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.

Autor:	Kang J; Department 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 States., Lee M; Center 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., Park M; Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea., Lee J; Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea., Lee S; School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea., Park J; Center 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., Koyanagi A; Research and Development Unit, Parc Sanitari Sant Joan de Deu, Barcelona, Spain., Smith L; Centre for Health, Performance and Wellbeing, Anglia Ruskin University, Cambridge, UK., Nehs CJ; 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 States., Yon DK; Center 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. Electronic address: yonkkang@gmail.com., Kim T; Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea. Electronic address: tae-kim@gist.ac.kr.
Jazyk:	angličtina
Zdroj:	Journal of advanced research [J Adv Res] 2024 Nov; Vol. 65, pp. 283-295. Date of Electronic Publication: 2023 Dec 13.
DOI:	10.1016/j.jare.2023.12.010
Abstrakt:	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. Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2024. Production and hosting by Elsevier B.V.)
Databáze:	MEDLINE
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