatment. If those products could be developed, shown to be safe and corrective, then you could imagine that they might mitigate the potential longer-term effects of antibiotics and allow for them to be used.

There are people who take what they call a “probiotic” to supposedly balance out the effects of antibiotics, but this is something more advanced than that, isn’t it?

Yes, and I should point out that Europe has banned the use of the term “probiotic” because there is insufficient data that supports the claims that are being made. These probiotics appear to deliver some organisms that, in a very transient fashion, alter the digestive state. But there is no evidence I’ve seen that it has any prolonged effect. If that’s what a probiotic is, that’s not what is being attempted here. This would be more of a restart, a wholesale restoration of the microbiome.

However, one should not think of the digestive system as a static container in which there are a set of organisms. It is dynamic. First of all, there is a constant interaction between the organisms and the human digestive system. Then you have the introduction of foods and other chemicals that we consume on a daily basis. So that dynamic space favours a stable ecosystem of organisms that can cohabit. That is what you need to restore. It’s not about introducing one organism, which behaves like a tourist – hanging out for a little while and then leaving. You have to decide what is a native culture, and what is a transient passer. That is the difference.

How are the kinds of treatment we’re talking about administered?

There are research groups developing pills for both discrete collections of organisms and extracted subsets of organisms from the gut microbe collection. The preliminary results are positive. Fecal transplants are still administered rectally in colonoscopies and enemas, etc. That will continue until there are pill forms safely demonstrated and approved by the regulatory authorities.

Are these treatments intended to be a one-off, to reset the microbiome in the gut, or would people need regular treatment over some time?

We do not know about the latter yet because the controlled studies have not been done. The published controlled trial for fecal transplants in Clostridium difficile infection requires up to two treatments for the reported effectiveness. People are looking for alternatives that are easier to manufacture and can be regulated, and that can be a one-off treatment. As we look into the future, we can foresee other conditions that will require periodic treatments over a longer time period.

How significant a development is this treatment? Are we talking about a revolution in healthcare?

I believe that the microbiome offers the foundation for a new treatment modality. There is clear potential for it to be revolutionary, but only when several different therapeutics can be delivered, and shown to be safe and regulated, as opposed to a treatment protocol.

A new treatment modality does not come along very often. If you look back at the history of biotechnology, when proteins first became drugs in the early 1980s, that was a revolution in hindsight. This is part of a line of occasional new treatment modalities that come about. If they proliferate and are represented in multiple products, then I’d say it would be correct to view them as revolutionary.

What kind of timescale are we talking about before these treatments are in general use?

There is a possibility that the very first product will be a variation of the FMT approach. That is more of a product variation than the treatment protocol and it could be in approvable form, or at least in late-stage clinical trials, in the next year or two. That has moved very quickly.

Beyond that, I think the novel products that go after broader diseases are probably four or five years away, depending on whether we can generate human proof of concept. In the pharmaceutical world, human proof of concept is a significant de-risking. Approval is obviously further de-risking, but the first step is proof. That exists in C difficile. I expect in the next three to five years we will see many more.

On this topic, just bear in mind that while I have talked about the gut microbiome, there is also a quite distinct microbiome in the mouth, and there are microbiota in various other areas of the body, such as the skin – all of which will certainly lend themselves to similar scrutiny and the potential development of health-giving products. I have little doubt that products will one day be developed for every different microbial niche on the body.

Author: Noubar Afeyan is managing partner at Flagship Ventures and the chair of the Global Agenda Council on Emerging Technologies. Reporting by Shane Richmond.

Image: Examples of bacterial growth in a microbiological laboratory at the Bulgarian Food Safety Agency in Sofia. June 9, 2011. REUTERS/Stoyan Nenov