Antibiotics accelerate diabetes

Antibiotics undoubtedly save lives, but could we be saddling some individuals with a lifelong increased risk of a range of immune conditions if we treat them at a young age with antibiotic drugs? New York University’s Martin Blaser thinks we are. Although they don’t know precisely how yet, as he explains to Chris Smith, his team has found that perturbing the microbiomes of infant mice prone to developing autoimmune diabetes dramatically accelerates the trajectory of their disease, perhaps mirroring what we’re also now seeing in human patients with type 1 diabetes…

Martin - This is a disease that has been accelerating in recent years. It's doubling in its incidence every 20 or 25 years. During the period of time, when this disease has been doubling, antibiotics have come on the scene. And so antibiotics are a possible factor in this disease and other diseases like obesity and asthma. And the way they may be playing a role is by affecting the human microbiome, the organisms that live in and on the human body. We know that antibiotics perturb the microbiome. Our hypothesis is that perturbing it early in life is what's causing this big increase.

Chris - So what was the experimental method here?

Martin - We did our work in mice. There's a kind of mouse called the NOD mouse that spontaneously develops type 1 diabetes. And we wanted to see could we accelerate the diabetes by giving the mice antibiotics early in life? And in fact we found it could in male mice. There were differences between males and females, which we are exploring, but almost everything I'm going to tell you has to do with male mice.

Chris - Right. So you have cohorts of mice. You either give them, I'm presuming, a control where they don't get any antibiotics or you give them a dose of broad spectrum antibiotics and then you follow them up and you ask do they or do they not have a higher or lower rate of diabetes subsequently?

Martin - Yes, you said it very nicely. We give the mice one course of a macrolide antibiotic very early in life and then we follow them to see if they will develop diabetes. And here's where we saw that even one course of antibiotics both accelerated the diabetes, it happened earlier, and actually more mice became diabetic.

Chris - And can you show that in line with using that microlide antibiotic you also do genuinely perturb the microbiome, and you perturb it in a consistent way in the treated animals

Martin - Yeah. So our first findings had to do with the effect of the antibiotic on the microbiome. And we found very general kinds of differences that were consistent across mice, and we were able to name specific organisms that were significantly perturbed and that were associated with the development of diabetes.

Chris - Now if that's the relationship that is causing the effect you're seeing, one would speculate then that if you put back the missing bugs or you just recolonise these animals with the microbiome they had before you fiddled with the antibiotics, you should be able to defer the diabetes risk. Did you do that experiment?

Martin - We are doing that experiment now which is to add back normal microbiota and ask the question can we get them back to their baseline?

Chris - Type 1 diabestes being an autoimmune condition. You're seeing an acceleration of the trajectory of the condition. You might think that it was some kind of loss of the normal gating processes that's holding the immune system back. Do you think that's what's happening when you perturb the microbiome in this way?

Martin - Yes. So the next part of the study was to look at the effects of these changes of the microbiome on the host. We focused mostly on the intestine of the host and our main focus there was on gene expression, which genes are turned on, which genes are turned off. And our first observation was that when we look at mice as they get older we can see a pathway of maturation. Over time, some genes are turned on and some genes are turned off. Now what we've found is that the antibiotic perturb microbiota very much altered this normal maturation.

Chris - There are a number of other immune related conditions that appear to be increasing in incidence in the modern era in line with things like diabetes and antibiotic use. Do you think we've got a common mechanism here then that we're exposing infants to large doses of antibiotics at critical window periods in the microbiome maturation period, and that is having a knock on effect for the way their immune system matures and, therefore, things like allergy risk and so on?

Martin - Yes, we agree with that too. We didn't study that in this paper but it is consistent with the parallel increases in such diseases like asthma. And in fact, when we looked at the gene expression we found many pathways that are seen in many different immunological conditions. We saw perturbation in these pathways and we also found perturbation in metabolic pathways also. Pathways about how the host is processing energy compounds for example. So we think this is all tied together, both metabolism and immunity.

Chris - So are we medically 'robbing Peter to pay Paul?' Because we're we're looking at the short term at how we keep young individuals safe and make sure that doctors don't get sued. But longer term are we saddling that individual with immunological consequences because of our defensive practice?

Martin - Yes, so that's an extremely important question. First let me just say that antibiotics are wonderful drugs. They are miraculous drugs, they've saved countless lives. But doctors and other health practitioners are using antibiotics more and more and more for very negligible illnesses in which it's thought that well since antibiotics have no real cost, no biological cost, we may as well try them. The mantra is 'it may not help but it won't hurt.' But we're finding more and more evidence that it may hurt and that it may change the arc of development. That's very concerning because antibiotics are so widely used in childhood all over the world.

Chris - Is it too late then? If this has been done to an individual is there any way of resetting the system or has this ship sailed?

Martin - That's a very important question. We don't know the answer. That's why we're doing restoration experiments to see, can we restore, can we get them back to their baseline? It's possible that the ship has sailed and that we have to focus on the next generation. On the kids who haven't been born yet so that we can prevent this fate for them. We can prevent this problem from getting worse.