Gut microbiota may be involved in Alzheimer’s disease pathology by dysregulating pyrimidine metabolism in APP/PS1 mice

Abstract

IntroductionAlzheimer’s disease (AD) is the most common form of dementia worldwide. The biological mechanisms underlying the pathogenesis of AD aren’t completely clear. Studies have shown that the gut microbiota could be associated with AD pathogenesis; however, the pathways involved still need to be investigated.AimsTo explore the possible pathways of the involvement of gut microbiota in AD pathogenesis through metabolites and to identify new AD biomarkers.MethodsSeven-month-old APP/PS1 mice were used as AD models. The Morris water maze test was used to examine learning and memory ability. 16S rRNA gene sequencing and widely targeted metabolomics were used to identify the gut microbiota composition and fecal metabolic profile, respectively, followed by a combined analysis of microbiomics and metabolomics.ResultsImpaired learning abilities were observed in APP/PS1 mice. Statistically significant changes in the gut microbiota were detected, including a reduction in β-diversity, a higher ratio of Firmicutes/Bacteroidota, and multiple differential bacteria. Statistically significant changes in fecal metabolism were also detected, with 40 differential fecal metabolites and perturbations in the pyrimidine metabolism. Approximately 40% of the differential fecal metabolites were markedly associated with the gut microbiota, and the top two bacteria associated with the most differential metabolites were Bacillus firmus and Rikenella. Deoxycytidine, which causes changes in the pyrimidine metabolic pathway, was significantly correlated with Clostridium sp. Culture-27.ConclusionsGut microbiota may be involved in the pathological processes associated with cognitive impairment in AD by dysregulating pyrimidine metabolism. B. firmus, Rikenella, Clostridium sp. Culture-27, and deoxyuridine may be important biological markers for AD. Our findings provide new insights into the host-microbe crosstalk in AD pathology and contribute to the discovery of diagnostic markers and therapeutic targets for AD.

The potential of the gut microbiome for identifying Alzheimer’s disease diagnostic biomarkers and future therapies

“…APP/PS1 mice combining 16SrRNA gene sequencing and extensively targeted metabolomics revealed that B. firmus , Rikenella , Clostridium sp. culture-27 , and deoxyuridine might be important biomarkers of AD ( Feng et al, 2022 ). Based on the GM differences in feces and blood established in the preliminary study, Li et al built a random forest model based on 11 genera of differences in stools and blood from AD patients and NC.…”

Metabolic modeling reveals the aging-associated decline of host-microbiome metabolic interactions in mice

“…According to the model predictions and brain metabolome data, the microbiome may play a key role in nucleotide salvage in the brain, which is essential for DNA damage repair and cellular homeostasis 88 . In addition, an association between neurodegeneration and microbial pyrimidine metabolism was observed in an experimental mouse model of Alzheimer’s disease 89 .…”

“…According to the model predictions and brain metabolome data, the microbiome may play a key role in nucleotide salvage in the brain, which is essential for DNA damage repair and cellular homeostasis 88 . In addition, an association between neurodegeneration and microbial pyrimidine metabolism was observed in an experimental mouse model of Alzheimer's disease 89 . In summary, we comprehensively characterized microbiome-host interactions in mice and identified pronounced aging-associated changes in these interactions primarily driven by a loss of microbial metabolic activity.…”

Multi-omics data reveals aberrant gut microbiota-host glycerophospholipid metabolism in association with neuroinflammation in APP/PS1 mice

“… 13 Among them, the metabolic pathway involved in the gut microbiota is an important way to affect the host. 14 For example, short-chain fatty acids (SCFAs) are the main metabolites produced by gut microbiota through the metabolism of indigestible dietary fibers. 15 SCFAs have been shown to participate in the pathological process of AD in various ways.…”

“…Recently, several studies have explored the relationship between gut microbiota and metabolic pathways in APP/PS1 mice through 16S rRNA gene sequencing and metabolomics. 14 , 18 However, most current studies only focus on the alteration and correlation of metabolite abundance in feces and blood, while there is a lack of research on the correlation characteristics of the spatial distribution of metabolites, gene expression levels, and pathological changes in the brains of AD. In this study, we not only used 16S rRNA gene sequencing and metabolomics to explore the variation characteristics of gut microbiota abundance and serum metabolism abundance but also combined spatial metabolomics, transcriptomics, neuroimaging, and pathology to explore the changes in the brain and identify their correlation in APP/PS1 mice.…”