Gut microbes can contribute to inflammaging, a term used to describe the chronic low-grade systemic inflammation linked with aging. This process may be driven by age-related changes in gut microbiome composition, leading to an inflammatory environment that degrades the intestinal epithelial barrier. These alterations and higher levels of gut microbial components in the systemic circulation, such as lipopolysaccharides (LPS), are linked to not only aging but diseases related to age, such as Alzheimer’s disease (AD). AD markers include the cerebral aggregation of phosphorylated tau (pTau) proteins and amyloid beta (Aβ). However, the role of intestinal inflammation in aging and AD remains unclear. A correlation between irritable bowel syndrome (IBS) and a higher risk of developing AD dementia has been indicated (Chen et al., 2016). Since IBS may disrupt the microbiome, leading to increased intestinal permeability, this suggests that intestinal inflammation and increased permeability may play a role in the development of AD (Wilms et al., 2020).
To explore whether greater gut inflammation is associated with advanced age and AD pathology, Heston et al. examined the correlation between intestinal inflammation, advanced age, and AD pathology. They measured calprotectin, a marker of intestinal inflammation that is elevated in diseases of gut barrier integrity, in fecal samples from 125 middle-aged and older adults across various disease stages: categorized as cognitively unimpaired (CU) with negative Aβ markers (Aβ−), n = 79; CU with positive Aβ markers (Aβ+), n = 33; AD Aβ+, n = 13). These measurements were correlated with the participant's age, cognitive function, and markers of AD pathology. As indicated by amyloid burden obtained by positron emission tomography neuroimaging (PET) and cerebrospinal fluid (CSF) biomarkers such as Aβ and pTau.
In this study, after adjusting disease stage, sex, and BMI, a significant association was found between advanced age and increased calprotectin levels (P = 0.027). Participants diagnosed with AD dementia, confirmed by the presence of amyloid plaques in the brain (AD Aβ+), showed higher calprotectin levels even in the earliest disease stages, compared to those without AD. This finding suggests a link between intestinal inflammation and brain pathology, which might contribute to AD progression. Notably, elevated calprotectin levels were observed in CU participants of advanced age (P=0.042), aligning with the concept of inflammaging and indicating a possible predictive value of calprotectin levels for future AD onset.
The study also used global Pittsburgh Compound B (PiB) distribution volume ratios (DVR) to assess the relationship between intestinal inflammation, brain Aβ burden, and disease status. Among CU Aβ+ participants, no significant correlation was found between calprotectin levels and global PiB DVR (P = 0.62). Further analysis revealed that the influence of calprotectin on amyloid levels was specific to the pathology and not dependent on age (P=0.17).
Additionally, the relationship between intestinal inflammation and cognitive decline
before the clinical diagnosis of AD in Aβ+ individuals was investigated. Cognitive functions, assessed by the Rey Auditory Verbal Learning Test (RAVLT) and the Trail Making Test Part B (TMT-B), showed that higher calprotectin levels correlated with poorer performance in delayed recall tasks among 103 CU participants. However, this association was not statistically significant after adjusting for factors like age and educational background, suggesting that gut inflammation is not a strong predictor of cognitive decline in early AD.
This research indicates that intestinal inflammation increases with age and is present in AD Aβ+individuals, potentially exacerbating amyloid accumulation. Elevated calprotectin levels in healthy individuals could be an early marker for disease risk, highlighting the importance of intestinal health in aging and AD. The findings support the notion that reducing intestinal inflammation might improve cognitive function in older adults, presenting a potential therapeutic target for addressing aging and AD.
However, the study did not include data on the gut microbiome, blood-based inflammation markers, and microbial translocation. A more comprehensive understanding of the gut microbiome’s role in intestinal permeability and its impact on AD pathology requires further research into these areas. Longitudinal studies are needed to determine whether high intestinal inflammation predicts more severe pathology and faster cognitive decline. Additionally, the participant cohort’s lack of diversity limits the generalizability of the findings, pointing to the need for future research with a broader population sample.
References
Chen, C.-H., Lin, C.-L. and Kao, C.-H. (2016) ‘Irritable bowel syndrome is associated with an increased risk of dementia: A nationwide population-based study’, PLOS ONE, 11(1). doi:10.1371/journal.pone.0144589.
FRANCESCHI, C. et al. (2000) ‘Inflamm‐aging: An evolutionary perspective on immunosenescence’, Annals of the New York Academy of Sciences, 908(1), pp. 244–254. doi:10.1111/j.1749-6632.2000.tb06651.x.
Heston, M. et al. (2023) 'Gut inflammation associated with age and Alzheimer’s disease pathology: a human cohort study,' Scientific Reports, 13, 18924 (2023). doi:10.1038/s41598-023-45929-z
Mulak, A. et al. (2019) ‘Fecal calprotectin as a marker of the gut immune system activation is elevated in parkinson’s disease’, Frontiers in Neuroscience, 13. doi:10.3389/fnins.2019.00992.
Valentini, L. et al. (2014) ‘Small intestinal permeability in older adults’, Physiological Reports, 2(4). doi:10.1002/phy2.281.
Wilms, E. et al. (2020) ‘Intestinal barrier function is maintained with aging – a comprehensive study in healthy subjects and irritable bowel syndrome patients’, Scientific Reports, 10(1). doi:10.1038/s41598-019-57106-2.
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