WK 3 DIS EPID

Antibiotic use and the development of inflammatory bowel disease: a national case/control study in Sweden

Long H. Nguyen, M.D.1,2, Anne K. Örtqvist, M.D.3,4, Yin Cao, Sc.D.2,6,7, Tracey G. Simon, M.D.1,2, Bjorn Roelstraete5, Mingyang Song, Sc.D.1,2,8, Amit D. Joshi, Ph.D.1,2, Kyle Staller, M.D.1,2, Andrew T. Chan, M.D.1,2,9,10 [Professor], Hamed Khalili, M.D.1,2, Ola Olén, M.D.3,11,12, Jonas F. Ludvigsson, M.D.5,13,14,15 [Professor] 1.Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

2.Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School Boston, MA, USA.

3.Division of Clinical Epidemiology, Karolinska Institutet, Stockholm, Sweden.

4.Department of Obstetrics and Gynecology, Visby Lasarett, Gotland, Sweden.

5.Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

6.Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St Louis, MO, USA.

7.Alvin J. Siteman Cancer Centre, Washington University School of Medicine, St Louis, MO, USA.

8.Departments of Epidemiology and Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

9.Broad Institute of MIT and Harvard, Cambridge, MA, USA.

10.Department of Immunology and Infectious Disease, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

11.Department of Clinical Science and Education, Karolinska Institutet, Stockholm, Sweden.

12.Sachs’ Children and Youth Hospital, Stockholm South General Hospital, Stockholm, Sweden.

13.Department of Paediatrics, Örebro University Hospital, Örebro, Sweden.

14.Division of Epidemiology and Public Health, School of Medicine, University of Nottingham, Nottingham, UK.

15.Department of Medicine, Columbia University College of Physicians and Surgeons, New York, USA.

Correspondence: Jonas F. Ludvigsson, M.D., Ph.D., Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, PO Box 281, SE-17177, Stockholm, Sweden, jonasludvigsson@yahoo.com. Author Contributions: study concept and design (LHN, JFL); acquisition of data (JFL); analysis and interpretation of data (LHN, JFL); drafting of the manuscript (LHN); critical revision of the manuscript (AKO, YC, TGS, BR, JS, ADJ, KDS, MS, ATC, HK, OO, JFL); statistical analysis (LHN, YC); study supervision (JFL)

HHS Public Access Author manuscript Lancet Gastroenterol Hepatol. Author manuscript; available in PMC 2021 April 09.

Published in final edited form as: Lancet Gastroenterol Hepatol. 2020 November ; 5(11): 986–995. doi:10.1016/S2468-1253(20)30267-3.

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Abstract

Background: Early life antibiotics have been linked to childhood inflammatory bowel disease

(IBD), but data on adults is mixed—particularly for ulcerative colitis (UC)—and is based on

smaller investigations that have not assessed risk among siblings with shared genetic/

environmental risk factors. Our objective was to determine the association of antibiotic therapy

and IBD in a large, population-based investigation.

Methods: We conducted a population-based prospective case-control study of individuals aged

≥16 years in ESPRESSO (Epidemiology Strengthened by histoPathology Reports in Sweden), the

Swedish Patient Register, and the Prescribed Drug Register to identify all consecutive cases of

incident IBD (2007–2016) based on histology and ≥1 diagnosis code for IBD or its subtypes: UC

and Crohn’s disease (CD). Cumulative antibiotic dispensations accrued until one year prior to the

time of matching for both study cases and up to five general population controls matched on the

basis of age, sex, county, and calendar year. We also included unaffected full siblings as a

secondary control group. Conditional logistic regression was used to estimate multivariable-

adjusted odds ratios (aORs) and 95% confidence intervals (CIs).

Findings: We identified 23,982 new IBD cases (15,951 UC, 7,898 CD, 133 IBD-unclassified),

28,732 siblings, and 117,827 controls. Prior use of antibiotics (never vs. ever) was associated with

a nearly two-times increased risk of IBD after adjusting for several risk factors (aOR 1·94, 95%

CI: 1·85–2·03). Compared to none, one (aOR 1·11, 95% CI: 1·07–1·15), two (aOR 1·38, 95% CI:

1·32–1·44) , and ≥three antibiotic dispensations (aOR 1·55, 95% CI: 1·49–1·61) were associated

with increased odds of IBD compared to controls. Increased risk was noted for UC and CD with

the highest estimates corresponding to broad-spectrum antibiotics. Notably, comparable, but

attenuated results were observed when siblings served as the referent (aOR 1·35, 95% CI: 1·28–

1·43).

Interpretation: Higher cumulative exposure to systemic antibiotic therapy, particularly those

with greater spectrum of microbial coverage, may be associated with an increase in risk for new-

onset IBD and its subtypes. The association between antimicrobial treatment and IBD did not

appear to differ when comparably predisposed siblings were used as the referent controls.

Funding: National Institutes of Health; Crohn’s and Colitis Foundation

Keywords

colonic microflora; IBD clinical; pharmacotherapy

INTRODUCTION

The inflammatory bowel diseases (IBD), ulcerative colitis (UC) and Crohn’s disease (CD),

are chronic inflammatory disorders of the gastrointestinal (GI) tract. Host genetics,

environmental factors, and the gut microbiome are known to contribute to etiopathogenesis

of IBD.1 While host genetics have been studied extensively, less clearly understood are the

contributions of specific environmental determinants to an alarming rise in IBD,

disproportionately affecting Europe, the U.S., and parts of the world undergoing rapid

economic development.2,3 Consequently, increased sanitation and widespread use of anti-

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infectious agents4 have been proposed as reasons why this emerging disparity in disease

burden is becoming more apparent—the so-called hygiene hypothesis. Prior large-scale

efforts have demonstrated that individuals with IBD harbour greater numbers of facultative

anaerobes (including Escherichia coli) and comparatively fewer obligate anaerobic

producers of short-chain fatty acids (SCFAs) compared to individuals free of IBD.5 With

growing appreciation for the richness and diversity of the gut microbiome and its role in

maintaining human health, so too has concern that antibiotics may perturb and permanently

alter these microbial communities, increasing risk for IBD and other disorders similarly

characterized by dysregulated host/microbial interactions.

Despite expanded reliance on antimicrobial therapy being a leading suspected culprit

contributing to this phenomenon, current studies are limited by small sample size,6–12 lack

of histopathologic case ascertainment,6–8,10,12–17 and mainly address risk associated with

paediatric IBD.13–18 Also, no studies have yet assessed whether risk related to antibiotics is

modified within families already genetically predisposed to the development of IBD. Finally,

careful assessment of pre-diagnostic antibiotic usage with an appropriate exclusionary/lead-

in period (i.e. a period of time for which antibiotic dispensations just prior to an IBD

diagnosis are not accrued) is necessary to limit the possibility of reverse causation, or

therapy prescribed for symptoms related to undiagnosed IBD. This is particularly important

for IBD, since the time to diagnosis may be delayed by four to nine months.19 Population-

scale investigations with careful case ascertainment and an appropriate lead-in period are

urgently needed to help settle this controversial and unsettled question.

Thus, to our knowledge, we conducted the single largest investigation assessing cumulative

exposure to antibiotic therapy and incident IBD, conservatively assessed at least one year

prior to disease diagnosis. We confirmed case status by requiring both compatible

histopathology and medical diagnosis coding, using the first occurrence of either criterion as

the date of diagnosis, and compared antibiotic usage for those afflicted to general population

controls in a large, nationally representative case-control study. To minimize the

confounding effect of childhood exposures and genetic susceptibility, we also compared IBD

cases to their unaffected, full siblings.

METHODS

Study design and participants

In Sweden, universal access to care is tax-funded and includes prescription medication

coverage.20 The Swedish National Board of Health and Welfare has collected patient-level

data on hospital discharges nationally since 1987 using the Swedish Patient Register. Each

patient record includes sex, date of birth, dates of hospital admission, as well as procedural

and discharge diagnoses systematized by International Classification of Diseases (ICD) code

(Fig. 1 and Appendix, p2). In 2001, this registry was expanded to outpatient specialty care,

including visits to gastroenterology providers. The positive predictive value for most

diagnoses in this register ranges between 85% and 95%.21 We further integrated this national

registry data with the Epidemiology Strengthened by histoPathology Reports in Sweden

(ESPRESSO) study.22 Briefly, the ESPRESSO study is an ongoing, comprehensive data

harmonizing effort involving each of the 28 pathology laboratories in Sweden. This includes

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all computerized GI pathology reports generated for clinical care or research purposes

between 1965 and 2016, encompassing more than 2.1 million unique individuals with

detailed information on topography (i.e. the anatomic location of the obtained tissue),

morphology, appearance, and the pathologist’s diagnostic impression. Finally, since July

2005, the Swedish Prescribed Drug Register has collected information on all medications,

including antibiotics, prescribed to the entire Swedish population, as well as the date of

redemption, amount dispensed, and dose allotted.20 Patient level data from the ESPRESSO

cohort and two national registries (Patient Register and the Prescribed Drug Register) were

linked by a unique personal identity number assigned at birth or at the time when permanent

residence was established. Thus, our study encompasses all consecutive eligible patients for

the period of overlap during which the National Patient Register, the ESPRESSO study, and

the Prescribed Drug Register were each actively enrolling (July 1, 2005 to December 31,

2016). This investigation was approved by the Stockholm Ethics Review Board (Protocol

2014/1287–31/4). Due to the strict registry-based nature of the study, informed consent was

waived.

Ascertainment of outcomes

Using predefined anatomic and histologic criteria, as well as the attending pathologist’s

diagnostic impression (Appendix, p2), we identified individuals in the ESPRESSO study

with GI tract histopathology compatible with the diagnosis of new-onset IBD and its

subtypes, UC and CD from 2005 to 2016. If a distinction between subtypes could not be

made, cases were defined as (non-infectious) indeterminate colitis or IBD-unclassified

(IBD-U). We then cross-referenced potential cases and the entirety of their inpatient and

outpatient records in search of at least one ICD code consistent with IBD.

We first excluded those with IBD-compatible pathology or ICD diagnostic coding prior to

our study baseline (2005). The date of IBD diagnosis was defined as the earliest between the

date of relevant pathology findings and the first appearance of an IBD-related diagnosis

code. In a random subset of individuals with both compatible histopathology and an ICD

code for IBD, we were able to validate case status using manual chart review in 95 of 100

individuals22 yielding a positive predictive value of 95% (95% CI: 89–99%). To account for

the possibility of reverse causation, or antibiotic therapy prescribed for symptoms related to

undiagnosed IBD, we did not count antibiotic dispensations in the one year leading up to

IBD diagnosis. Consequently, to conservatively ensure adequate at-risk exposure time (since

antibiotics were not counted in the preceding 12 months), we excluded IBD cases diagnosed

within the first 18 months of study baseline/initiation of the Swedish Prescribed Drug

Register (Appendix, p8).

At the time of ESPRESSO inclusion, individuals were paired with up to five reference

controls from the general population, matched on the basis of age, sex, calendar year, and

county. Controls with undiagnosed IBD at the time of matching were allowed to later

become cases if they met the prespecified diagnostic criteria, and they were then

subsequently matched to five other reference controls of their own. Additionally, to further

assess the association between cumulative antibiotic usage and IBD among genetically

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related individuals, we also identified and enrolled unaffected full siblings of our index cases

still living at the time of their siblings’ IBD diagnosis.22

Ascertainment of primary exposure and other covariates

Our primary exposure, cumulative antibiotic usage up to one year prior to IBD diagnosis,

defined as the cumulative sum of antibiotic dispensations. This was assessed using the

Swedish Prescribed Drug Register and categorized using established World Health

Organization (WHO) Anatomical Therapeutic Chemical (ATC) codes for the therapeutic

subgroup of antibacterials approved for systemic usage. To achieve adequate case balance,

we collected information on number of dispensations (categorized into zero, one, two, and

three or greater dispensations, corresponding with median/interquartile values for

dispensations across the entire study population). We also collected information on the

cumulative number of prescribed days, as well as the cumulative defined daily dose (cDDD).

In secondary analyses to further define the relationship between antimicrobial coverage,

dysbiosis, and risk of IBD, we assessed whether different ATC classes of antibiotics

(penicillins, cephalosporins, macrolides, fluoroquinolones, tetracyclines, sulphonamides,

and other) and spectrum of coverage (broad vs. narrow)23 influenced risk of disease

(Appendix, p3).

When available, we obtained data on level of education (≤9 years, 10–12 years, ≥13 years,

and unknown) from Statistics Sweden and the longitudinal integrated database for health

insurance and labour market studies, which since 1990 has annually updated administrative

information from the labour market and educational and social sectors for all individuals

aged 16 years or older. This information is available in more than 98% of all individuals

aged 25–64 years.24 We also calculated the number of inpatient and outpatient encounters

(continuous) for each participant during the study period up until the time of matching.

Statistical Analysis

To evaluate the association between antecedent antibiotic therapy and IBD, we performed

conditional logistic regression between IBD cases and reference controls to estimate crude

and multivariable-adjusted odds ratios (ORs) and their 95% confidence intervals (CIs)

conditioned on matching factors (age, sex, calendar year, and county of residence) and

further adjusted for potential confounding factors (education level and healthcare utilization,

the latter defined as the number of inpatient and outpatient encounters during follow up).

Tests for linear trend were calculated using the midpoint of each frequency category as a

continuous variable. Two-sided p-values of <0.05 were considered statistically significant.

As a sensitivity analysis and to assess the robustness of our primary findings, we lengthened

the lead-in period from one year in our primary analysis to a more conservative two years.

We also performed subgroup analyses according to the spectrum of antibiotic coverage and

class of antibiotic therapy prescribed. We conducted a joint association analysis to determine

whether the number of combined broad or narrow-spectrum dispensations altered the

association between antimicrobial therapy and IBD, in effect, a test of interaction between

two risk factors. Finally, to minimize the influence of genetic predisposition and shared

childhood exposures, we compared cases to their (unmatched) full siblings using logistic

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regression with adjustment for age, sex, year of match, county, education level, and

healthcare utilization. Statistical analyses were performed using SAS version 9.4 (Cary, NC,

USA) and R 3.5.1 (Vienna, Austria).

Role of Funding Sources

Sponsors had no role in study design, the collection, analysis, and interpretation of data,

report writing, and the decision to submit for publication. The corresponding author had full

access to all of the data and the final responsibility to submit for publication.

RESULTS

We identified 32,690 unique individuals aged ≥ 16 years in the ESPRESSO study with GI

tract histopathology compatible with the diagnosis of new-onset IBD and its subtypes, UC

and CD from 2005 to 2016. After excluding individuals with a compatible IBD ICD

diagnosis code at or prior to baseline and individuals without adequate exposure time

according to our prespecified lead-in period, we enrolled 23,982 cases of biopsy and

diagnosis code-confirmed IBD between January 1, 2007 and December 31, 2016 (15,951

UC, 7,898 CD, 133 IBD-U). Patients with IBD were comparable to their 117,827 matched

controls by mean age (35 years), sex (52% male), education level, and region of residence,

but tended to have more frequent engagement with inpatient and outpatient providers (Table

1 and Appendix, p5). Among these general population individuals, only 952 (0.8%)

individuals would become cases themselves and were thus matched to their own reference

individuals. We found a strong correlation between the presence of an IBD-compatible ICD

code recorded in the inpatient setting with one in the outpatient setting (Spearman ρ for IBD,

CD, and UC each > 0.62), which would suggest that either clinical setting (e.g. inpatient or

outpatient) is suitable for valid case identification.

Prior use of antibiotics was associated with a nearly two-times increased risk of IBD after

adjusting for several risk factors (multivariable OR 1·94, 95% CI: 1·85–2·03). Increased

cumulative antibiotic use was associated with an increased risk for new-onset IBD and its

two primary subtypes, UC and CD (Table 2). Inclusive of our matching criteria (age, sex,

calendar year and county), education level, and number of prior inpatient and outpatient

encounters, multivariable conditional logistic regression demonstrated a frequency-

dependent relationship between increased antibiotic prescriptions and risk of IBD (P-trend

<·0001). We found that three or more antibiotic dispensations at least one year prior to

diagnosis was associated with a 55% increased risk for IBD (multivariable OR 1·55, 95%

CI: 1·49–1·61) compared to no prior use. Due to significant collinearity in their measure,

results were similar when cumulative antibiotic therapy was assessed by number of days

prescribed or cDDD (data not shown). Risk estimates were slightly higher for CD compared

to UC. Our estimates were not materially altered when a two-year, rather than one-year lead-

in was employed (multivariable OR for ≥3 dispensations compared to never use 1·47, 95%

CI: 1·41–1·53; P-trend<·0001). Results remained consistent when we removed controls who

eventually became cases (data not shown).

Subgroup analyses by spectrum of antibiotic coverage demonstrated an increased risk

among patients reporting more frequent use of broad-spectrum antibiotics compared to

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narrow spectrum (Table 3). Heterogeneity in risk estimates appeared most pronounced for

CD, though formal tests for interaction were highly significant for IBD, UC, and CD (all P-

interaction <·0001). There was no clear synergistic effect between increasing frequency of

combined broad and narrow-spectrum antimicrobial therapy (data not shown). Each class of

antibiotic assessed, categorized by World Health Organization ATC subgroup, was

associated with a statistically significant increase in risk per dispensation compared to never

users (multivariable OR between 1·03–1·20; Fig. 2), highest for each dispensation of a

cephalosporin class antibiotic (multivariable OR for IBD 1·20, 95% CI: 1·14–1·25). To

further ensure our primary findings were not a consequence of infections related to

undiagnosed IBD (i.e. confounding by indication), we compared the usage of a composite

antibiotic, either ciprofloxacin or metronidazole—two commonly prescribed antibiotics for

bacterial gastroenteritis—and found comparable results to our overall estimate

(multivariable OR for IBD compared to never users of 1·15, 95% CI: 1·11–1·20). In general,

we found consistent results between UC and CD. A stratified analysis by age group

appeared to demonstrate a greater association among older individuals, perhaps suggesting

that environmental exposures may play an outsized role in older onset IBD, while other

factors may contribute to early-onset IBD, which tends to have a more dramatic disease

course (Appendix, p6).

Finally, among individuals with a genetic predisposition to disease development and to

partially account for shared but unspecified childhood exposures, we compared

antimicrobial therapy rates among IBD cases and their full siblings, where available. Nearly

70% of cases (n=16,353) had at least one living sibling identified in our cohort, all of whom

were captured by linkage to the National Patient Register. When comparing 28,732 full

siblings free of IBD to their related cases, as expected, their mean age, region of residence,

and education levels were all comparable (Appendix, p7). Notably, their number of inpatient

and outpatient encounters were similarly elevated—like their case siblings—compared to

unrelated reference individuals, suggesting similar childhood exposures, infections,

predilection for chronic disease, and access to comparable childhood care. When siblings

were used as the referent group, IBD risk estimates were only slightly attenuated compared

to general population controls, with a multivariable OR of 1·35 (95%CI: 1·28–1·43; P-trend

<·0001) when comparing three or greater antibiotic dispensations to none (Table 4).

Estimates were comparable for both UC and CD.

DISCUSSION

In this population-based study of nearly 24,000 unique IBD patients during a 10-year study

period provided, we demonstrate a potential frequency-dependent relationship between the

number of antibiotic dispensations and the development of UC and CD. This potential

association appeared to be robust to adjustment for age, sex, level of education, and degree

of healthcare utilization. Furthermore, this possible risk association appeared greater with

more frequent use of broad-spectrum antibiotics, which supports the hypothesis linking

greater excursions from the normal gut ecological state caused by antimicrobial therapy to

elevated risk for chronic disease development.

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To our knowledge, this is the largest investigation exploring the link between prior

antimicrobial therapy and subsequent risk for IBD, which not only allowed for subgroup

analyses that produced more confident risk estimates by WHO antibiotic class, but linked

more frequent antibiotic therapy to risk of UC, a disease subtype for which prior, smaller

investigations have produced mixed results. Moreover, in a secondary analysis among cases

and their IBD-free siblings with whom they likely shared childhood exposures, as well as a

genetic predilection for the development of IBD, we were able to show that risk associated

with antibiotic use was only minimally attenuated when compared to tests against general

reference individuals. This comparison among similarly predisposed persons provides

further evidence to implicate cumulative antibiotic exposure as an independent risk factor in

the etiopathogenesis of IBD, regardless of underlying genetic susceptibility.

Disentangling the environmental exposures that may culminate in the diagnosis of IBD is

critically important, particularly as some data may suggest that risk of IBD due to antibiotics

may be restricted to developed areas of the world.3 Globally, rates of IBD are rising,

particularly in areas undergoing rapid economic development. Since these trends are

unlikely to be explained by drastic, population-level changes in underlying genetic

architecture, the widespread adoption of increased sanitation and pervasive use of anti-

infectious agents have been implicated.25–28 Despite considerable progress in our

understanding of IBD’s genetic and familial underpinnings, concordance rates among

monozygotic, i.e. genetically identical, twins is still just 20–50%,29 highlighting the

importance of considerable non-genetic determinants in new-onset IBD, such as antibiotic

therapy.

Our primary findings are biologically plausible. While antibiotics have been widely

beneficial for the maintenance of human health, they greatly impact the fragile ecology of

human gut microbial communities, resulting in individualized and sometimes incomplete

recovery from such insults, predisposing users to long-term chronic disease risk.30–33 The

consequences of altering the taxonomic makeup and collective activities of the gut

microbiome can influence IBD risk through several, interconnected mechanisms, including a

change in vital metabolic functions, vitamin and nutrient production, as well as energy

extraction. Most critically, gut microbial perturbations promote the onset of intestinal barrier

dysfunction34,35, altered immune response,36,37 defective autophagy,38 and permissive

pathogenic blooms39–41 that are typically viewed as inciting events as early as several years

prior to the development of IBD. Notably, our group has previously linked early life

antibiotic exposures to a more severe, paediatric form of the disease, adding credibility to

the current findings.15

Epidemiologic evidence on the relationship between antimicrobial therapy and risk of IBD

has been mounting, though it is possible that publishing bias may have resulted in

comparatively fewer negative studies. The largest and most recent meta-analysis to date,

encompassing 7,208 IBD patients from 11 separate investigations—cumulatively,

approximately ⅓ the size of the present study—have noted similar findings with respect to

antibiotic therapy and risk of CD and also observed heterogeneous risk estimates related to

class of antibiotic therapy42 and included several studies in which no clear association was

noted. However, Ungaro et al were unable to couple antibiotic use to an increase in risk for

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UC, possibly due to sample size considerations (collective number of UC patients, n=

2,935). More recently, a case-control study of 455 IBD patients by Aniwan et al demonstrated an association between antimicrobial therapy and risk of UC, albeit with much

stronger risk estimates across IBD and its subtypes (adjusted OR for IBD 2.93, 95% CI:

2·40–3·58; for UC 2·94, 95% CI: 2·23–3·88).7 However, compared to our nationally

representative, population-based study, they enrolled individuals from an ethnically and

socioeconomically homogenous region of the U.S. Given our a priori hypothesis linking

hygiene, economic development, and increased utilization of antibiotics to IBD, it is unclear

how generalizable their findings may be. Additionally, Aniwan et al only excluded

prescriptions in the three months prior to diagnosis, increasing the possibility of reverse

causation, or therapy initiated for symptoms due to undiagnosed IBD, a disease for which

the time to diagnosis may be delayed by months.19 Our study did not allow dispensations to

accrue in the one year prior to IBD diagnosis/time of match, making it much less likely that

antibiotics were masking symptoms of IBD that had already developed, and our estimates

were not significantly attenuated when we employed an even stricter two-year lead-in

period. Finally, comparable observational studies have helped elucidate the role of

antibiotics in other GI conditions, such as colorectal cancer and its precursor lesions and

celiac disease.

Strengths of this investigation include the enrolment of all consecutive, eligible patients with

new-onset IBD from a population-based register over a ten-year study period, limiting

selection bias. In Sweden, there is universal medication coverage with virtually complete

information on all drug dispensations, including antibiotics, minimizing ascertainment bias

(<0.3% of all prescriptions lack identifying information).43 To complement the use of a

large, nationally representative sample, we employed stringent outcome ascertainment,

requiring both compatible histopathologic findings and confirmatory ICD coding for

adjudicating cases. With a positive predictive value of 95%, this validated method of case

identification allowed us to confidently leverage and retain the power to detect even

relatively modest risk increases among certain antibiotic classes, such as cephalosporins

(multivariable OR 1.20 for IBD per dispensation) and penicillins (multivariable OR 1·05).

Thus, we were able to demonstrate that all antimicrobial classes tested conferred additive—

at times, modest—disease risk, strongly arguing for universal antibiotic stewardship and

prescriber restraint.

We acknowledge several limitations. As with all large-scale pharmacoepidemiologic studies,

medication dispensation ascertained through the Swedish Prescribed Drug Register may not

capture any given patient’s actual usage. However, due to the short-term nature of most

antibiotic courses and the presumption that most dispensations were attributable to positive

symptoms suggestive of an infection, adherence was not likely a major issue. Furthermore,

such bias would have resulted in attenuation towards the null from non-differential

misclassification. The Prescribed Drug Register does not contain information on hospital

administered drugs, though this could be partially accounted for in our multivariable models

adjusting for number of hospitalizations over the follow-up period. Given the observational

nature and epidemiologic scale of this investigation, the possibility of unmeasured

confounding remains, and our case-control design did not allow estimates of incidence rates

and absolute risks. Our results will need to be validated in other populations given Sweden’s

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elevated rates of IBD2,44,45 and lower antibiotic dispensation patterns compared to other

nations.46,47 We did not have information on the type of infection/indication for antibiotics

dispensed. We found a low rate of IBD-U during the study period, which may be a function

of improved histopathologic criteria,48,49 our focus on adult-onset IBD,50,51 and a prolonged

lead-in period which may not have allowed IBD-U to develop from presumed UC or CD

cases.48,51 Finally, we cannot fully eliminate the possibility of reverse causation (therapy

initiated for undiagnosed IBD) or confounding by indication (therapy initiated for GI

infections related to IBD), though we attempted to minimize this in several ways. First, by

only accounting for prescriptions at least one year prior to diagnosis, we can be more

confident that antibiotic dispensations were not likely to be prescribed for undiagnosed IBD,

a disease with a typical time to diagnosis between four and nine months.19 An even more

stringent sensitivity analysis extended the lead-in period to two years, which demonstrated

similar findings. We also demonstrated a consistent frequency-response relationship in our

primary analysis and a secondary analysis for an elevated risk for broad-spectrum antibiotics

that are more likely to adversely impact gut microbial communities. Lastly, we used an

early, conservative date of diagnosis (at the time of either the earliest IBD-compatible

histopathology or ICD coding) which minimizes the time period for which antibiotic

dispensations could be attributable to symptoms of IBD.

In closing, we found that higher cumulative exposure to systemic antibiotic therapy in the

past 10 years, particularly those with greater spectrum of microbial coverage, was associated

with an increase in risk for new-onset IBD and its two main subtypes, UC and CD. The

relationship between antimicrobial treatment and IBD was not materially altered when

comparably predisposed siblings were used as the referent controls. Further studies are

needed to investigate how antibiotics may permanently alter gut microbial communities,

potentially culminating in disease development, and whether that risk may be reduced by

probiotics to prevent expansive blooms of pathogenic bacteria in place of beneficial

microbes affected by antibiotic treatment.

Supplementary Material

Refer to Web version on PubMed Central for supplementary material.

Funding & Grant Support:

National Institutes of Health (NIH) grants T32CA009001 (LHN), Loan Repayment Program (LHN), K07CA218377 (YC), R00CA215314 (MS); Crohn’s and Colitis Foundation Research Fellowship Award (LHN) and Senior Investigator Award (ATC, HK); the American Gastroenterological Association Research Scholars Award (LHN), and the Massachusetts General Hospital Stuart and Suzanne Steele Research Scholars Award (ATC). Funders had no role in study design, data collection, analysis or interpretation of data, manuscript writing, or decision to submit for publication. The corresponding author had full access to all of the data and the final responsibility to submit for publication.

Declaration of Interests:

KS reports grants from AstraZeneca, Gelesis, and Takeda, personal fees from Shire, Boston Pharmaceuticals, and Arena, all unrelated to the scope of the submitted work. HK received unrelated grant funding and consulting fees from Pfizer and Takeda. JFL coordinates a separate study on behalf of the Swedish IBD quality register (SWIBREG).

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RESEARCH IN CONTEXT

Evidence before this study

Rates of inflammatory bowel disease (IBD) are increasing, particularly in Europe, the

U.S., and other parts of the world undergoing rapid economic development, increased

sanitation, and more frequent use of antibiotics. With growing appreciation for the gut

microbiome’s role in maintaining human health, so too has concern that antibiotics may

perturb and permanently alter these fragile microbial communities. We searched PubMed

for articles published between January 1, 1990 and April 30, 2020, using the terms

“inflammatory bowel disease” and “antibiotics”. Despite this compelling rationale, prior

efforts to address this question have been conflicting—particularly in ulcerative colitis—

and have been characterized by smaller-scale investigations with the most recent meta-

analysis on the topic (with 11 prior studies and 7,208 IBD cases) disclosing a pooled

odds ratio (OR) of 1.57 for risk of IBD, 1.74 for risk of Crohn’s disease, and was not

significantly different for ulcerative colitis (OR 1.08; Ungaro et al, Am J Gastroenterol

2014). Thus, it remains controversial and unsettled as to whether or not antibiotic therapy

is linked to new-onset IBD.

Added value of this study

Among 23,982 individuals with IBD matched to 117,827 controls, number of antibiotic

dispensations was significantly associated with risk for both ulcerative colitis and

Crohn’s disease in a frequency-dependent fashion. Risk appeared greater with more

frequent use of broad-spectrum antibiotics. The positive association between antibiotic

therapy and IBD remained observable even when cases were compared to their

unaffected siblings with whom they likely shared genetic susceptibilities and childhood

exposures, offering further support for the potential, independent role of antibiotics in

IBD development.

Implications of all the available evidence

Our findings, if confirmed in longer-term prospective studies in humans or mechanistic

pre-clinical investigations, suggest the need to further emphasize antibiotic stewardship to

prevent the rise in dysbiosis-related chronic diseases, including IBD.

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Figure 1: Study overview

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Figure 2: Antibiotic use by antibiotic class and inflammatory bowel disease comparing cases and their

matched general population controls, 2007–2016. Conditional logistic regression matched

for age, sex, and county and further adjusted for number of inpatient and outpatient

encounters and education level. Referent group had no prior exposure to antibiotics of any

kind at the time of matching. Cumulative dispensations accrued from study baseline up until

one year prior to diagnosis/match. IBD includes ulcerative colitis, Crohn’s disease, and IBD-

unclassified. Abbreviations: OR - odds ratio, CI - confidence interval, IBD - inflammatory

bowel disease, UC - ulcerative colitis, CD - Crohn’s disease.

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Table 1:

Patient characteristics at the time of inflammatory bowel disease diagnosis and their matched general

population controls, 2007–2016

Cases

n=23,982 #

Controls n=117,827

Ulcerative colitis n=15,951

Crohn’s disease n=7,898

Age, years 36 [24–56] 31 [19–51] 35 [22–54]

<18 1,755 (11) 1,686 (21) 17,699 (15)

18–24 2,552 (16) 1,422 (18) 20,421 (17)

25–34 3,190 (20) 1,343 (17) 22,785 (19)

35–44 2,233 (14) 948 (12) 15,843 (13)

45–54 1,914 (12) 790 (10) 13,451 (12)

55–64 2,072 (13) 869 (11) 13,487 (12)

≥65 2,235 (14) 840 (11) 14,141 (12)

Male sex, n (%) 8,543 (54) 3,997 (51) 62,010 (52)

Region of residence, n (%)

Northern Sweden 1,417 (9) 590 (7) 9,926 (8)

Southeastern Sweden 1,816 (11) 923 (12) 13,572 (12)

Southern Sweden 3,030 (19) 1,518 (19) 22,390 (19)

Stockholm-Gotland 3,071 (19) 2,047 (26) 25,229 (21)

Uppsala-Örebro 3,489 (22) 1,592 (20) 25,216 (21)

Western Sweden 3,026 (19) 1,178 (15) 20,922 (18)

Unknown 102 (1) 50 (1) 572 (1)

Education, n (%)

≤9 years 2,829 (18) 1,540 (20) 21,030 (18)

10–12 years 7,121 (45) 3,473 (44) 50,542 (43)

≥13 years 5,563 (35) 2,430 (31) 41,092 (35)

Unknown 438 (3) 455 (6) 5,163 (4)

Number of encounters*, n

Inpatient 2 [0–4] 2 [0–4] 1 [0–3]

Outpatient 5 [2–11] 6 [2–13] 3 [1–9]

Calendar year

2007–2009 4,786 (30) 2,186 (28) 34,449 (29)

2010–2013 7,031 (44) 3,570 (45) 52,373 (44)

2014–2016 4,134 (26) 2,142 (27) 31,005 (26)

Values are median [IQR] or absolute figures (percentages). Polytomous variables may not sum to 100% due to rounding.

# includes ulcerative colitis, Crohn’s disease, and IBD-unclassified

* calculated the number of inpatient and outpatient encounters (continuous) for each participant during the study period up until the time of

matching/case diagnosis.

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Table 2.

Overall antibiotic use and inflammatory bowel disease comparing cases and their matched general population

controls, 2007–2016

Cumulative antibiotic use

No use 1 dispensation 2 dispensations ≥3 dispensations P-trend*

Inflammatory bowel disease (IBD) #

Cases, n (%) 9,677 (40) 4,813 (20) 3,087 (13) 6,405 (27)

Controls, n (%) 56,240 (48) 24,864 (21) 13,152 (11) 23,571 (20)

Unadjusted OR (95% CI)† 1·0 (ref) 1·14 (1·10, 1·19) 1·46 (1·40, 1·53) 1·78 (1·71,1·84) <·0001

Multivariable OR (95% CI)‡ 1·0 (ref) 1·11 (1·07, 1·15) 1·38 (1·32, 1·44) 1·55 (1·49, 1·61) <·0001

Ulcerative colitis (UC)

Cases, n (%) 6,587 (41) 3,274 (21) 2,004 (12) 4,086 (26)

Controls, n (%) 37,642 (48) 16,570 (21) 8,656 (11) 15,481 (20)

Unadjusted OR (95% CI) 1·0 (ref) 1·16 (1·11, 1·22) 1·39 (1·32, 1·47) 1·63 (1·55, 1·71) <·0001

Multivariable OR (95% CI) 1·0 (ref) 1·13 (1·08, 1·19) 1·33 (1·25, 1·41) 1·47 (1·40, 1·54) <·0001

Crohn’s disease (CD)

Cases, n (%) 3,030 (38) 1,521 (19) 1,061 (14) 2,286 (29)

Controls, n (%) 18,255 (47) 8,152 (21) 4,425 (11) 7,986 (21)

Unadjusted OR (95% CI) 1·0 (ref) 1·18 (1·10, 1·26) 1·56 (1·44, 1·69) 1·94 (1·81, 2·07) <·0001

Multivariable OR (95% CI) 1·0 (ref) 1·14 (1·06, 1·22) 1·46 (1·35, 1·58) 1·64 (1·53, 1·76) <·0001

Cumulative dispensations accrued from study baseline up until one year prior to diagnosis/match

Abbreviations: OR - odds ratio, CI - confidence interval

# Includes ulcerative colitis, Crohn’s disease, and IBD-unclassified

† Conditional logistic regression matched for age, sex, calendar year, and county

‡ Further adjusted for number of inpatient and outpatient encounters and education level

* Calculated using the median of each category as a continuous variable.

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Table 3.

Spectrum of antibiotic coverage and inflammatory bowel disease comparing cases and their matched general

population controls, 2007–2016

Cumulative antibiotic use

No prior use 1 prior dispensation 2 prior dispensations ≥3 prior dispensations P-interaction

Inflammatory bowel disease (IBD) #

Broad-spectrum antibiotics <0·0001

Cases, n (%) 9,677 (57) 3,690 (22) 1,592 (9) 2,040 (12)

Controls, n (%) 56,240 (66) 16,302 (19) 5,803 (7) 6,620 (8)

Multivariable OR (95% CI)‡ 1·0 (ref) 1·31 (1·25, 1·37) 1·58 (1·48, 1·68) 1·69 (1·59, 1·79)

Narrow-spectrum antibiotics

Cases n (%) 9,677 (44) 5,212 (24) 2,797 (13) 4,109 (19)

Controls n (%) 56,240 (52) 25,023 (23) 11,768 (11) 15,134 (14)

Multivariable OR (95% CI) 1·0 (ref) 1·18 (1·13, 1·22) 1·37 (1·30, 1·43) 1·49 (1·43, 1·56)

Ulcerative colitis (UC)

Broad-spectrum antibiotics <0·0001

Cases n (%) 6,587 (60) 2,440 (21) 1,015 (9) 1,299 (11)

Controls n (%) 37,642 (66) 10,934 (19) 3,873 (7) 4,465 (8)

Multivariable OR (95% CI) 1·0 (ref) 1·29 (1·22, 1·36) 1·50 (1·38, 1·63) 1·57 (1·45, 1·70)

Narrow-spectrum antibiotics

Cases n (%) 6,587 (45) 3,524 (24) 1,779 (11) 2,590 (18)

Controls n (%) 37,642 (52) 16,571 (23) 7,775 (11) 9,750 (14)

Multivariable OR (95% CI) 1·0 (ref) 1·20 (1·15, 1·26) 1·28 (1·21, 1·36) 1·43 (1·35, 1·52)

Crohn’s disease (CD)

Broad-spectrum antibiotics <0·0001

Cases n (%) 3,030 (54) 1,236 (22) 587 (11) 729 (13)

Controls n (%) 18,255 (66) 5,277 (19) 1,909 (7) 2,130 (8)

Multivariable OR (95% CI) 1·0 (ref) 1·40 (1·29, 1·52) 1·79 (1·60, 2·00) 1·78 (1·59, 1·99)

Narrow-spectrum antibiotics

Cases n (%) 3,030 (42) 1,667 (23) 1,003 (14) 1,497 (21)

Controls n (%) 18,255 (51) 8,310 (23) 3,933 (11) 5,317 (15)

Multivariable OR (95% CI) 1·0 (ref) 1·21 (1·13, 1·30) 1·50 (1·37, 1·63) 1·57 (1·44, 1·70)

Cumulative dispensations accrued from study baseline up until one year prior to diagnosis/match.

Abbreviations: OR - odds ratio, CI - confidence interval

# Includes ulcerative colitis, Crohn’s disease, and IBD-unclassified

† Conditional logistic regression matched for age, sex, and county. Referent group is no antibiotic use of any kind.

‡ Further adjusted for number of inpatient and outpatient encounters and education level

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Table 4:

Overall antibiotic use and inflammatory bowel disease comparing cases and their unaffected siblings, 2007–

2016

Cumulative antibiotic use

No prior use 1 prior dispensation 2 prior dispensations ≥3 prior dispensations P-trend

Inflammatory bowel disease (IBD) #

Cases, n (%) 6,502 (40) 3,407 (21) 2,170 (13) 4,274 (26)

Siblings, n (%) 12,688 (44) 6,278 (22) 3,341 (12) 6,425 (22)

Multivariable OR (95% CI)‡ 1·0 (ref) 1·06 (1·01, 1·12) 1·32 (1·24, 1·41) 1·35 (1·28, 1·43) <0·0001

Ulcerative colitis (UC)

Cases, n (%) 4,428 (41) 2,279 (21) 1,392 (13) 2,739 (25)

Siblings, n (%) 8,459 (45) 4,209 (22) 2,204 (11) 4,160 (22)

Multivariable OR (95% CI) 1·0 (ref) 1·06 (0·99, 1·14) 1·23 (1·13, 1·34) 1·29 (1·20, 1·39) <0·0001

Crohn’s disease (CD)

Cases, n (%) 2,036 (38) 1,117 (20) 762 (14) 1,514 (28)

Siblings, n (%) 4,073 (43) 2,030 (21) 1,111 (12) 2,221 (24)

Multivariable OR (95% CI) 1·0 (ref) 1·13 (1·02, 1·25) 1·41 (1·26, 1·58) 1·46 (1·23, 1·62) <0·0001

Cumulative dispensations accrued from study baseline up until one year prior to case diagnosis.

Abbreviations: OR - odds ratio, CI - confidence interval

# Includes ulcerative colitis, Crohn’s disease, and IBD-unclassified

‡ Further adjusted for age, sex, county, number of inpatient and outpatient encounters, and education level

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