Adam Faye, MD, Reviews Research on the Association Between Antibiotic Exposure and IBD

Dr Adam Faye elaborates on how antibiotic exposure puts adults aged 40 years and older at an increased risk for developing inflammatory bowel disease.

Adam Faye, MD, is an assistant professor of medicine and population health at the Inflammatory Bowel Disease Center at NYU Langone Health.

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Transcript:

Priyam Vora:
Welcome to this podcast from the Gastroenterology Learning Network. I'm your host, Priyam Vora, and today we are talking with Dr. Adam Faye. Dr. Faye is an Assistant Professor of Medicine and Population Health at the Inflammatory Bowel Disease Center at NYU Langone Health. We are going to discuss his research on the association between antibiotic exposure and the development of IBD.

Thank you for joining us today, Dr. Faye. I understand that antibiotics have been implicated in the development of IBD among younger individuals; however, not much is known on this assessment among adults. Is this what prompted your research?

Dr. Adam Faye:
Absolutely. Well, first of all, thanks so much for having me on the podcast and I really appreciate it. And that's exactly right. So when we look at the incidence of IBD, you can see that there is this bimodal peak. So there are younger individuals who develop IBD, but then there's also a population of older adults who develop inflammatory bowel disease. We really don't know a lot about the older adult population who develops inflammatory bowel disease. What we do know from some of the prior data is that they perhaps have less of a genetic predisposition. And the reason we think that is partially because older adults are less likely to have a family history with someone who has inflammatory bowel disease as compared to younger adults.

And when you look at some of the polygenetic risk scores, they seem to be lower for older adults. So we don't quite understand the complex pathogenesis of inflammatory bowel disease. We know it's some genetics, we know it's some environment, but perhaps this bimodal peak in older adults, maybe the environment is playing more of a role.

And so we know that antibiotics, or at least there's been data in the past that have shown antibiotics have been important in the prenatal life, early life exposure. But what about across the ages? So what about antibiotic exposure as you're an adult and as you're an older and adult? So that's really what prompted this study.

Priyam Vora:
Thank you. Would you be able to describe your study, the number of patients and the parameters?

Dr. Adam Faye:
Of course. So in order to really do this, you need a population-based study where you can follow patients over time because essentially what we're looking for is antibiotic exposure and then the number of individuals that develop inflammatory bowel disease. So what we did was we took the nationwide population in Denmark and we looked at all individuals 10 years or older. And this was from the years 2000 to 2018. And this actually was around 6.1 million individuals, which contributed about 87 million person-years of follow up. And what we did was we just essentially followed individuals over time, looked at their antibiotic exposure within essentially 5 years prior to those times, and then looked at the development of IBD as we prospectively followed the population.

Priyam Vora:
And what did you find?

Dr. Adam Faye:
So we really had 3 main questions to ask. One, do we see any difference with the number of courses of antibiotics? So is it just as simple as did you have a course of antibiotics or do we actually see a dose-response relationship where the more courses, the higher the risk? We also wanted to look at the timing of antibiotic uses. So depending on when you used antibiotics, were you more likely to develop inflammatory bowel disease? And then we also wanted to look at specific classes. There's tons of different classes and drugs within antibiotics, so what about these different classes? Do they have differential risks?

What we found was very interesting. When we look at the number of courses of antibiotics, and again, we modeled this over time so that a single individual, the way we design the study, could contribute person-years to the no antibiotic exposure. Then they receive a course of antibiotics and they go into the antibiotic exposure and then after 5 years they can actually return back to the no antibiotic exposure. So this way we can really model antibiotic use over time.

And so what we found was that the more courses of antibiotics, actually the higher the risk. And this was for all individuals. So we've bin them as ages 10 to 40, ages 40 to 60, and 60 or older. And you can see for all 3 groups, the more antibiotic courses, the higher the risk. And we look 1, 2, 3, 4, and 5-plus. And when you look at the individual risk categories, you can actually see that older adults, so 40 to 60 and greater than 60, at a higher risk than those individuals who are 10 to 40.

When we looked at timing, we actually included a 1-year lag time essentially from the antibiotic exposure. So you were prescribed an antibiotic and then you essentially contributed an additional year to no antibiotic exposure until you started contributing time to the antibiotic exposure. You may say, "Well, why did you include an extra year?" The reason being sometimes inflammatory bowel disease can go undiagnosed for a couple months or for a year. And so patients can be having symptoms of GI, whatever it be, diarrhea or other things. And they may be receiving antibiotics because someone thinks they potentially have a concomitant infection, but truly they have undiagnosed inflammatory bowel disease. So to try to wash out some of that associational or reverse causation, we included this 1-year lag time and we actually did an additional analysis including a 2-year lag time and saw similar results.

But when you look at the timing of antibiotic use, the closer the time, so within 1 to 2 years after the exposure, was actually the highest risk of developing inflammatory bowel disease. But even out to 5 years, this risk still persisted. So even 5 years after an antibiotic exposure, there was still an increased risk of developing inflammatory bowel disease for all age groups considered. And then the third and perhaps most interesting finding we had was to look at different antibiotic classes. And what we actually saw was for both ulcerative colitis and Crohn's disease 2 antibiotic classes persistently popped up as the 2 at the highest risk. And these were the nitroimidazoles and the fluroquinolones. And these antibiotics we do commonly use to treat gastrointestinal infections. But what you see is that many of the other antibiotic classes, which we commonly don't use to treat gastrointestinal infections, are also associated with the development, but a slightly lower risk.

And then there was one class in particular, which was nitrofuratoin, which actually was not associated with any risk of developing inflammatory bowel disease. And this is an antibiotic that is often used to treat urinary tract infections. It doesn't really infect affect the intestinal microbiome. It's mostly absorbed in the small intestine.

So again, it's anytime you do a population-based study epidemiologic, it's observational data, which we can say associations, but it starts to paint a picture where we're using antibiotics that don't really impact the intestinal microbiome, doesn't seem to have a risk. Whereas those that impact the intestinal microbiome and those that impact it the most or the nitroimidzoles and fluroquinolones that really are targeting pathogens in the GI tract, those have the highest risk. It starts to get a sense of perhaps how antibiotics are contributing to the development of inflammatory bowel disease.

Priyam Vora:
That's excellent. Actually, you covered the next 2 questions. So during your research, did anything particular strike out regarding the trends in the usage of antibiotics, maybe based on age or gender?

Dr. Adam Faye:
Yeah, that's a great question. So since we didn't quite model it so that we looked at users of antibiotics versus nonusers, just because the overwhelming majority of people when you follow them over time, get a course of antibiotics. So when you actually look at the data, over 90% of individuals received a course of antibiotics in their lifetime. So that's also why we helped model it where an individual could be in the no antibiotic group for several years, then being the exposed to 1, 2, or even 3 at the same time antibiotics, and then again come back to the no antibiotic exposure. But you do see pretty similar distributions in terms of sex. So males and females have pretty similar usage of antibiotics. You see a little bit of a higher usage within older adults, and that makes sense clinically. We see a lot more comorbidities and infections that can happen. So when you look at the truly, truly younger adults or middle-aged, there's a little bit of a signal that there's less frequent antibiotic usage, but again, pretty similar across the board.

Priyam Vora:
So I know you touched upon the subject of genetic predisposition playing a role in triggering IBD, but what other conditions also play a role such as diabetes or COVID?

Dr. Adam Faye:
Yeah, absolutely. So that's a great question. So there's a lot of research being done by some of my colleagues as well in trying to figure out what are the environmental factors in addition to the genetic factors that are really predisposing individuals to develop inflammatory bowel disease. And so we know of a few, but we're still discovering a lot more. But what we see is that the incidence is really rising and particularly for middle-aged younger adults, even some older adults as well. And when you look at some of the data, you can see this exposure to Western diets. So individuals who are migrating to more places with Western diets and inflammatory diets, that can potentially be a trigger. We know smoking can be a trigger for Crohn's disease, although it may be protective for ulcerative colitis.

There's other factors such as appendicitis, which is quite interesting and is actually starting to be looked at a little bit more now where perhaps it's contributing to the development of Crohn's disease but maybe perhaps is protective for ulcerative colitis. So there's a couple of different environmental factors. There's a lot more being thought about as well, but what are the exact environmental factors and how is this complex interplay actually occurring?

And the other question that we had is do the environmental factors that contribute to a specific person's development of inflammatory bowel disease, does that actually translate into their phenotypes or how they present and what their disease course looks like? So what I mean by that is someone who developed inflammatory bowel disease, maybe after antibiotic use or after an infection versus someone who developed it early on with mostly a genetic predisposition or perhaps had smoking as a driver, do these really translate into different clinical phenotypes that we see? So when you look 20, 30 years with their disease, are they very different and is that driven in some way by the environment, by their genetics and so forth? So we don't know, but that is more research on the horizon that we're hoping to accomplish.

Priyam Vora:
Thank you. There have been efforts in recent years to educate physicians about overprescribing antibiotics and how that has contributed to the development of drug-resistant strains of bacteria. Do you think a similar outreach to internal medicine, pediatricians, and family practitioners could help them be more conscious of using antibiotics among patients who may have a family history of IBD or other risk factors?

Dr. Adam Faye:
Yeah, I think so. Yeah, I think that that's a great point and I really do. So certainly someone with a family history, certainly someone with other potentially autoimmune diseases or immune-mediated diseases. In the clinical setting, it can be very difficult when you have someone who's sitting in front of you potentially not feeling well. But I think we have to remember if it's a viral infection or we think it's viral or we really think it's going to be a self-limiting illness and maybe antibiotics won't actually actually help, then perhaps we should be more selective and really try to not give antibiotics if they're not indicated. Obviously antibiotics are a complete game changer for medicine in terms of being able to help our patients and when they're indicated, they absolutely should be given, 1000%, never withheld. But in the cases where again, it's potentially viral or self-limiting illness and not really indicated, perhaps we should withhold.

And the reason being is that it's not just antibiotics that affect the gastrointestinal system, but if you look at the different classes, many of the antibiotic classes actually contributed to the development or were associated with the development of inflammatory bowel disease. So even if we think we're giving an antibiotic for a respiratory illness or something else of that nature, those antibiotics still can change the intestinal microbiome and still may trigger something in the development of inflammatory bowel disease. So it's not just the antibiotics that we used for the GI tract as well. I think that's a key to remember.

Priyam Vora:
That's great. Last question before we part. Do you have any plans to expand this to a broader study?

Dr. Adam Faye:
There're definitely a couple different research trajectories which should come out of this. One is really taking a look now to the intestinal microbiome and trying to discern what exact changes are occurring as a result of antibiotic use and how is that leading to the development of inflammatory bowel disease. There's another along the same lines, but we obviously use antibiotics in the setting of an infection and there's been some data to show that infections alone may contribute to the development of IBD, but antibiotics plus infection may lead to an additional risk. So really trying to understand what's the role of the infection, what's the role of the antibiotic, and also looking at how different classes can lead to the development of inflammatory bowel disease.

I think another area, which I touched upon briefly just before, but it's really looking at what about individuals who do develop inflammatory bowel disease after antibiotic use compared to individuals who maybe don't have a recent history of antibiotic use. Do they have different courses of disease? Do their diseases present and have different phenotypes going forward? So that would be another thing to look at to see how we're perhaps influencing the disease with the use of some of these medications. So that's I think some of the research hopefully coming down the pike that will help elucidate some of these findings. And again, take it from an association study and really try to drive at causality what are the changes here that's occurring and how they translate to the clinical phenotypes and clinical outcomes that we're seeing within our patients, which is always what we're driving at, trying to get to the bottom of that so we can really help predict, prevent, and provide optimal care.

Priyam Vora:
That's great. We would love to hear more on that.

Dr. Adam Faye:
Perfect.

Priyam Vora:
Thank you so much for taking the time to talk to us.

Once again for our listeners, that was Dr. Adam Faye speaking about the association between antibiotic exposure and the development of IBD. Thank you, Dr. Faye.

Dr. Adam Faye:
Thank you so much for having me today.