Scientists at Washington University in St. Louis have identified specific alterations in gut microbiota composition related to preclinical neuropathology of Alzheimer’s disease. The findings might help discover novel gut-derived biomarkers to predict the disease risk.
The study is published within the journal Science Translational Medicine.
Study: Gut microbiome composition could also be an indicator of preclinical Alzheimer’s disease. Image Credit: ArtemisDiana / Shutterstock
Background
The human gut microbiota accommodates a plethora of microbial communities which can be compositionally and functionally district from one another. Gut microbes and metabolites derived from them play crucial roles in regulating many physiological processes, starting from immune functions to neurological functions.
Gut microbiota dysbiosis is defined as altered or imbalanced composition and variety of gut microbiota. Evidence suggests a link between gut microbiota dysbiosis and the pathogenesis of Alzheimer’s disease (AD) and other neurodegenerative diseases.
AD is a progressive disease characterised by memory loss and cognitive decline. Imaging studies have shown that AD pathophysiology regularly progresses from preclinical AD to symptomatic AD through a series of neurodegenerative changes. Preclinical AD is characterised by the presence of disease-specific biomarkers with none apparent symptoms. Essentially the most outstanding clinical biomarkers of AD are pathogenic β-amyloid (Aβ) and tau protein.
In the present study, scientists have examined cognitively normal individuals with and without preclinical AD to find out whether changes in gut microbiota can predict AD risk.
Study design
The scientists compared gut microbiota composition and performance between cognitively normal individuals with and without markers of early preclinical AD. In total, 164 individuals were examined, with 49 exhibiting preclinical AD biomarkers.
Stool samples collected from the participants were analyzed to discover specific gut microbiota characteristics related to preclinical AD or known biomarkers of AD. Moreover, the scientists evaluated whether gut microbiota characteristics can improve the performance of machine-learning models developed to discover individuals liable to developing AD.
Necessary observations
Preclinical AD status of the participants was determined based on several clinical examinations, including magnetic resonance imaging (MRI), positron emission tomography (PET), cerebrospinal fluid (CSF) evaluation for Aβ and tau protein, and cognitive testing. This led to the identification of 115 healthy individuals and 49 individuals with preclinical AD.
The comparison of gut microbiota characteristics between the groups was conducted after adjusting for dietary intake and several other clinical covariates, including age, body mass index (BMI), apolipoprotein ε4 (APOE ε4) carrier status (genetic risk factor), diabetes, and hypertension.
Metagenomic sequencing of stool samples was conducted to find out the relative abundance of microbial species and microbial pathways. The findings revealed no significant difference within the Firmicutes/Bacteroidetes ratio between healthy individuals and people with preclinical AD. The gut microbiota alpha diversities were also similar between the groups.
Taxonomic profiles of the gut microbiota showed significant differences between the groups. This finding suggests that the human gut microbiota may change early in AD before the onset of specific symptoms.
Association between gut microbiota profiles and preclinical AD characteristics
The comparison of gut microbiota measures with the quantity of Aβ plaques and tau proteins revealed a major association of gut microbiota taxonomic profiles with Aβ plaques and tau proteins.
Nonetheless, no such association was observed for neurodegenerative markers. This could possibly be explained by the proven fact that neurodegeneration occurs later within the clinical course of AD and that Aβ plaques and tau proteins are the early biomarkers to detect preclinical AD.
Specific gut microbiota characteristics in preclinical AD
The evaluation of taxonomic and microbial pathway data after adjusting for clinical covariates revealed that certain microbial species, including Dorea formicigenerans, Oscillibacter sp. 57_20, Faecalibacterium prausnitzii, Coprococcus catus, and Anaerostipes hadrus have essentially the most specific association with preclinical AD status.
A complete of 13 gut microbial species showed essentially the most specific association with health status. Of them, seven belonged to the Bacteroides genus.
Regarding microbial pathways, arginine and ornithine degradation pathways and glutamate degradation pathways showed essentially the most specific association with preclinical AD status and health status, respectively.
Performance of machine learning models for preclinical AD status
The performance of preclinical AD status prediction models was tested with and without gut microbiota characteristics. Along with participants’ demographic data and clinical covariates, these models initially included all available AD markers, including Aβ, tau, neurodegeneration, and genetic risk markers.
To find out the best predictive performance, AD biomarkers, apart from genetics, were rationally omitted from the models, abandoning only demographic characteristics and clinical covariates.
The findings revealed that in models that omitted AD biomarkers apart from genetics, the inclusion of gut microbiota taxonomic characteristics caused 6.8% and 27.1% improvements in prediction accuracy and specificity, respectively. Furthermore, in models that omitted AD biomarkers, including genetics, the inclusion of taxonomic characteristics caused 11.2 and 13.7% improvements in accuracy and sensitivity, respectively.
These findings indicate that the utility of microbial features as an indicator of preclinical AD increased with greater scarcity of accessible data for established AD biomarkers.
Study significance
The study provides global and specific differences in gut microbiota composition between individuals with and without preclinical AD. In other words, the study identifies gut microbiota composition as an indicator of preclinical AD.