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
Introduction: Although the association between Alzheimer's disease (AD) and constipation is controversial, its causality and underlying mechanisms remain unknown. Objectives: To investigate the potential association between slow gut transit and AD using epidemiological data and a murine model....
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| Language: | English |
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Elsevier
2024-11-01
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| Series: | Journal of Advanced Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2090123223003971 |
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| author | Jiseung Kang Myeongcheol Lee Mincheol Park Jibeom Lee Sunjae Lee Jaeyu Park Ai Koyanagi Lee Smith Christa J. Nehs Dong Keon Yon Tae Kim |
| author_facet | Jiseung Kang Myeongcheol Lee Mincheol Park Jibeom Lee Sunjae Lee Jaeyu Park Ai Koyanagi Lee Smith Christa J. Nehs Dong Keon Yon Tae Kim |
| author_sort | Jiseung Kang |
| collection | DOAJ |
| description | Introduction: Although the association between Alzheimer's disease (AD) and constipation is controversial, its causality 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. |
| format | Article |
| id | doaj-art-aa75581117624fbeb9fc64db0e965438 |
| institution | OA Journals |
| issn | 2090-1232 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Advanced Research |
| spelling | doaj-art-aa75581117624fbeb9fc64db0e9654382025-08-20T01:48:03ZengElsevierJournal of Advanced Research2090-12322024-11-016528329510.1016/j.jare.2023.12.010Slow 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 miceJiseung Kang0Myeongcheol Lee1Mincheol Park2Jibeom Lee3Sunjae Lee4Jaeyu Park5Ai Koyanagi6Lee Smith7Christa J. Nehs8Dong Keon Yon9Tae Kim10Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea; Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA, United States; Division of Sleep Medicine, Harvard Medical School, Boston, MA, United StatesCenter for Digital Health, Medical Science Research Institute, Kyung Hee University Medical Center, Kyung Hee University College of Medicine, Seoul, Republic of Korea; Department of Regulatory Science, Kyung Hee University, Seoul, Republic of KoreaDepartment of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Republic of KoreaDepartment of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Republic of KoreaSchool of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Republic of KoreaCenter for Digital Health, Medical Science Research Institute, Kyung Hee University Medical Center, Kyung Hee University College of Medicine, Seoul, Republic of Korea; Department of Regulatory Science, Kyung Hee University, Seoul, Republic of KoreaResearch and Development Unit, Parc Sanitari Sant Joan de Deu, Barcelona, SpainCentre for Health, Performance and Wellbeing, Anglia Ruskin University, Cambridge, UKDepartment of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA, United States; Division of Sleep Medicine, Harvard Medical School, Boston, MA, United StatesCenter for Digital Health, Medical Science Research Institute, Kyung Hee University Medical Center, Kyung Hee University College of Medicine, Seoul, Republic of Korea; Department of Regulatory Science, Kyung Hee University, Seoul, Republic of Korea; Department of Pediatrics, Kyung Hee University Medical Center, Kyung Hee University College of Medicine, Seoul, Republic of Korea; Corresponding authors at: Center for Digital Health, Medical Science Research Institute, Kyung Hee University Medical Center, Kyung Hee University College of Medicine, Seoul, Republic of Korea (D. K. Yon); Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea (T. Kim).Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea; Corresponding authors at: Center for Digital Health, Medical Science Research Institute, Kyung Hee University Medical Center, Kyung Hee University College of Medicine, Seoul, Republic of Korea (D. K. Yon); Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea (T. Kim).Introduction: Although the association between Alzheimer's disease (AD) and constipation is controversial, its causality 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.http://www.sciencedirect.com/science/article/pii/S2090123223003971Alzheimer’s diseaseCohortConstipationEpidemiological dataMouse modelGut-brain axis |
| spellingShingle | Jiseung Kang Myeongcheol Lee Mincheol Park Jibeom Lee Sunjae Lee Jaeyu Park Ai Koyanagi Lee Smith Christa J. Nehs Dong Keon Yon Tae Kim 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 Journal of Advanced Research Alzheimer’s disease Cohort Constipation Epidemiological data Mouse model Gut-brain axis |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | Alzheimer’s disease Cohort Constipation Epidemiological data Mouse model Gut-brain axis |
| url | http://www.sciencedirect.com/science/article/pii/S2090123223003971 |
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