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In the past decade, research into the bidirectional connection between the gut and the brain has upended our understanding of these two organs by associating central nervous system (CNS) functions like emotions and cognition with peripheral intestinal function. This crosstalk in communication has piqued the interest of researchers studying neurodegenerative diseases like Alzheimer’s and cognitive decline.¹

Multiple studies have found that older adults living with chronic gastrointestinal inflammation may develop dementia earlier than those who do not have the condition. Specifically, several large population-based studies found that inflammatory bowel disease (IBD) may be linked to a 1.12 to 2-fold increased risk of developing dementia, with onset at a younger age than that of the general population.^2,3

This study compared the risk for dementia in 1,742 adults (age 45 and older) with IBD and 17,420 controls matched for sex, access to health care, and dementia-related comorbid conditions.² During cognitive health follow-up evaluations over the course of 16 years, the rate of dementia diagnosis was almost four times higher in patients with IBD than in controls. In addition, IBD patients were diagnosed with dementia at the mean age of 76.2 years versus the average age of 83.5 years among controls. Among dementia types, the risk of developing Alzheimer’s dementia demonstrated the greatest increase, and disease risk appeared to increase with IBD chronicity—meaning that dementia risk appeared to be associated with early IBD diagnosis.²

Research in 2021 supports these findings, with some subtle differences.³ A retrospective cohort study included patients aged over 60 with an initial diagnosis of IBD (Crohn’s disease (CD) or ulcerative colitis (UC)) who were followed in 1,159 German general practices between January 1995 and December 2014. The study included 3,850 patients with and 3,850 patients without IBD and revealed a higher cumulative incidence of dementia in IBD patients than in non-IBD patients after the follow-up period. However, the cumulative incidence of dementia differed within IBD subtypes; it was significantly higher in UC patients than in CD patients. Models showed that IBD is associated with a 1.22-fold increase in the risk (95% CI: 1.07-1.39) of developing dementia. UC patients had a 1.25-fold higher risk of developing dementia (95% CI: 1.07-1.46), while CD was not significantly associated with an increased risk of dementia (HR: 1.17, 95% CI: 0.93-1.47).³

Approximately 30% of IBD patients develop symptoms of the disease before the age of 21 years.⁴ These findings suggest a role for the gut-brain axis in dementia development, with the disruption of the intestinal epithelial barrier and the microbial imbalance that are associated with IBD potentially facilitating the passage of gut microbial-derived neurotoxic metabolites into the central nervous system.² The gut-brain axis is the bidirectional communication between the gut and the brain, which occurs through multiple pathways that include hormonal, neural, and immune mediators.⁵ Scientists are beginning to unravel whether brain and behavioral alterations precede gut dysfunction and dysbiosis or vice versa.⁵

Results from studies like this suggest that inflammation may be a key factor in disease development along the gut-brain axis and indicate that chronic inflammation and an imbalance in gut bacteria may contribute to cognitive decline. Other human and animal studies suggest that IBD often presents with an increased incidence of psychiatric disorders and cognitive dysfunction.^6-9

A systematic review and meta-analysis of the population-based studies on dementia and IBD was undertaken in 2022, evaluating the mounting evidence that suggests that there may be a causal relationship or common pathogenic pathway between IBD and dementia.¹⁰ The results, an analysis of pooled data from over 2.3 million participants, show a unidirectional association between IBD and dementia, with IBD patients having a 1.23-times higher risk of developing dementia. The risk of developing dementia significantly increased after IBD diagnosis, which did not vary by age, gender, dementia subtype, or IBD subtype including UC and CD.¹⁰

The exact mechanism for the interactions between IBD and dementia remains unknown; however, several pathways may be involved, including an increased systemic inflammatory burden, dysbiosis of the gut microbiome, and impaired blood-brain barrier into the central nervous system.¹⁰ The systematic review and meta-analysis concluded that although further clarification is needed on the causal relationship between IBD and dementia, data suggests that IBD onset is associated with subsequent dementia diagnosis, whether as a risk factor or prodromal symptom.¹⁰

The role of the gut microbiome in the pathogenesis of chronic neurodegenerative disorders such as Alzheimer’s disease will continue to unfold. Broadening our understanding of the interaction between the gut and the brain could lead to beneficial therapeutic strategies for improving human health, as researchers study how factors like environment and diet influence microbiome-gut-brain regulation. Throughout life, a range of healthy lifestyle factors, including exercise, limited intake of processed foods, avoidance of prolonged restricted diets, and consumption of fermented foods, adequate dietary fiber, and a phytonutrient-diverse diet all promote a healthy microbiome.¹¹ Implementing practical lifestyle approaches for a healthy intestinal microbiome and supporting immune health may enhance patient engagement and improve outcomes.

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References

1. Saji N, Murotani K, Hisada T, et al. The relationship between the gut microbiome and mild cognitive impairment in patients without dementia: a cross-sectional study conducted in Japan. Sci Rep. 2019;9(1):19227. doi:1038/s41598-019-55851-y
2. Zhang B, Wang HE, Bai Y-M, et al. Inflammatory bowel disease is associated with higher dementia risk: a nationwide longitudinal study. Gut. 2021;70(1):85-91. doi:1136/gutjnl-2020-320789
3. Zingel R, Bohlken J, Kostev K. Association between inflammatory bowel disease and dementia: a retrospective cohort study. J Alzheimers Dis. 2021;80(4):1471-1478. doi:3233/JAD-210103
4. Karwowski CA, Keljo D, Szigethy E. Strategies to improve quality of life in adolescents with inflammatory bowel disease. Inflamm Bowel Dis. 2009;15(11):1755-1764. doi:1002/ibd.20919
5. De Palma G, Collins SM, Bercik P, Verdu EF. The microbiota-gut-brain axis in gastrointestinal disorders: stressed bugs, stressed brain or both? J Physiol. 2014;592(14):2989-2997. doi:1113/jphysiol.2014.273995
6. Gampierakis I-A, Koutmani Y, Semitekolou M, et al. Hippocampal neural stem cells and microglia response to experimental inflammatory bowel disease (IBD). Mol Psychiatry. 2021;26(4):1248-1263. doi:1038/s41380-020-0651-6
7. Do J, Woo J. From gut to brain: alteration in inflammation markers in the brain of dextran sodium sulfate-induced colitis model mice. Clin Psychopharmacol Neurosci. 2018;16(4):422-433. doi:9758/cpn.2018.16.4.422
8. Bonaz BL, Bernstein CN. Brain-gut interactions in inflammatory bowel disease. Gastroenterology. 2013;144(1):36-49. doi:1053/j.gastro.2012.10.003
9. Martin-Subero M, Anderson G, Kanchanatawan B, Berk M, Maes M. Comorbidity between depression and inflammatory bowel disease explained by immune-inflammatory, oxidative, and nitrosative stress; tryptophan catabolite; and gut-brain pathways. CNS Spectr. 2016;21(2):184-198. doi:1017/s1092852915000449
10.  Liu M, Li D, Hong X, Sun Z. Increased risk for dementia in patients with inflammatory bowel disease: a systematic review and meta-analysis of population-based studies. Front Neurol. Published online May 13, 2022. doi:3389/fneur.2022.813266
11.  Centers for Disease Control and Prevention. Inflammatory bowel disease prevalence (IBD): data and statistics. Reviewed April 14, 2022. Accessed August 2, 2022. https://www.cdc.gov/ibd/data-statistics.htm#:~:text=Inflammatory%20Bowel%20Disease%20Prevalence%20(IBD,%25%20or%202%20million%20adults)