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Irritable bowel syndrome and Parkinson’s disease risk:
register-based studies
1✉
Bojing Liu , Arvid Sjölander1, Nancy L. Pedersen1,2, Jonas F. Ludvigsson1,3,4,5, Honglei Chen6, Fang Fang7 and Karin Wirdefeldt1,8
To examine whether irritable bowel syndrome (IBS) was related to the future risk of Parkinson’s disease (PD), we conducted a
nested case-control study in the Swedish total population including 56,564 PD cases identified from the Swedish Patient Register
and 30 controls per case individually matched by sex and year of birth. Odds ratios (ORs) with 95% confidence intervals (CIs) for
having a prior diagnosis of IBS were estimated using conditional logistic regression. We furthermore conducted a cohort study
using the Swedish Twin Registry following 3046 IBS patients identified by self-reported abdominal symptoms and 41,179 non-IBS
individuals. Through Cox proportional hazard models, we estimated hazard ratios (HRs) and 95% CIs for PD risk. In the nested case-
control study, 253 (0.4%) PD cases and 5204 (0.3%) controls had a previous IBS diagnosis. IBS diagnosis was associated with a 44%
higher risk of PD (OR = 1.44, 95% CI 1.27–1.63). Temporal relationship analyses showed 53% and 38% increased risk of PD more
than 5 and 10 years after IBS diagnosis, respectively. In the cohort analysis based on the Swedish Twin Registry, there was no
statistically significantly increased risk of PD related to IBS (HR = 1.25, 95% CI = 0.87–1.81). Our results suggest a higher risk of PD
diagnosis after IBS. These results provide additional evidence supporting the importance of the gut–brain axis in PD.
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npj Parkinson’s Disease (2021)7:5 ; https://doi.org/10.1038/s41531-020-00145-8
INTRODUCTION altered bowel habits12,13. IBS is categorized into three subtypes
Parkinson’s disease (PD) is a neurodegenerative disease defined according to the predominant stool patterns, IBS-diarrhea, IBS-
by the cardinal motor symptoms tremor, bradykinesia, rigidity, constipation, and mixed IBS with both constipation and diar-
and postural imbalance1. PD is characterized by selective loss of rhea14. The pathogenesis of IBS is complex and traditionally
dopaminergic neurons in the substantia nigra pars compacta and focused on motility, visceral sensation, dysfunction of the
aggregations of α-synuclein in Lewy bodies and Lewy neurites1. gut–brain axis, and psychological stress, while recent evidence
The so-called gut–brain axis and associated inflammatory condi- has highlighted the involvement of altered gut microbiota,
tions have gained much attention in the etiology and pathogen- increased intestinal permeability, and immune activation, such
esis of PD2. Although still controversial, Braak’s hypothesis as low-grade mucosal inflammation12,13,15.
suggested that, in some PD patients, the pathology may first Few studies have examined the relationship between IBS and
start in the enteric nervous system (ENS) and later spread to the PD risk. One cohort study using data from the Taiwan National
central nervous system (CNS) via the vagus nerve3–5. In line with Health Insurance program reported a 48% higher risk of PD for IBS
this, constipation can occur prior to PD motor symptoms by patients16. However, the results are limited by short follow-up (
B. Liu et al.
2
for number of hospital visits, we found a 31% increased risk of
Table 1.Characteristics of Parkinson’s disease (PD) cases and controls
PD ≥5 years after IBS.
from Swedish total population 1987–2010, N = 1,753,484.
PD cases, N (%) Controls, N (%) OR (95% CI)a Cohort analysis in the Swedish Twin Registry
Characteristics of the twins in the Screening Across the Lifespan of
Total 56,564 (100) 1,696,920 (100) –
Twins Study (SALT) are shown in Table 3. At baseline, we identified
Sex 3046 individuals with IBS and 41,179 persons without based on
Male 31,807 (56.2) 954,210 (56.2) – self-reported abdominal symptoms. Female sex, older age, higher
Female 24,757 (43.8) 742,710 (43.8) – education level, alcohol consumption, and ever smokers were
Age at the index date, years more prevalent among people with IBS, while the comorbidity
12 7075 (12.5) 191,965 (11.3) 1 We examined the association between IBS and subsequent PD risk
Chronic obstructive pulmonary disease (COPD) in two complementary epidemiological databases, the nationwide
No 55,244 (97.7) 1,648,443 (97.1) 1 health registers and the Swedish Twin Registry. In the nationwide
Yes 1,320 (2.3) 48,477 (2.9) 0.81 (0.77–0.86) nested case-control study, we observed higher PD risk both ≥5
and ≥10 years after specialist IBS diagnosis. Statistical significance
Comorbidity index
of the associations remained in several sensitivity analyses. In the
0 33,514 (59.2) 1,061,214 (62.5) 1 twin cohort, self-reported symptom-based IBS was not statistically
1–2 17,447 (30.8) 480,548 (28.3) 1.16 (1.14–1.19) significantly associated with PD risk.
≥3 5,603 (9.9) 155,158 (9.1) 1.16 (1.13–1.20) Our results are consistent with a previous study that reported a
a 48% increased PD risk among IBS patients16. Similar to that
Conditional on birth year and sex matching pairs.
study16, we did not notice any difference by sex, but the
association appeared to be stronger for older (age at diagnosis
≥50 years) than younger (age at diagnosisB. Liu et al.
3
Table 2. Irritable bowel syndrome (IBS) diagnosis and risk of Parkinson’s disease (PD), nationwide case-control analysis.
PD cases Controls Model 1a Model 2b
N N OR (95% CI) OR (95% CI)
Non-IBS 56,311 (99.6) 1,691,716 (99.7) 1 1
IBS 253 (0.4) 5204 (0.3) 1.46 (1.29–1.66) 1.44 (1.27–1.63)
Years before index dateB. Liu et al.
4
Table 3. Characteristics of the cohort based on SALT Swedish twins,
N = 44,225.
IBS, N (%) Non-IBS, N (%) p-Valuea
Total 3046 (100) 41,179 (100)
SexB. Liu et al.
5
1–2, or ≥3 points) according to Deyo’s modification of the Charlson’s
Comorbidity Index47 (ICD codes in Supplementary Table 2).
Cohort study in the Swedish Twin Registry: Age at the interview was
categorized as ≤59, 60–69, 70–79, or ≥80 years. Information on educational
attainment (≤9, 10–12, >12 years, or unknown), smoking status (ever or
never), and alcohol consumption in the past month (yes or no) was
retrieved from the telephone interviews. Via linkage to the Patient Register,
we created the same variable as in the nested case-control study to
quantify comorbidities before the end of follow-up.
Statistical analysis
In the nested case-control study, the associations between IBS and PD risk
were expressed as odds ratios (ORs) with 95% confidence intervals (CIs)
estimated from conditional logistic regression. We performed analyses in
two steps: first, conditional on sex and birth year matched sets, and
second, additionally adjusted for country of birth, educational attainment,
COPD, and comorbidity index. We analyzed the IBS in relation to PD risk
during different time periods before the index date (B. Liu et al.
6
causal, with a large E-value indicating more robust results52. Second, to 15. Raskov, H., Burcharth, J., Pommergaard, H. C. & Rosenberg, J. Irritable bowel
examine the influence of potential surveillance bias, i.e. that patients with syndrome, the microbiota and the gut-brain axis. Gut Microbes 7, 365–383 (2016).
IBS had more frequent hospital admissions than those without and 16. Lai, S. W., Liao, K. F., Lin, C. L. & Sung, F. C. Irritable bowel syndrome correlates with
therefore were more likely to receive PD diagnosis, we further adjusted for increased risk of Parkinson’s disease in Taiwan. Eur. J. Epidemiol. 29, 57–62 (2014).
total number of hospital visits in quartiles (i.e. 0–1, 2–4, 5–9, and ≥10 visits 17. Liu, B. Parkinson’s Disease Etiology: Beyond the Brain and Late Adulthood. Ph.D.
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inpatient diagnosis34, we also conducted additional analyses restricting the 18. Mertsalmi, T. H. et al. More than constipation - bowel symptoms in Parkinson’s
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alpha of 0.05. Standardized survival curves were estimated and plotted in R stipation and irritable bowel syndrome in Parkinson’s disease patients according
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Health and Welfare and Statistics Sweden. We are not allowed to make the data systematic review and meta-analysis. Dig. Liver Dis. 51, 38–42 (2019).
publicly available according to the Swedish privacy laws. Request to access these 27. Park, S. et al. Patients with inflammatory bowel disease are at an increased risk of
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ACKNOWLEDGEMENTS
The study was supported by the Swedish Research Council (Grant Nos. 2013–02488,
2017–02175), the Karolinska Institutet-National Institutes of Health Doctoral Partner-
ship Program in Neuroscience, the Parkinson Research Foundation in Sweden, and
the Swedish Parkinson Foundation. F.F. is supported by the Senior Researcher Award Open Access This article is licensed under a Creative Commons
at Karolinska Institutet. H.C. is supported by a start-up fund from Michigan State Attribution 4.0 International License, which permits use, sharing,
University (GE100455), the Parkinson’s Foundation (Grant No. PF-IMP-1825), and the adaptation, distribution and reproduction in any medium or format, as long as you give
Office of the Assistant Secretary of Defense for Health Affairs, through the Parkinson’s appropriate credit to the original author(s) and the source, provide a link to the Creative
Research Program (Award No. W81XWH-17-1-0536). Commons license, and indicate if changes were made. The images or other third party
material in this article are included in the article’s Creative Commons license, unless
indicated otherwise in a credit line to the material. If material is not included in the
AUTHOR CONTRIBUTIONS article’s Creative Commons license and your intended use is not permitted by statutory
Study concept: K.W., H.C., and F.F.; Study design: K.W., F.F., H.C., B.L.; Data management, regulation or exceeds the permitted use, you will need to obtain permission directly
statistical analysis, and manuscript drafting: B.L.; Guidance on statistical analysis: from the copyright holder. To view a copy of this license, visit http://creativecommons.
A.S.; Interpretation of results and critical revision of the manuscript: all authors. org/licenses/by/4.0/.
FUNDING © The Author(s) 2021
Open Access funding provided by Karolinska Institute.
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