Microbial Manifesto: The Global Push to Understand the Microbiome

h pylori bacteria — An illustration of *Helicobacter pylori* bacteria

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Alan Brown is a writer and blogger for the Kavli Foundation. Read more perspective pieces on the Kavli Expert Voices landing page. Brown contributed this article to Live Science's Expert Voices: Op-Ed & Insights.

Microbes could soon be at the top of the world's big-science list. Late last year, a consortium of scientists from 50 U.S. institutions proposed the "Unified Microbiome Initiative," a national effort to advance our understanding of microbiomes, communities of single-celled organisms such as bacteria, viruses and fungi.

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Reaching those ambitious goals will require an equally ambitious effort to develop new tools and collaborations, building on breakthroughs in the analysis of microbial DNA, proteins and metabolites. Such analyses show that microbial communities can be incredibly diverse , including hundreds of thousands of different microbial species, all interacting with one another. In the human gut, those microbes aid digestion, but they may also impact obesity, allergies and even brain development. Beyond our bodies, microbes created the Earth's oxygen-rich atmosphere, and enable plant and ocean life to thrive.

Janet Jansson is chief scientist of biology in the Earth and Biological Sciences Directorate at Pacific Northwest National Laboratory (PNNL) and sector lead for PNNL research in the Department of Energy's Biological Systems Science Division. She coordinates two of PNNL’s biology programs: the Microbiomes in Transition (MinT) initiative to study how climate and environmental changes impact natural and human microbiomes and the DOE Foundational Scientific Focus Area, Principles of Microbial Community Design.

Rob Knight is the founder of the American Gut Project, an open-access project to survey the digestive system’s microbiome and its effect human health and development. He holds appointments at the University of California, San Diego School of Medicine and Department of Computer Science and Engineering, where he develops bioinformatics systems to classify and interpret large sets of biological data.

Jeff Miller: There are a lot of factors that came together to cause this explosion of interest. One, certainly, is the ability to rapidly sequence DNA. And over the past 10 years or so, we've seen a progression of technologies that allow us to characterize microbial communities with increasing resolution and sophistication. But we've also encountered many bottlenecks along the way. And interpreting this massive amount of sequenced data is one of those bottlenecks.

Rob Knight: I agree. I think it's really the combination of the DNA sequencing tools getting much cheaper, and the computational tools, including the toolkits that we developed, that make the information much more accessible to a broad community of users. I think what we will see in the future are tools that will go beyond taking inventories of species or inventories of genes and instead provide much more insight about how these species and genes function. But that is going to require a whole lot of additional development of both the software and the knowledge base to use that software.

Janet Jansson: Yes. With DNA sequencing we get information about the composition of microbiomes, but it's also interesting to know what those microbes are doing. For example, if we could understand their protein or metabolite composition, we could get a better understanding of what they're doing in different kinds of habitats and inside our bodies. There are a lot of developments in these areas, but those tools are still lagging behind the sequencing technologies.

The field has progressed rapidly. But we've reached a plateau that has to do with the limitations of the current technologies. We need to be able to see microbial communities where they live, in real time. We want to know what are they doing. What genes are they expressing? What proteins are they making? What metabolites are they synthesizing? How are they responding to each other and their environments?

Knight: Well, the issue is that big data and magic are not quite the same thing. There's a lot of advances that need to happen on the algorithm side. In general, machine learning and generic algorithms will give you a good, but not ideal, answer to a particular scientific question. And the more information you can put in at the beginning to tailor those algorithms to your specific problem, the better you'll do.

The other thing is that although we're producing a tremendous amount of data, we're still limited by the amount of data—it’s still not enough—and by our ability to interpret it. The problem a lot of people are facing right now is that they have collected so much microbial community information. They have over a thousand species that they don't understand. They are listing a million genes they don't understand. Then they are going onto measuring other types of molecules using metatranscriptomics or metaproteomics or metabolomics where, again, they create very large inventories that they also don't understand.

Knight: It's a little worse than that. You're flying out there in your UFO, and you just take a big chunk of that city, grind it up, look at all the DNA and chemicals, and try to make sense of it. That can be an effective or ineffective way to understand the city. You will get an understanding of some of the chemical processes that are going on, and some of the genes that are expressed. But you're not going to learn a lot about the sociology or how those organisms communicate.

Miller: Right. In fact, we know the functions of only about half of the genes that we detect in these communities. And of the half we think we know, the amount of mis-annotation and improper context annotation, are also significant. So we're trying to put a puzzle together with only some of the pieces. And if you look at small molecules, this situation is even worse. About two percent of the metabolites that are found in the typical microbial community map to known structures. And only a fraction of those two percent are on known biochemical pathways. So we need more information.

In the permafrost, we have a huge reserve of carbon that is currently trapped in that environment. So what happens to that carbon as the permafrost thaws and the microorganisms start to become active and degrade the carbon? Are they going to release a lot more carbon dioxide to the atmosphere and make the global warming process worse? At a very fundamental level, we need to understand what those microorganisms are doing.

Knight: Yes, but so far, that's limited to just a very small number of people. For example, there was a really nice paper in Cell by Eran Segal and Eran Elinav of Israel's Weizmann Institute of Science. It showed that based on your microbiome, you can predict what foods will have good or bad impacts on your blood sugar. The drawback, so far, is that they can only do that in the Israeli population, where the food item inventory is somewhat different from what you would see in the United States, for example. But that technology is on the horizon and improving very rapidly.

As far as probiotics go, there's not a lot of evidence that probiotics improve general health in humans, though there is some intriguing data in mice. On the other hand, there's a fair number of probiotics that have been clinically studied in well-conducted randomized controlled trials. For a number of conditions, like, irritable bowel syndrome, post-antibiotic diarrhea, and so forth, there are particular probiotics on the market that have been clinically validated.

However, it's kind of like drugs, where certain probiotics are good for particular conditions, but not something that you should take generally. And in the same way that you would expect for drugs, most people don't need to take most probiotics most of the time, or at least not the ones that have been studied so far. So, I think it's fair to say that public enthusiasm is greatly outstripping the actual evidence. But there is some evidence underlying that enthusiasm.

But that's very different than looking at what we know now, and asking, okay, how would you engineer or reengineer this system? Would a small consortia of bacteria be a good way to decrease fatty tissue and increase muscle mass with diet? So, as Rob said, we haven't yet gotten to the point where we have applied our modern understanding of microbiomes to probiotics now in the marketplace. But the potential for doing that is definitely there.

So, to answer your question, it could cure infectious diseases. A great example is Clostridium difficile-induced diarrhea, which is caused by antibiotics. The best cure that we know is fecal microbiome transplantation from a healthy donor. It is about 90 percent effective, so we know it can work. It's very crude, and so the question now is how to make it better through more refined science, rather than hit-and-miss empirical testing.

Knight: It's important to remember that this is not just for the future. There are people walking around, alive now, who would be dead had they not received fecal microbiome transplants. This is really a current technology that works and is being clinically applied now. And what we need to do is to refine it. But it's not something that's in the future, it's something that's here today. [Body Bugs: 5 Surprising Facts About Your Microbiome ]

Jansson: Before I address that, I just want to go back to our earlier discussion about probiotics. In addition to changing our microbiome, we can also influence it through the food we put into it. This is also a strategy that is sometimes successful, though not very well understood. Instead of a probiotic, it’s called a prebiotic. For example, you can eat what is called a resistant carbohydrate or starch, which is not easy to digest. So it makes it to your intestine relatively intact. This allows the microorganisms in your gut to consume and ferment it, and that's beneficial for the colonic health.

As for actually manipulating an ecosystem on a large scale, this is, of course, difficult. There have been people who have talked about fertilizing the oceans by adding iron, to buffer or mitigate the impact of increasing CO2 concentrations. But when it comes to permafrost, how to prevent the degradation of the carbon that is trapped there? That is difficult. But by gaining knowledge about the types of organisms that are there and the ones that become active when the permafrost does begin to thaw, we can at least predict the implications of those changes.

The issue is that we didn't understand at all what we were doing or what our impacts on those microbiomes were. So, it's not that we can't change them. We are already changing them. And have already changed them. The question's more, "Can we change them in a more nuanced and directed way, where we have a better understanding of the ways that we can change them, at the microbiome level as opposed to the industrial or occupational level?"

Jansson: I can tell you that this is a real hot area of research right now. My group and several other groups are trying to establish the link between the host's genome and the microbiome. I can say that preliminary evidence – there have been a few publications mainly looking at mouse models – suggest that there is a link. Rob's taken a more historical perspective, looking at different types of human populations and the impact of ancestral lifestyles on microbiomes. Rob, maybe you want to comment on that?

Miller: To add one thing to what Rob said, we've coevolved with our microbial communities since long before we became Homo sapiens. We have only about a dozen genes in our genome to digest complex carbohydrates. The microbiota in our gastrointestinal tract brings hundreds of genes that do that for us. And so, when we eat a healthy high fiber diet, what we're really doing is relying on these microbial consortia to digest that food for us, so that we can take some of the products and use them for energy and other purposes.

Miller: Diversity. Microbes – whether you're studying pathogens, beneficial microbes, or microbes in any context – are enormously diverse. The concept of a species has to be reconsidered when you're talking about microbes, because they're not only diverse, but constantly exchanging genetic information. They are truly a constantly moving target, and the extent of their functional diversity is mind-boggling.

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