Irritable Bowel Syndrome Is Associated with an Increased Risk of Dementia: A Nationwide Population-Based Study

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Abstract

Purpose

Abnormal interaction in the brain–gut axis has emerged as one of the relevant pathophysiological mechanisms for the development of irritable bowel syndrome (IBS). Moreover, the brain–gut axis has recently been demonstrated to be crucial for the maintenance of cognitive performance. Therefore, we assessed the risk of dementia following diagnosis of IBS.

Methods

Using the Taiwan National Health Insurance Research Database (NHIRD) to obtain medical claims data from 2000 to 2011, we employed a random sampling method to enroll32 298 adult patients with IBS and frequency-matched them according to sex, age, and baseline year with 129 192 patients without IBS.

Results

The patients with IBS exhibited an increased risk of dementia [adjusted hazard ratio (aHR) = 1.26, 95% confidence interval (CI) = 1.17–1.35]after adjustment for age, sex, diabetes, hypertension, stroke, coronary artery disease (CAD), head injury, depression, and epilepsy, and the overall incidence of dementia for the cohorts with and without IBS was 4.86 and 3.41 per 1000 person-years, respectively. IBS was associated with an increased risk of dementia in patients older than 50 years in both male and female, and in those with comorbidity or without comorbidity. After adjustment for age, sex, and comorbidity, patients with IBS were also more likely to develop either non- Alzheimer’s disease (AD) dementia (aHR = 1.24, 95% CI = 1.15–1.33) or AD (aHR = 1.76, 95% CI = 1.28–2.43).

Conclusions

IBS is associated with an increased risk of dementia, and this effect is obvious only in patients who are ≥50 years old.

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Most cited references 18

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Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation

Jae-Woong Lee, Yong Kyung Lee, Dong Yuk … (2008)

Background Alzheimer's disease (AD) is characterized by extensive loss of neurons in the brain of AD patients. Intracellular accumulation of beta-amyloid peptide (Aβ) has also shown to occur in AD. Neuro-inflammation has been known to play a role in the pathogenesis of AD. Methods In this study, we investigated neuro-inflammation and amyloidogenesis and memory impairment following the systemic inflammation generated by lipopolysaccharide (LPS) using immunohistochemistry, ELISA, behavioral tests and Western blotting. Results Intraperitoneal injection of LPS, (250 μg/kg) induced memory impairment determined by passive avoidance and water maze tests in mice. Repeated injection of LPS (250 μg/kg, 3 or 7 times) resulted in an accumulation of Aβ1–42 in the hippocampus and cerebralcortex of mice brains through increased β- and γ-secretase activities accompanied with the increased expression of amyloid precursor protein (APP), 99-residue carboxy-terminal fragment of APP (C99) and generation of Aβ1–42 as well as activation of astrocytes in vivo. 3 weeks of pretreatment of sulindac sulfide (3.75 and 7.5 mg/kg, orally), an anti-inflammatory agent, suppressed the LPS-induced amyloidogenesis, memory dysfunction as well as neuronal cell death in vivo. Sulindac sulfide (12.5–50 μM) also suppressed LPS (1 μg/ml)-induced amyloidogenesis in cultured neurons and astrocytes in vitro. Conclusion This study suggests that neuro-inflammatory reaction could contribute to AD pathology, and anti-inflammatory agent could be useful for the prevention of AD.

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Quantitative meta-analysis identifies brain regions activated during rectal distension in irritable bowel syndrome.

Kirsten Tillisch, Emeran Mayer, Jennifer S. Labus (2011)

The responsiveness of the central nervous system is altered in patients with irritable bowel syndrome (IBS). However, because of variations in experimental paradigms, analytic techniques, and reporting practices, little consensus exists on brain responses to visceral stimulation. We aimed to identify brain regions consistently activated by supraliminal rectal stimulation in IBS patients and healthy subjects (controls) by performing a quantitative meta-analysis of published studies. Significant foci from within-group statistical parametric maps were extracted from published neuroimaging studies that employed rectal distension. Voxel-based activation likelihood estimation was applied, pooling the results and comparing them across groups. Across studies, there was consistent activation in regions associated with visceral afferent processing (ie, thalamus, insula, anterior midcingulate) among IBS patients and controls, but considerable differences in the extent and specific location of foci. IBS patients differed from controls in that there were more consistent activations in regions associated with emotional arousal (pregenual anterior cingulate cortex, amygdala) and activation of a midbrain cluster, a region playing a role in endogenous pain modulation. Controls showed more consistent activation of the medial and lateral prefrontal cortex. Patients with IBS have greater engagement of regions associated with emotional arousal and endogenous pain modulation, but similar activation of regions involved in processing of visceral afferent information. Controls have greater engagement of cognitive modulatory regions. These results support a role for central nervous system dysregulation in IBS. These findings provide specific targets for guiding development of future neuroimaging protocols to more clearly define altered brain-gut interactions in IBS. Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

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Neuroinflammation, oxidative stress and the pathogenesis of Alzheimer's disease.

Rodrigo A. Cunha, Catarina de Oliveira, Paula Agostinho (2009)

Alzheimer's disease (AD) is the most common neurodegenerative disorder that affects the elderly. The increase of life-expectancy is transforming AD into a major health-care problem. AD is characterized by a progressive impairment of memory and other cognitive skills leading to dementia. The major pathogenic factor associated to AD seems to be amyloid-beta peptide (Aβ) oligomers that tend to accumulate extracellularly as amyloid deposits and are associated with reactive microglia and astrocytes as well as with degeneration of neuronal processes. The involvement of microglia and astrocytes in the onset and progress of neurodegenerative process in AD is becoming increasingly recognized, albeit it is commonly accepted that neuroinflammation and oxidative stress can have both detrimental and beneficial influences on the neural tissue. However, little is known about the interplay of microglia, astrocytes and neurons in response to Aβ, especially in the early phases of AD. This review discusses current knowledge about the involvement of neuroinflammation in AD pathogenesis, focusing on phenotypic and functional responses of microglia, astrocytes and neurons in this process. The abnormal production by glia cells of pro-inflammatory cytokines, chemokines and the complement system, as well as reactive oxygen and nitrogen species, can disrupt nerve terminals activity causing dysfunction and loss of synapses, which correlates with memory decline; these are phenomena preceding the neuronal death associated with late stages of AD. Thus, therapeutic strategies directed at controlling the activation of microglia and astrocytes and the excessive production of pro-inflammatory and pro-oxidant factors may be valuable to control neurodegeneration in dementia.

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Author and article information

Contributors

Andreas Stengel: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 5 January 2016

Publication date Collection: 2016

Volume: 11

Issue: 1

Electronic Location Identifier: e0144589

Affiliations

[1 ]Digestive Disease Center, Show-Chwan Memorial Hospital, Changhua, Taiwan

[2 ]Hungkuang University, Taichung, Taiwan

[3 ]Meiho University of Technology, Pingtung, Taiwan

[4 ]Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan

[5 ]College of Medicine, China Medical University, Taichung, Taiwan

[6 ]Graduate Institute of Clinical Medical Science, School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan

[7 ]Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan

Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, GERMANY

Author notes

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: C-HC C-HK. Analyzed the data: C-HC C-LL C-HK. Wrote the paper: C-HC C-LL C-HK. Administrative support: C-HK; Collection and assembly of data: C-HC C-LL C-HK; Final approval of manuscript: C-HC C-LL C-HKao.

* E-mail: d10040@ 123456mail.cmuh.org.tw

Article

Publisher ID: PONE-D-15-38462

DOI: 10.1371/journal.pone.0144589

PMC ID: 4701489

PubMed ID: 26731277

SO-VID: 5465f5de-742c-4e11-929f-6acd66ee287c

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

History

Date received : 2 September 2015

Date accepted : 15 October 2015

Page count

Figures: 1, Tables: 4, Pages: 12

Funding

This study is supported in part by Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW104-TDU-B-212-113002); China Medical University Hospital, Academia Sinica Taiwan Biobank, Stroke Biosignature Project (BM104010092); NRPB Stroke Clinical Trial Consortium (MOST 103-2325-B-039 -006); Tseng-Lien Lin Foundation, Taichung, Taiwan; Taiwan Brain Disease Foundation, Taipei, Taiwan; Katsuzo and Kiyo Aoshima Memorial Funds, Japan; and CMU under the Aim for Top University Plan of the Ministry of Education, Taiwan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study.

Custom metadata

Data Availability All data and related metadata were deposited in an appropriate public repository. The data on the study population that were obtained from the NHIRD ( http://w3.nhri.org.tw/nhird/date_01.html) are maintained in the NHIRD ( http://nhird.nhri.org.tw/).

Irritable Bowel Syndrome Is Associated with an Increased Risk of Dementia: A Nationwide Population-Based Study

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Abstract

Purpose

Methods

Results

Conclusions

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PLOS Climate

Most cited references 18

Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation

Quantitative meta-analysis identifies brain regions activated during rectal distension in irritable bowel syndrome.

Neuroinflammation, oxidative stress and the pathogenesis of Alzheimer's disease.

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