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Peng TR, Lin HH, Yang LJ, Huang YY, Wu TW, Chao YC. The impact of inflammatory bowel disease on dementia risk: a current systematic review and meta-analysis. Sci Rep 2025; 15:12852. [PMID: 40229330 PMCID: PMC11997168 DOI: 10.1038/s41598-025-96331-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Accepted: 03/27/2025] [Indexed: 04/16/2025] Open
Abstract
Emerging evidence indicates that inflammatory bowel disease (IBD) and dementia may share underlying pathological mechanisms and risk factors. However, the association between a prior IBD diagnosis and the subsequent risk of dementia remains largely unexplored. We conducted a comprehensive search of PubMed, Embase, and the Cochrane Library up to February 4, 2025, without language restrictions. Two reviewers independently extracted data and evaluated methodological quality and risk of bias. Observational studies comparing dementia risk in IBD and non-IBD populations were included. Pooled effect estimates for odds ratios (OR) were calculated using random-effects models. A total of 10 population-based studies, involving 7,895,339 participants (269,387 with IBD), were included. Meta-analysis of eight studies showed a significant association between IBD and dementia risk (OR 1.17, 95% CI: 1.08-1.27, P = 0.0001). However, IBD was not associated with an increased risk of Alzheimer's disease (AD) (OR 1.15, 95% CI: 0.98-1.36, P = 0.09). Stratified analysis by IBD type revealed a positive association between both ulcerative colitis (UC) and Crohn's disease (CD) and dementia risk (UC: OR 1.15, 95% CI: 1.05-1.25, P = 0.002, I² = 81%; CD: OR 1.26, 95% CI: 1.11-1.43, P = 0.0003, I² = 53%). This study identifies a significant correlation between IBD and dementia, suggesting that IBD patients have an elevated risk of developing dementia. However, current evidence is insufficient to establish a causal relationship. Further research should explore whether effective IBD treatments can mitigate this risk and elucidate the underlying pathophysiological mechanisms connecting these conditions.
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Affiliation(s)
- Tzu-Rong Peng
- Department of Pharmacy, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, No. 289, Jianguo Road, Xindian Dist., New Taipei City, 23142, Taiwan, ROC
| | - Hung-Hong Lin
- Department of Pharmacy, Chia-Nan University of Pharmacy and Science, Tainan, Taiwan, ROC
| | - Li-Jou Yang
- Department of Pharmacy, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, No. 289, Jianguo Road, Xindian Dist., New Taipei City, 23142, Taiwan, ROC
| | - Yu-Ying Huang
- Department of Pharmacy, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, No. 289, Jianguo Road, Xindian Dist., New Taipei City, 23142, Taiwan, ROC
| | - Ta-Wei Wu
- Department of Pharmacy, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, No. 289, Jianguo Road, Xindian Dist., New Taipei City, 23142, Taiwan, ROC.
| | - You-Chen Chao
- Department of Internal Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, No. 289, Jianguo Road, Xindian Dist., New Taipei City, 23142, Taiwan, ROC.
- School of Medicine, Tzu Chi University, Hualien, Taiwan, ROC.
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Escalante J, Artaiz O, Diwakarla S, McQuade RM. Leaky gut in systemic inflammation: exploring the link between gastrointestinal disorders and age-related diseases. GeroScience 2025; 47:1-22. [PMID: 39638978 PMCID: PMC11872833 DOI: 10.1007/s11357-024-01451-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 11/20/2024] [Indexed: 12/07/2024] Open
Abstract
Global average life expectancy has steadily increased over the last several decades and is projected to reach ~ 77 years by 2050. As it stands, the number of people > 60 years currently outnumbers children younger than 5 years, and by 2050, it is anticipated that the global population of people aged > 60 years will double, surpassing 2.1 billion. This demographic shift in our population is expected to have substantial consequences on health services globally due to the disease burden associated with aging. Osteoarthritis, chronic obstructive pulmonary disease, diabetes, cardiovascular disease, and cognitive decline associated with dementia are among the most common age-related diseases and contribute significantly to morbidity and mortality in the aged population. Many of these age-related diseases have been linked to chronic low-grade systemic inflammation which often accompanies aging. Gastrointestinal barrier dysfunction, also known as "leaky gut," has been shown to contribute to systemic inflammation in several diseases including inflammatory bowel disease and irritable bowel syndrome, but its role in the development and/or progression of chronic low-grade systemic inflammation during aging is unclear. This review outlines current literature on the leaky gut in aging, how leaky gut might contribute to systemic inflammation, and the links between gastrointestinal inflammatory diseases and common age-related diseases to provide insight into a potential relationship between the intestinal barrier and inflammation.
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Affiliation(s)
- Jonathan Escalante
- Gut-Barrier and Disease Laboratory, Department of Anatomy and Physiology, The University of Melbourne, Melbourne, VIC, 3021, Australia
| | - Olivia Artaiz
- Gut-Barrier and Disease Laboratory, Department of Anatomy and Physiology, The University of Melbourne, Melbourne, VIC, 3021, Australia
| | - Shanti Diwakarla
- Gut-Barrier and Disease Laboratory, Department of Anatomy and Physiology, The University of Melbourne, Melbourne, VIC, 3021, Australia
- The Florey Institute of Neuroscience and Mental Health, Parkville, VIC, 3010, Australia
| | - Rachel M McQuade
- Gut-Barrier and Disease Laboratory, Department of Anatomy and Physiology, The University of Melbourne, Melbourne, VIC, 3021, Australia.
- The Florey Institute of Neuroscience and Mental Health, Parkville, VIC, 3010, Australia.
- Australian Institute for Musculoskeletal Science (AIMSS), The Melbourne University and Western Health, Melbourne, VIC, 3021, Australia.
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Liao OL, Xie SY, Ye J, Du Q, Lou GC. Association between inflammatory bowel disease and all-cause dementia: A two-sample Mendelian randomization study. World J Psychiatry 2024; 14:15-25. [PMID: 38327884 PMCID: PMC10845233 DOI: 10.5498/wjp.v14.i1.15] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 12/03/2023] [Accepted: 12/26/2023] [Indexed: 01/19/2024] Open
Abstract
BACKGROUND Numerous observational studies have documented a correlation between inflammatory bowel disease (IBD) and an increased risk of dementia. However, the causality of their associations remains elusive. AIM To assess the causal relationship between IBD and the occurrence of all-cause dementia using the two-sample Mendelian randomization (MR) method. METHODS Genetic variants extracted from the large genome-wide association study (GWAS) for IBD (the International IBD Genetics Consortium, n = 34652) were used to identify the causal link between IBD and dementia (FinnGen, n = 306102). The results of the study were validated via another IBD GWAS (United Kingdom Biobank, n = 463372). Moreover, MR egger intercept, MR pleiotropy residual sum and outlier, and Cochran's Q test were employed to evaluate pleiotropy and heterogeneity. Finally, multiple MR methods were performed to estimate the effects of genetically predicted IBD on dementia, with the inverse variance wei-ghted approach adopted as the primary analysis. RESULTS The results of the pleiotropy and heterogeneity tests revealed an absence of significant pleiotropic effects or heterogeneity across all genetic variants in outcome GWAS. No evidence of a causal effect between IBD and the risk of dementia was identified in the inverse variance weighted [odds ratio (OR) = 0.980, 95%CI : 0.942-1.020, P value = 0.325], weighted median (OR = 0.964, 95%CI : 0.914-1.017, P value = 0.180), and MR-Egger (OR = 0.963, 95%CI : 0.867-1.070, P value = 0.492) approaches. Consistent results were observed in validation analyses. Reverse MR analysis also showed no effect of dementia on the development of IBD. Furthermore, MR analysis suggested that IBD and its subtypes did not causally affect all-cause dementia and its four subtypes, including dementia in Alzheimer's disease, vascular dementia, dementia in other diseases classified elsewhere, and unspecified dementia. CONCLUSION Taken together, our MR study signaled that IBD and its subentities were not genetically associated with all-cause dementia or its subtypes. Further large prospective studies are warranted to elucidate the impact of intestinal inflammation on the development of dementia.
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Affiliation(s)
- Ou-Lan Liao
- Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
- Department of Gastroenterology, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu 322000, Zhejiang Province, China
| | - Si-Yuan Xie
- Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
| | - Jun Ye
- Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
| | - Qin Du
- Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
- Department of Gastroenterology, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu 322000, Zhejiang Province, China
| | - Guo-Chun Lou
- Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
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Fan JS, Wang M, Chen N, Sun BC, Zhang QB, Li Y, Huang MJ. Association between inflammatory bowel disease and risk of stroke: a systematic review and meta-analysis of cohort studies. Front Neurol 2023; 14:1204727. [PMID: 38046580 PMCID: PMC10693426 DOI: 10.3389/fneur.2023.1204727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 10/25/2023] [Indexed: 12/05/2023] Open
Abstract
Background/objectives Recently, four meta-analyses have explored the association between inflammatory bowel disease (IBD) and the risk of stroke. These studies have demonstrated that people with IBD may be at an increased risk of stroke. However, some limitations such as high heterogeneity and the lack of uniformity in the types of research, especially the reuse of some sample sizes, cannot be neglected. These factors reduce the credibility of their research conclusions. Therefore, we conducted a meta-analysis to explore this possible association. Methods PubMed, Embase, and Web of Science were searched from inception to 30 June 2023. A random effects model with the generic inverse variance method was used in this meta-analysis. The Review Manager software was used to obtain all relative risks (RRs) and their 95% confidence intervals (CIs). Publication bias was tested, and sensitivity and subgroup analyses were conducted to explore possible heterogeneities. Results This meta-analysis included 12 cohort studies (involving 4,495,055 individuals). Meta-analysis of these data has shown that IBD was associated with an increased risk of stroke (RR = 1.19, 95%CI:1.14-1.24, p < 0.00001). Our results were stable and robust in subgroup and sensitivity analyses. Conclusions Our results suggest that IBD is associated with an increased risk of stroke. To reduce the incidence of stroke, patients with IBD are encouraged to undergo stroke risk assessments, especially for young female patients; assessing the risk of ischemic stroke is of particular importance. Prospective studies considering stroke subtypes, IBD severity and treatments, regions, and other confounding factors are needed to further explore the nature of each association. Systematic review registration https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022373656.
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Affiliation(s)
- Jin-Shan Fan
- Department of Intensive Care Unit (ICU), Qian Jiang Central Hospital of Hubei Province, Qian Jiang Hospital Affiliated to Renmin Hospital of Wuhan University, Qian Jiang Clinical Medical College, Health Science Center, Yangtze University, Qianjiang, China
| | - Meng Wang
- Department of Neurology, The Third Clinical Medical College of China, Three Gorges University, Gezhouba Central Hospital of Sinopharm, Yichang, China
| | - Ni Chen
- Department of Ophthalmology, The Third Clinical Medical College of China, Three Gorges University, Gezhouba Central Hospital of Sinopharm, Yichang, China
| | - Bai-chao Sun
- Department of Ophthalmology, The Third Clinical Medical College of China, Three Gorges University, Gezhouba Central Hospital of Sinopharm, Yichang, China
| | - Qi-Bing Zhang
- Department of Neurology, The Third Clinical Medical College of China, Three Gorges University, Gezhouba Central Hospital of Sinopharm, Yichang, China
| | - Yong Li
- Department of Neurology, The Third Clinical Medical College of China, Three Gorges University, Gezhouba Central Hospital of Sinopharm, Yichang, China
| | - Ming-Jie Huang
- Department of Ophthalmology, The Third Clinical Medical College of China, Three Gorges University, Gezhouba Central Hospital of Sinopharm, Yichang, China
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Kim JS, Chen MH, Wang HE, Lu CL, Wang YP, Zhang B. Inflammatory Bowel Disease and Neurodegenerative Diseases. Gut Liver 2023; 17:495-504. [PMID: 36843420 PMCID: PMC10352055 DOI: 10.5009/gnl220523] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 01/08/2023] [Accepted: 01/12/2023] [Indexed: 02/28/2023] Open
Abstract
A growing body of evidence has demonstrated an intricate association between inflammatory bowel disease (IBD) and neurodegenerative conditions, expanding beyond previous foci of comorbidities between IBD and mood disorders. These new discoveries stem from an improved understanding of the gut-microbiome-brain axis: specifically, the ability of the intestinal microbiota to modulate inflammation and regulate neuromodulatory compounds. Clinical retrospective studies incorporating large sample sizes and population-based cohorts have demonstrated and confirmed the relevance of IBD and chronic neurodegeneration in clinical medicine. In this review, we expound upon the current knowledge on the gut-microbiome-brain axis, highlighting several plausible mechanisms linking IBD with neurodegeneration. We also summarize the known associations between IBD with Parkinson disease, Alzheimer disease, vascular dementia and ischemic stroke, and multiple sclerosis in a clinical context. Finally, we discuss the implications of an improved understanding of the gut-microbiome-brain axis in preventing, diagnosing, and managing neurodegeneration among IBD and non-IBD patients.
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Affiliation(s)
- Jin Sun Kim
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA
| | - Mu-Hong Chen
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan
- Division of Psychiatry, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Institute of Brain Science, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Hohui E. Wang
- Department of Psychiatry, University of California San Francisco, San Francisco, CA, USA
| | - Ching-Liang Lu
- Institute of Brain Science, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Endoscopy Center for Diagnosis and Treatment, Taipei Veterans General Hospital, Taipei, Taiwan
- Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yen-Po Wang
- Institute of Brain Science, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Endoscopy Center for Diagnosis and Treatment, Taipei Veterans General Hospital, Taipei, Taiwan
- Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Bing Zhang
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA
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Xing Y, Li P, Jia Y, Zhang K, Liu M, Jiang J. Association of inflammatory bowel disease and related medication exposure with risk of Alzheimer's disease: An updated meta-analysis. Front Aging Neurosci 2023; 14:1082575. [PMID: 36711203 PMCID: PMC9878281 DOI: 10.3389/fnagi.2022.1082575] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 12/29/2022] [Indexed: 01/13/2023] Open
Abstract
Background Chronic systemic inflammation may be associated with neurocognitive decline, but the relationships between inflammatory bowel disease and related medications and the risk of Alzheimer's disease remain unclear. Methods We performed a meta-analysis to evaluate the associations of ulcerative colitis, Crohn's disease and related medications with risk of Alzheimer's disease. We identified cohort and case-control studies by searching PubMed, Embase and Web of Science up to August 2022. Results Seven eligible studies with 20,174 cases of Alzheimer's disease were included in the meta-analysis. Six studies reported the association between ulcerative colitis and risk of Alzheimer's disease; five studies reported the association between Crohn's disease and risk of Alzheimer's disease. Meta-analysis combining these studies did not reveal any significant association of ulcerative colitis or Crohn's disease with risk of Alzheimer's disease. The pooled relative risks were 1.16 (95%CI: 0.96, 1.41) and 1.17 (95%CI: 0.84, 1.62) for ulcerative colitis and Crohn's disease, respectively. High heterogeneity was detected across the studies. Of note, there was an inverse association between inflammatory bowel disease related medication exposure and risk of Alzheimer's disease. The pooled relative risk of three studies for Alzheimer's disease was 0.86 (95%CI: 0.75, 0.99). No publication bias was detected. Conclusion This study does not support the association of ulcerative colitis and Crohn's disease with the risk of Alzheimer's disease. However, medications for the treatment of inflammatory bowel disease might be associated with a lower risk of Alzheimer's disease.
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Liu N, Wang Y, He L, Sun J, Wang X, Li H. Inflammatory bowel disease and risk of dementia: An updated meta-analysis. Front Aging Neurosci 2022; 14:962681. [PMID: 36275009 PMCID: PMC9581261 DOI: 10.3389/fnagi.2022.962681] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Accepted: 08/29/2022] [Indexed: 11/17/2022] Open
Abstract
Background Growing evidence suggests that inflammatory bowel disease (IBD) and dementia share pathological mechanisms and pathogenic risk factors. However, the previously diagnosed IBD and the subsequent risk of developing dementia are largely unknown. Aim The purpose of this review is to assess the association between IBD and subsequent dementia diagnosis. Methods We searched PubMed, Embase, and Cochrane library from database inception to February 1, 2022. Two reviewers independently extracted data and assessed methodological quality and risk of bias. Observational study that reported the possibility of dementia in IBD and non-IBD populations were included. Eligible studies were pooled effect estimates for relative risk (RR) through fixed-or random-effects models as appropriate. Results More than 3,181,549 participants from nine studies met the inclusion criteria. Previous IBD diagnosis did not increased the risk of subsequent all-cause dementia (RR, 1.32; 95% CI, 0.98–1.77) and AD-dementia (RR, 1.62; 95% CI, 0.96–2.76). Subgroup analyses based on study design indicated that cohort studies (RR, 1.30; 95% CI, 1.09–1.55) reported an increased risk of all-cause dementia, but were not applicable to AD-dementia (RR, 1.27; 95% CI, 0.94–1.72). Positive associations between IBD patients and all-cause dementia did not differ by age and gender in cohort studies. Both ulcerative colitis (UC) (RR, 1.39; 95% CI, 1.00–1.94) and Crohn’s disease (RR, 1.46; 95% CI, 1.08–1.98) are associated with increased risk of all-cause dementia. Conclusion Evidence regarding dementia risk assessment in IBD patients is conflicting, which may be influenced by study design. More prospective cohort studies are needed to determine their relationship. Systematic review registration [https://www.prosper-isd.net], identifier [CRD42021284116].
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Affiliation(s)
- Nanyang Liu
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yi Wang
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - Lanye He
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jiahui Sun
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - Xing Wang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- *Correspondence: Xing Wang,
| | - Hao Li
- Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Hao Li,
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Lima CCG, Peerani F. Editorial: IBD and the risk of dementia - the jury is still out. Aliment Pharmacol Ther 2022; 56:1078-1079. [PMID: 35995748 DOI: 10.1111/apt.17141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Affiliation(s)
- Camila Cunha Gonzaga Lima
- Division of Gastroenterology and Hepatology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
| | - Farhad Peerani
- Division of Gastroenterology and Hepatology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
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