Vitamin B12 bacterial thieves

10 October 2018

Interview with

Aaron Wexler, Vanderbilt University

Vitamins are molecules that we can’t make ourselves and that we rely on our diets to supply. But we’re not alone, because many of the chemicals we need bacteria depend upon too; and this can sometimes bring us into conflict with our own microbes. Aaron Wexler explains to Chris Smith how this works for vitamin B12...

Aaron - We're fundamentally interested in answering the question what does it take to be a successful gut bacterium. And so we know from previous work in our lab - we used a model gut bacterium, part of a geneus called bacteroides that's almost universally present among human populations - one of the things it takes is the ability to take up the small molecule vitamin B12.

Chris - Now when you say a "good microbiome" member, is that good for the bacterial outcome or is that good for the host?

Aaron - So when I was saying a successful gut bacterium, I was speaking predominantly on the side of the bacterium. So they want to colonize the gut, and so if they are not doing their job right they'll go extinct from that environment

Chris - But, equally, if they're too promiscuous and too greedy there could be consequences for the host too, couldn't there?

Aaron - That's certainly the case. Most of these bacteria are localised to the large intestine and they seem to do just fine there. And we get some benefits from them in terms of digestion, in terms of small molecules like Vitamin K, and folate. However, when they find themselves in the wrong location in the intestine, such as the small intestine, then we start seeing problems in people.

Chris - And do those problems include include things related to B12?

Aaron - Yes. So these bacteria are very good at taking up vitamin B12. One of the focuses of this paper was a particular protein called BTG that we identified, which is on the surface of these bacteria and has a very high affinity for vitamin B12. So when these bacteria with these proteins with high affinity for B12 find themselves in the small intestine and grow to large densities, then they start taking the B12 away from our proteins.

Chris - What, because that particular B12 binding protein is so good at doing it's job it's better than our own one, and so if you put the two head to head in a competition the bacteria win?

Aaron - That's certainly the case in vitro. So when we take this human protein called Intrinsic Factor that we used to take a vitamin B12, give it vitamin B 12. But then we incubate it with this bacterial protein , we find that in a very short period of time the bacterial protein has taken almost all of the B12 away from this human protein. So we can reason that a similar process might be occurring in humans and in the small intestine when these bacteria grow to too larger numbers.

Chris - It's like throwing a bulldog and a poodle a lamb chop isn't it and asking who's going to win? Why has the bacterium evolved to have this incredible scavenging power for B12 then.? Obviously it's a valuable molecule but this sounds like a case of overkill to die for?

Aaron - That's right. I think it relates more to competition with the bacteria over B12 versus competition with humans for B12. So I think stealing B12 from intrinsic factor, the human protein, I think that's accidental. And I think it's a consequence of competition for vitamin B12 between gut bacteria versus between humans and gut bacteria. So these bacteria are, like I said, they live predominantly in the large intestine and the densities of bacteria there are are very high. And so with high bacterial densities you get a high level of inter-bacterial competition for nutrients. The human intrinsic factor has also evolved with humans over the course of our evolutionary history and it's not used to competing with gut bacteria for vitamin B12. And so when these bacteria find themselves in high numbers in the small intestine where intrinsic factor is, it just so happens that these bacteria will win that competition pretty much every time.

Chris - So does this fill in that sort of clinical gap then, because we knew that classes of patients do end up with a deficiency in B12, and they do have a bacterial overgrowth and now this explains why these bacteria are able to render us B12 deficient?

Aaron - I think it's reasonable to say that this is an explanation for that. We don't know for sure that this is happening in these patients because we haven't done the experiments to prove that. However the in vitro data that we did collect suggests that this is a reasonable hypothesis.

Chris - Now how did you actually stumble on this in the first place?

Aaron - We were studying B12 uptake in these gut bacteria. And we found that a certain class of gut bacteria called Bacteroides contained the same four components involved in vitamin B12 uptake as E. coli does, and E. coli is the classic bacterium in which vitamin B12 update had been studied. So these bacteroides species in our gut contain the same four proteins, but they contain extra genes that are adjacent to these genes encoding these transporters in bacteroides, and these genes didn't have known functions. And one of these genes, which we called BTG, turned out to be the surface protein with high affinity for vitamin B12.

Chris - So what did you do, a little bit of conclusion jumping where you thought well, they're in the same region so they might be involved? So you then went and looked at them and found oh hey presto, one of them really is involved in this and this is the function?

Aaron - Yes. So we couldn't assume, just based on their genetic location, that they were involved in B12 transport. To get at that answer we took a molecular genetic approach first by deleting BTG, and when we did that we found that these bacteria struggled to grow in low concentrations of B. The second clue came from studies we did where we found the intracellular concentration of B12 was lower in bacteria that lacked this protein.

Chris - So what are you going to look at next?

Aaron - We have some clues that suggest that BTG isn't the end of the story. That there may be other components at play and we don't know what they're doing. Another thing would be to try to get at the clinical side which is to try to figure out if BTG really is the key piece that explains why a small intestinal overgrowth of bacteria leads to vitamin B12 deficiency in people.


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