강지승 (GIST, Harvard Medical School)

한빛사논문

조회1,073

GIST, Harvard Medical School

CV File 142 kb

J. Adv. Res., 13 December 2023 | https://doi.org/10.1016/j.jare.2023.12.010 Slow gut transit increases the risk of Alzheimer’s disease: an integrated study of the bi-national cohort in South Korea and Japan and Alzheimer’s disease model mice

Jiseung Kang ^a,b,c,1, Myeongcheol Lee ^d,e,1, Mincheol Park ^a, Jibeom Lee ^a, Sunjae Lee ^f, Jaeyu Park ^d,e, Ai Koyanagi ^g,h, Lee Smithⁱ, Christa J Nehs ^b,c, Dong Keon Yon ^d,e,j, Tae Kim ^a

^aDepartment of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea

^bDepartment of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States

^cDivision of sleep medicine, Harvard Medical School, Boston, Massachusetts, United States

^dCenter for Digital Health, Medical Science Research Institute, Kyung Hee University Medical Center, Kyung Hee University College of Medicine, Seoul, Republic of Korea

^eDepartment of Regulatory Science, Kyung Hee University, Seoul, Republic of Korea

^fSchool of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea

^gResearch and Development Unit, Parc Sanitari Sant Joan de Deu, CIBERSAM, ISCIII, Barcelona, Spain

^hCatalan Institution for Research and Advanced Studies (ICREA), Pg. Lluis Companys, Barcelona, Spain

ⁱCentre for Health, Performance and Wellbeing, Anglia Ruskin University, Cambridge, UK

^jDepartment of Pediatrics, Kyung Hee University Medical Center, Kyung Hee University College of Medicine, Seoul, Republic of Korea

¹These authors contributed equally to this work.

Corresponding authors : Dong Keon Yon, Tae Kim

Abstract

Introduction

Although the association between Alzheimer's disease (AD) and constipation is controversial, its casualty and underlying mechanisms remain unknown.

Objectives

To investigate the potential association between slow gut transit and AD using epidemiological data and a murine model.

Methods

We conducted a bi-national cohort study in South Korea (discovery cohort, n=3,130,193) and Japan (validation cohort, n=4,379,285) during the pre-observation period to determine the previous diagnostic history (2009-2010) and the follow-up period (2011-2021). To evaluate the causality, we induced slow gut transit using loperamide in 5xFAD transgenic mice. Changes in amyloid-beta (Aβ) and other markers were examined using ELISA, qRT-PCR, RNA-seq, and behavioral tests.

Results

Constipation was associated with an increased risk of AD in the discovery cohort (hazard ratio, 2.04; 95% confidence interval [CI], 2.01–2.07) and the validation cohort (hazard ratio; 2.82; 95% CI, 2.61–3.05). We found that loperamide induced slower gut transit in 5xFAD mice, increased Aβ and microglia levels in the brain, increased transcription of genes related to norepinephrine secretion and immune responses, and decreased the transcription of defense against bacteria in the colonic tissue.

Conclusion

Impaired gut transit may contribute to AD pathogenesis via the gut-brain axis, thus suggesting a cyclical relationship between intestinal barrier disruption and Aβ accumulation in the brain. We propose that gut transit or motility may be a modifiable lifestyle factor in the prevention of AD, and further clinical investigations are warranted.

논문정보

형식Research article
게재일2023년 12월 (BRIC 등록일 2023-12-14)
연구진국내 연구진
분야 바이오·의료융합 > 다학제 융합/복합

댓글 작성 로그인

CV 열람하기

연락처 보기