Microbiome plant toxin and drug digestion

A few years ago it was discovered that intestinal microbes can detoxify certain drugs and affect the dose that a patient effectively receives. Eggerthella lenta, for instance, can degrade the cardiac drug digoxin. What scientists didn’t know was why they do this, and what role this might serve for the microbe. Now a broad sweep taking in a larger range of E. lenta strains has revealed something very intriguing: the genes that do this seem to serve no direct purpose for the bacterium, and not all strains carry them. So, could the bacteria be making these gene products, Peter Turnbaugh suggests to Chris Smith, just for our benefit, to keep their hosts happy...

Peter - Our lab is really interested in ways in which bacteria that are found within our gut metabolise the drugs that we take. We've known that microbes can impact drug metabolism for many years, but we know very little about the details, and how important they are for the outcome of a given medication.

Chris - Now when you say they metabolise the drugs that we swallow, they change them in some way. Is that because they just naturally happen to have metabolic pathways, enzymes, that can do that? Or is there more to it than that?

Peter - Yes that's one of them questions that we tackle here. There's a general question of why bacteria would choose to metabolise a drug. Is that because they're intentionally targeting the drug with enzymes that are specifically evolved to modify those types of compounds? Or is it because they're intending to metabolise something else that's normally in the body and they have promiscuous enzyme activities. So their enzymes may actually be able to accept, not just normal compounds that are found in the body but also drugs.

Chris - So how did you look into this?

Peter - We, a few years ago, had identified two genes that were found in this prevalent member of our gut microbiome named Eggerthella lenta by using something called RNA sequencing. So we have looked for genes that were turned on in the presence of the drug. And that really allowed us to zoom in and focus on these two particular genes. But one of the challenges was that, at the time, we didn't know whether or not these genes were the correct ones responsible for the reaction, and we knew very little about their biochemistry and how exactly they worked. To get at that, we started comparing a broad collection of different strains. Originally, we had discovered that not all strains of this particular type of bacterium are the same. So, by expanding that now to 25 different strains, we were able to look across the entire genome of this bacterium and find that there is actually just one set of genes that's found in all of the strains that can metabolise the drug digoxin, and missing in strains that can't metabolize the drug.

Chris - Now it's interesting isn't it, that the bacterium has this ability? When you look at that gene and you look at the biochemistry that's making the degradation of the drug possible, what does it tell you about the possible role for that gene in this group of bacteria?

Peter - Well what's really surprising is that we found that this enzyme doesn't work very well against compounds that are normally in the body. It seems to only be capable of metabolising digoxin, this cardiac drug, as well as other closely related compounds that represent other toxic compounds found in plants. And so, you know, unlike what we had expected it doesn't look like this enzyme is acting on compounds that are normally found in the body, it seems to be really specifically tailored for plant toxins.

Chris - So what's it doing there?

Peter - Yeah, I mean, it's still really a mystery why bacteria would hang onto a gene and an enzyme that doesn't normally have an important role in the body. Could be that we just haven't found what it's normally metabolising in our body. Or alternatively it could be that the bacteria are just maintaining these really specialised enzymes in the off chance that we may ingest a toxin.

Chris - Well people do say we should regard the microbiome as an additional organ in its own right, because of the huge number of molecular "knives and forks" that they bring to the table. So this, sort of, could fit that couldn't it, in the sense that we could be providing a home for these bugs and the payback is that they detoxify things from plants that we eat?

Peter - Yeah I think that's a really fascinating way to think about it. What's surprising to me is that this may be a case where the particular knife or fork these bacteria is using to deal with these toxins may not benefit the bacterium itself but may only serve to benefit the bacteria through this indirect effect on the host.

Chris - Now given that you've discovered this and that it may be potentially generalisable to many more organisms and therefore many other compounds. Something like a third of the top 10 agents in a doctor's medicine bag have direct origins in nature. So does this mean then that we actually probably, should be a lot more careful about how we trial agents and how we test agents that are already active in order to take into account what you have found here.

Peter -  Yeah, it's something we think about a lot in our lab, how this information could be used in drug development or even after drugs are on the market. Can we gather data that would help us determine whether or not the microbiome is having an effect on a particular drug.