An integral view of gut microbiome diversity and functional metabolic changes of a gut-brain axis associated with dementia based on metagenomic analysis

Abstract

Background: Growing evidence highlights the vital role by gut microbiota in brain health through the gut-brain axis, which involves neural, immune, endocrine, and metabolic signaling pathways. Disruption of this axis through microbial dysbiosis is increasingly linked to cognitive disorders, including dementia. However, the specific taxa and pathways involved remain poorly characterized. This study investigates taxonomic and functional shifts in the gut microbiome across healthy individuals, mild dementia, and dementia patients, aiming to identify microbial signatures and metabolic alterations associated with cognitive decline.

Methods: A total of 184 participants (aged 60-98) were recruited and grouped into healthy, mild dementia, and dementia categories based on Clinical Dementia Rating scores. Demographic and clinical data were collected through structured interviews. Fecal samples were collected from participants and DNA was extracted and subjected to 16S rRNA gene sequencing. Sequencing data were processed using QIIME2 and classified using the SILVA database. Alpha (Shannon, Inverse Simpson) and beta diversity (Bray-Curtis PCoA) were analyzed between participant groups. Functional prediction was performed with PICRUSt2 to estimate KEGG orthologs from normalized ASVs. Statistical analyses were conducted in R using Kruskal-Wallis and PERMANOVA tests to assess group-level differences.

Results: Dementia patients exhibited the highest proportion of unique ASVs (32.1%) but showed reduced alpha diversity compared to mild dementia and healthy controls. PCoA revealed distinct microbial clustering across groups, explaining 19.3% of total variance, with dementia samples forming a unique cluster. Taxonomically, dementia samples were enriched in Firmicutes and pro-inflammatory genera such as Peptoclostridium and Scardovia, while healthy controls harbored more SCFA-producing taxa like Lachnospiraceae_UCG-001. Co-occurrence networks in dementia were more complex, with increased inter-species connectivity and key drivers including Dorea and Clostridium innocuum. Functionally, dementia samples showed enrichment of vanillate degradation pathways and depletion of neuroprotective pathways like ergothioneine and vitamin E biosynthesis, correlating with specific microbial signatures.

Conclusions: Cognitive decline was associated with reduced microbial diversity and selective enrichment of pro-inflammatory taxa, reflecting gut ecological instability due to dementia. Microbial composition shifted progressively with dementia severity, indicating disease-specific gut microbial restructuring. Moreover, the loss of key functional microbial metabolites such as neuroprotective and anti-inflammatory metabolites supports targeting such metabolites and their producing gut microbiota as a therapeutic strategy for dementia. Future studies should ensure generalization by recruiting multi-center participants with strict guidelines for monitoring confounders.

Keywords: Cognitive Decline; Dementia; Gut microbiota; Gut–Brain axis; Neuroprotective Metabolites.