Microbiome diversity and host disease

The microbiome is often regarded as “the organ that everyone formerly overlooked”; in us, it’s the assemblage of 50 trillion plus bacteria, fungi and viruses that live in us and on us, see our dinner before we do, detoxify poisons, train our immune system, liberate calories we otherwise couldn’t access, and fend off infections by microbial nasties we want to exclude. And one observation that has been made is that when we get ill, the microbiome is often off-kilter too. But what came first? Did the disruption to the microbiome lead to a disease domino effect, or did the disease alter our biochemistry and that, in turn, destabilised the microbiome? Well, it looks like it’s the latter. As she explains to Chris Smith, Iva Veseli, at the Helmholtz Institute for Functional Marine Biodiversity, in Oldenburg, Germany, has found that in people with inflammatory bowel disease, who predictably have a deranged microbiome, it’s not so much that there’s a specific microbe spectrum linked to the disease: instead, the conditions seem to provoke a breakdown in the cooperation between the elements of the microbiome, so bugs that would formerly trade biochemicals among themselves cease to do so, and instead a community of biochemically independent microbes emerges…

Iva - One of the big open questions in the gut microbiome field is why does the diversity of the gut microbiome decrease in people who have gastrointestinal diseases or disorders? So many individuals who suffer from these conditions host fewer different types of microbes in their gut. So whereas a healthy person's gut might include thousands of different microbial populations, for a person with a health issue, that number is less. And this is an important question because what happens to the gut microbiome can inform how we treat or diagnose these conditions. So for instance, if we learn something about the gut microbiome being implicated in the cause of a disease, then we know that, oh, we can maybe treat this by changing the microbiome.

Chris - So is my microbiome more narrow when I have a gastrointestinal problem because some problem has led to it becoming more narrow or did it narrow and then cause my problem?

Iva - That's the big chicken versus the egg, what comes first kind of problem plaguing the gut microbiome field at the moment. Those two directions of causality are very complicated to disentangle. People have tried to do it via sort of associations of, okay, do we see certain kinds of microbes in people with diseases than in healthy people? But unfortunately, so far, there hasn't, at least for some of the diseases. So for instance, in our study, we specifically looked at inflammatory bowel disease or IBD. So at least for IBD, there isn't one blanket answer to, yes, these microbes seem to always appear in people with this disease. And so what that sort of implied to us was that there's not one sort of bad microbe that is sort of helping to cause the disease. The causality might be going in the other direction.

Chris - And how did you actually investigate that?

Iva - We looked at it from the angle of microbial metabolic activity and collaborations between different microbes. You might know that in the human gut and in fact, in a lot of different environments where microbes live, it's not like every microbe can produce all of the molecules that it needs for itself to live. Instead, some of the microbes can produce some of the stuff and some of the microbes can produce all of the stuff and they sort of exchange molecules between each other.
And this is a phenomenon known as cross-feeding, which is very common within the gut microbiome. Previous studies that had looked at the gut microbiome in disease conditions had started to see that these collaborations seem to be breaking down when disease happens. So we tried to look in a lot of different people who had inflammatory bowel disease and a lot of different people who are healthy. We tried to see, are these microbes having lots of metabolic capacity to produce their own compounds via biosynthesis pathways?

Chris - How did you do that? Did you literally take samples and test them?

Iva - So we actually took a computational approach to do this. So I wrote some software that is able to look at the DNA of multiple organisms in a community and predict from that DNA what sorts of metabolic activities the organisms can conduct. Stuff like this microbe can produce the amino acid proline, or this microbe can produce the nucleotide adenine. And from looking at those sorts of prediction data, we were able to assess, is the general biosynthetic capacity in the IBD gut microbiome higher than in the healthy gut microbiome? And the answer was yes.

Chris - So someone else had basically looked at the nuts and bolts of what bugs were there genetically, and it was that data that you could then use to then extract these metabolic implications from?

Iva - Indeed. So there's been lots of studies on the gut microbiome in inflammatory bowel disease. And we basically took a bunch of these public samples, they're called metagenomes because they basically contain all the microbes within a person's gut community. And then we were able to compare copy numbers of metabolic pathways encoded in the samples from each group.

Chris - So take us through then what you actually see, and then perhaps we can speculate as to why.

Iva - It turns out that in the gut communities in people with IBD, there's a lot more metabolic capacity per microbe than in the people with a healthy state. So what that practically means is generally in the IBD gut communities, the microbes that are living there can make a lot of stuff for themselves. So they're very self-sufficient. They don't rely on any other microbes in their surroundings to give them stuff. And in contrast, in the healthy group, those gut microbes are very interdependent. So they cannot make stuff for themselves, meaning that they need to get it from their neighbours, essentially.

Chris - It's like a breakdown in world trade, isn't it? When everyone's getting on very well, countries are trading with each other, and you don't need to have self-sufficiency because you can buy it from your neighbouring country. But when everyone falls out, then you have to have your own raw materials and do everything yourself just to make sure you've got enough of everything. Do you think that that then is again a cause of the acceleration of the disease or a consequence?

Iva - I certainly think that the gut microbiome is not the initial, at least not a major initial cause of someone getting a disease. And the other way around, when someone has a disease, you know, their immune system activity, the drugs that they take to manage their symptoms, those all exhibit a stress on the gut microbes, which then causes members of the population to die out and all of this sort of trading that the microbes are doing to break down, leaving only the self-sufficient survivors behind. Whether or not having only self-sufficient microbes in your gut then further causes a progression of the disease is another open question.

Chris - What do you think the implications of this are? It's academically fascinating and it gives us a different insight and a totally different angle on how we see these communities working together. But where do we go from here?
Now you've got this observation, what do we want to know next and how can we build on this?

Iva - Well, personally, I think that I guess the field should maybe try to shift away from finding, you know, the bad microbiome or trying to implicate in any possible way the microbiome as part of your cause of disease and instead focus on other potential causes of these conditions with complex etiologies. So looking for genetic markers rather than saying that the microbiome is the thing that is going to cause the disease and then potentially save us all. Because for instance, there's a lot of interest right now in people trying to create probiotic cocktails that could help treat somebody's gastrointestinal disorder. There's no guarantee that stuff like that would work if it's true that the microbiome is only reacting to a person having disease and not actually part of the cause.