Antibiotics Increase Risk for Inflammatory Bowel Disease in Older Adults

Inflammatory bowel disease (IBD) is a group of autoimmune diseases — Crohn disease (CD) and ulcerative colitis (UC) — that primarily affect the gastrointestinal (GI) tract. Although the pathophysiology of IBD is not fully understood, it is evident that both endogenous and exogenous factors play a significant role in its pathogenesis.¹ While it is well known that there is a genetic predisposition to IBD — at least 200 known risk loci have been identified so far — the tremendous rise in the incidence of IBD in recent decades, particularly in developing countries,clearly indicates that other factors are involved in the pathogenesis of IBD.^2-4

It is widely known that gut microbiota play a significant role in the pathophysiology of IBD. The most compelling evidence for this association is the pro-colitogenic effect of the microbiota of patients with IBD and the modification of the intestinal inflammation phenotype caused by the changes in the gut microbiota in both mice and humans, notably via fecal microbiota transplantation.^5-7 Antibiotic-induced alterations of the gut microbiota have long been explored as a potential trigger for IBD.

In a population-based cohort study, published in May 2022, researchers sought to investigate the association between cumulative antibiotic use, the timing of antibiotic use, and the association between specific antibiotic classes and the development of new-onset IBD in patients aged 60 years and older. ⁸ The study reported that antibiotic use, regardless of class, was associated with an increased risk for older-onset IBD, with the risk being the highest with antibiotic use 1 to 2 years before IBD diagnosis.

The study included a total of 2,327,796 individuals aged 60 to 90 years identified from Denmark nationwide registries between 2000 and 2018, and information on antibiotics use was extracted from the Danish National Prescription Register. Incidence rate ratios (IRRs) for IBD according to antibiotic use 1 to 5 years before IBD diagnosis were calculated and adjusted for age, sex, and calendar period.

The study resulted in 22,670,484 person-years of follow-up, during which 10,773 new cases of UC and 3,825 new cases of CD were identified. A high IRR for IBD was observed with any antibiotic use (IRR, 1.64; 95% CI, 1.58-1.71) with a positive dose-response (1 course of antibiotics: IRR, 1.27; 95% CI, 1.21-1.33; 2 courses: IRR, 1.54; 95% CI, 1.46-1.63; 3 courses: IRR, 1.66; 95% CI, 1.67-1.77; 4 courses: IRR, 1.96; 95% CI, 1.83-2.09; 5+ courses: IRR, 2.35; 95% CI, 2.24-2.47). The IRR for IBD was high with antibiotic use 1 to 2 years before diagnosis (IRR, 1.87; 95% CI, 1.79-1.94) compared with antibiotic use 2 to 5 years before diagnosis (IRR, 1.42; 95% CI, 1.36-1.48). Moreover, all antibiotic classes were associated with the development of IBD, including those not used to treat GI infections. Specifically, fluoroquinolones, nitroimidazoles, and macrolides had the highest IRR.

To gain further insights on the findings, we interviewed the lead researcher of the study and assistant professor of medicine and population health at NYU Grossman School of Medicine, Adam S. Faye, MD, MS.

What are the key findings of your study?

Dr Faye: The key findings of our study were 3-fold:

1. Any antibiotic usage in the past 5 years among adults 60 years and older was associated with an increased risk [for] IBD. Moreover, we saw evidence of a dose-response, meaning the more antibiotics prescribed in this time period, the higher the risk of developing IBD.
2. The risk [of] developing IBD was highest around the time of antibiotic usage but persisted with antibiotic use up to 10 years before diagnosis.
3. Antibiotics treating [GI] pathogens, which often have a high impact on the [GI] microbiome, were associated with the highest risk of developing IBD. Conversely, antibiotics that [have] minimal impact on the [GI] microbiome were not associated with an increased risk of developing IBD among older adults.

What are the clinical implications of your study results, and how can they be applied to clinical practice?

Dr Faye: There are 2 main clinical implications:

1. As a public health measure, antibiotics should be used judiciously not only to limit the development of multi-drug resistant organisms but also to limit the incidence of older-onset IBD. Additionally, in practice, health care providers should keep in mind that many antibiotics can impact the [GI] microbiome, including those not used to treat a GI infection. Thus, in cases where a mild illness is being empirically treated or is expected to self-resolve in a few days, it may be more prudent to hold off prescribing antibiotics immediately. Nevertheless, this should not prevent prescribing antibiotics when indicated or needed.
2. IBD should be higher on our differential diagnosis among older individuals with ongoing [GI] symptoms and prior antibiotic exposure. This can be particularly helpful in practice, since older-onset IBD can sometimes be challenging to diagnose.

The study findings indicated that antibiotics are associated with IBD development regardless of class. How can antibiotics negatively affect the gut, and how might they lead to the manifestation of IBD?

Dr Faye: We found that most antibiotic classes led to the development of older-onset IBD but found that antibiotics with minimal impact on the intestinal microbiome did not increase the risk [for] older-onset IBD; for example, nitrofurantoin which is often used to treat urinary tract infections, did not increase risk [for] IBD. We think antibiotics are likely to change both the composition and proportion of microbes in the intestine, and when this homeostatic balance is disturbed, it may increase the risk of developing IBD — our hypothesis at this time, given our findings. Much research is ongoing in this domain to further explore this finding.

Did the study also include antibiotic classes used to treat IBD complications? If yes, can antibiotics used for IBD further increase the risk or worsen IBD complications?

Dr Faye: Yes, we included antibiotic classes that are often used to treat [GI] infections, which are common in IBD, and therefore used to treat IBD complications. This warrants further study, but I think they are less likely to increase the risk [for] IBD complications (though certain antibiotics can increase the risk [for] Clostridium difficile infection). Antibiotics used to treat IBD complications often target GI infections or abscesses and, when treated, will likely decrease the overall inflammatory burden, thereby positively impacting disease activity. However, we need to explore how antibiotics used for other indications (non-GI/IBD-related) may impact IBD disease activity.

Given that antibiotics are also used in IBD, what could be the potential role of antibiotics as a risk factor and as a treatment modality in older adults?

Dr Faye: Antibiotics are used among older patients with IBD and a related infection or persistent perianal disease. This study looks at antibiotic use as a trigger for the development of IBD but does not look at how antibiotics may impact or influence IBD course once IBD is already present, so it is difficult to say. That being said, we see in prior studies of adults with IBD that antibiotics can have a favorable impact on disease course; for example, antibiotics after surgical resection of CD can potentially decrease the likelihood of a recurrence. 

The study also found that more courses of antibiotics increase the risk for IBD in older adults. Does antibiotic resistance have an effect on new-onset IBD in older adults? Did it play a role in your study findings?

Dr Faye: Yes, we found that the more courses of antibiotics received in the preceding years, the higher the risk of developing IBD. Antibiotic resistance is specific to the pathogen/infection, so we would need to look specifically at infection data pertaining to this. However, we can say that multiple antibiotics (or broad-spectrum antibiotics) may be used with antibiotic-resistant infections, which may impact the risk of developing IBD. Both broad-spectrum antibiotics and multiple courses of antibiotics can significantly impact the microbiome and increase the risk of developing IBD, but the specific risk of pathogens/infections needs to be further investigated to say directly whether drug-resistant organisms carry a different risk as opposed to drug-sensitive organisms.

Are there any measures to reduce the risk for new-onset IBD in older adults with a history of antibiotic use? Will taking a probiotic course along with antibiotics help mitigate the risks?

Dr Faye: This is a great question — it is possible that by repopulating the microbiome with something like probiotics, we may be able to mitigate this risk. This, however, needs further research, along with determining the [GI] microbiome changes that may be important in the development of older-onset IBD.

What are the future implications of your study results, and what further studies are required?

Dr Faye: Future research should focus on exploring the intestinal microbiome changes that result from antibiotic use and contribute to the development of older-onset IBD, as well as the role of additional environmental factors, so that we can move towards prediction and prevention. 

References

1. Ledder O. Antibiotics in inflammatory bowel diseases: do we know what we’re doing?. Transl Pediatr. 2019;8(1):42-55. doi:10.21037/tp.2018.11.02
2. Liu JZ, van Sommeren S, Huang H, et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat Genet. 2015;47(9):979-986. doi:10.1038/ng.3359
3. McGovern DPB, Kugathasan S, Cho JH. Genetics of Inflammatory Bowel Diseases. Gastroenterology. 2015;149(5):1163-1176.e2. doi:10.1053/j.gastro.2015.08.001
4. Kaplan GG. The global burden of IBD: from 2015 to 2025. Nat Rev Gastroenterol Hepatol. 2015;12(12):720-727. doi:10.1038/nrgastro.2015.150
5. Britton GJ, Contijoch EJ, Mogno I, et al. Microbiotas from Humans with Inflammatory Bowel Disease Alter the Balance of Gut Th17 and RORγt⁺ Regulatory T Cells and Exacerbate Colitis in Mice. Immunity. 2019;50(1):212-224.e4. doi:10.1016/j.immuni.2018.12.015
6. Paramsothy S, Kamm MA, Kaakoush NO, et al. Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial. Lancet. 2017;389(10075):1218-1228. doi:10.1016/S0140-6736(17)30182-4
7. Sokol H, Landman C, Seksik P, et al. Fecal microbiota transplantation to maintain remission in Crohn’s disease: a pilot randomized controlled study. Microbiome. 2020;8(1):12. doi:10.1186/s40168-020-0792-5
8. Faye A, Allin K, Iversen A, Agrawal M, Faith J, Colombel JF, Jess T. DOP06 Antibiotics as a risk factor for older onset IBD: A population-based cohort study. J Crohns Colitis. 2022;16(1):i056. doi:10.1093/ecco-jcc/jjab232.045  

This article originally appeared on Gastroenterology Advisor