Antibiotics, hormone therapy, oral contraceptives, and long-term nonsteroidal medications in IBD

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Research Express | The relationship between antibiotics, hormone therapy, oral contraceptives and long-term nonsteroidal drugs and IBD - Results of the prospective rural and urban Q1 epidemiological study (PURE)

The PURE study is a large prospective cohort study conducted in North America, Europe, South America, Africa, the Middle East, South Asia, Southeast Asia, and China. The baseline age of participants ranged from 35 to 70 years, from 21 countries/regions, covering urban and rural areas. The data included in the analysis were participants recruited in January 2003 and followed up until July 2019 (follow-up every 3 years). On December 15, 2022, Clin Gastroenterol Hepatol (2021IF=13.576) published online the relationship between antibiotics, hormone therapy, oral contraceptives, and long-term non-steroidal drugs and IBD-the results of the prospective urban and rural Q1 epidemiological study (PURE).

｜Background｜
Inflammatory bowel disease (IBD) includes Crohn's disease (CD) and ulcerative colitis (UC), and its pathogenesis may originate from changes in the intestinal microbiome of susceptible hosts, causing activation of the intestinal immune system. Although the exact cause of IBD is still unclear, studies have shown that many potential risk factors can lead to dysbiosis of the intestinal microbiome, leading to the progression of IBD. IBD is highly prevalent in high-income countries, but the overall incidence tends to be stable; the incidence of IBD in developing countries is growing rapidly, indicating that environmental exposure has a great impact on the incidence of IBD, among which drugs are gradually recognized as a broad category of risk factors.
Nonsteroidal anti-inflammatory drugs, antibiotics, and oral contraceptives have been well studied as risk factors for IBD, but these associations remain unclear due to research limitations. Therefore, further research in more heterogeneous populations is needed to better understand whether drugs can serve as risk factors for the progression of IBD. This report describes the relationship between drug use and the risk of IBD using the Prospective Urban and Rural Epidemiology (PURE) cohort.
| Research Results |
A total of 133,137 participants who had at least 1 cycle of follow-up assessment were included in this study, and most of them had 2 or 3 follow-up assessments (86,173; 64.7%). During the median follow-up period of 11.0 years (interquartile range, 9.2-12.2 years), a total of 571 participants were diagnosed with IBD during the follow-up assessment. The mean age of participants was 50.3 years (SD, 9.7 years), and nearly 60% of the population was female. Overall, the 571 participants with IBD had similar baseline characteristics compared with those without IBD.
Across the entire study population, angiotensin-converting enzyme inhibitors (5,861; 4.4%), diuretics (5,272; 4%), aspirin (5,323; 4%), oral/injectable hypoglycemic agents (5,232; 3.9%), and beta-blockers (5,027; 3.8%) were the most commonly used medications at baseline. In addition, approximately one-third of women reported current or former use of oral contraceptives at baseline.
A total of 947 participants (0.7%) reported baseline antibiotic use, of whom 16 had IBD progression. After minimal adjustment, baseline antibiotic use was significantly associated with the development of IBD (OR, 3.10; 95% CI, 1.88-5.14; P < .001). Of the 24,610 women (31.1%) who reported previous or baseline oral contraceptive use, 185 developed IBD. Among female participants, ever or current oral contraceptive use at baseline was also significantly associated with IBD progression after minimal adjustment (OR, 2.40; 95% CI, 1.90-3.04; P < .001). Similarly, participants who used hormonal medications at baseline (405; 0.3%) were more likely to develop IBD after minimal adjustment compared with those who did not use hormonal medications (OR, 4.81; 95% CI, 1.97-11.77; P = .001). A total of 2939 participants (2.2%) reported baseline NSAID use, of whom 29 developed IBD progression. Baseline NSAID use was also significantly associated with IBD progression (OR, 1.81; 95% CI, 1.24-2.65; P = .002).

The relationship between baseline medication use and the development of IBD
Sensitivity analyzes assessed whether long-term medication use (defined as medication use at baseline and follow-up assessments) had any effect on the results. The analysis evaluated drugs that were significantly associated with IBD progression. Twenty-five of the 947 participants who were taking antibiotics at baseline continued taking antibiotics at follow-up assessments. Of the 16 participants who took antibiotics at baseline and developed IBD progression, none were on long-term antibiotic use. Additionally, among participants who were using steroids at baseline and who developed IBD progression, none were on long-term steroids. When fully adjusted for covariates, participants who used long-term NSAIDs were more likely to have IBD (aOR, 5.58; 95% CI, 2.26-13.80; P<0.001). Short-term use of NSAIDs (used at baseline but not at follow-up assessments) was not significantly associated with IBD progression.
｜Discussion｜
In this large prospective cohort study, multiple associations were found between medication use and IBD: antibiotic use, hormonal medications including oral contraceptives, and long-term use of nonsteroidal anti-inflammatory drugs were all associated with IBD progression.
Today, there is increasing recognition of the complex interactions between genetic predispositions and environmental factors. More than 100 genes have been identified as being associated with IBD susceptibility, although genetic factors alone are insufficient to explain the growing prevalence of IBD in both developed and developing countries, as well as the dramatic rise in incidence in developing countries. Global use of medications (both prescription and over-the-counter) has been increasing over the past 20 years, with more than half of the world's population now estimated to use 1 dose per person per day, a 33% increase compared to 2005. The regions with the greatest development gains tend to have the greatest increases in drug use, including India, China, Brazil, Indonesia and Africa, which historically were the regions with the lowest drug use. Given the epidemiological patterns of IBD and global changes in drug use, there is a need to better understand medications as potential environmental risk factors for IBD progression.
Analysis of the study showed an association between baseline NSAID use and increased odds of developing IBD, particularly among long-term NSAID users. A similar increasing trend was found after accounting for aspirin alone (aOR, 1.65; 95% CI, 1.18-2.29; P=0.003). Long-term use of NSAIDs can alter and disrupt the intestinal barrier, potentially predisposing individuals to developing IBD. This may be multifactorial, including local effects, prostaglandin reduction, and microbial dysbiosis, ultimately altering intestinal permeability, motility, and the production of oxidative species, which collectively influence and exacerbate the inflammatory response.
The study also observed that baseline antibiotic use was associated with increased odds of IBD. Antibiotic exposure in healthy humans has been shown to alter the gut microbiota, with increased frequency and duration of antibiotic exposure leading to persistent dysbiosis. These changes in gut microbial diversity and the loss of protective microbial species secondary to antibiotic exposure have previously been shown to be environmental risk factors for IBD in a dose-dependent manner. Furthermore, different classes of antibiotics have different effects on the gut microbiome. Previous studies have reported different associations between antibiotic classes and IBD, with metronidazole associated with a consistently increased risk compared with other classes. This study did not allow further subgroup analysis by antibiotic class, and the study was unable to determine indications for antibiotic prescribing, but the study studied had the benefit of a large and diverse population analyzed prospectively.
The study also found that women's baseline and previous/current use of oral contraceptives were also associated with increased odds of IBD. Previous literature has shown mixed results for the association between oral contraceptive use and IBD. The exact mechanisms underlying the hormonal relationship and risk of IBD and effects on the gastrointestinal environment are less clear, although it has been suggested that estrogens may affect the humoral immune system and alter the colonic barrier.
｜Conclusion｜
As the global burden of IBD increases, it is imperative to identify the environmental determinants that may contribute to this trend. In this study, antibiotics, hormonal medications, oral contraceptives, and long-term use of nonsteroidal anti-inflammatory drugs were all associated with a higher risk of IBD. More research is needed to further clarify the exact risk profile of the drugs identified in the study. However, this study illustrates the importance of caution when prescribing antibi