Microbiome drives age-dependent shifts in brain transcriptomic programs at the single-cell level in Drosophila

TL;DR

This study shows how gut microbes affect brain gene activity in fruit flies, especially as they age, with specific effects on glial cells and neurons.

Contribution

The first single-cell transcriptomic atlas of Drosophila brain cells reveals microbiome-driven, age-dependent gene expression changes.

Findings

Microbiome influences brain gene expression in glial cells and dopaminergic neurons, especially in older flies.

DEGs are enriched in mitochondrial activity, energy metabolism, and Notch signaling pathways.

Older flies show a shift in gut microbiome diversity linked to stronger brain transcriptional responses.

Abstract

The gut microbiome plays a critical role in brain function and the brain-gut axis, yet its cellular and molecular mechanisms remain unclear. Here, we present the first comprehensive single-cell transcriptomic atlas of brain cells from adult Drosophila melanogaster raised under axenic and microbiome-associated conditions, spanning young and old ages. Profiling 34,427 cells across 101 clusters, we annotated 56 cell types and identified cell type-specific gene signatures influenced by the microbiome. Transcriptional shifts were most pronounced in old flies, with glial cells and dopaminergic neurons among the most microbiome-responsive cell types. Differentially expressed genes (DEGs) were enriched in pathways related to mitochondrial activity, energy metabolism, and Notch signaling. We also quantified age-associated changes in the gut microbiome, observing reduced Acetobacter dominance and increased microbial diversity that corresponded with heightened brain transcriptional responses. These findings illuminate the cell type-specific impacts of the microbiome on brain gene expression and lay the groundwork for understanding the molecular underpinnings of the microbiome-gut-brain axis.

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