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<p>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 <i>Drosophila melanogaster</i> 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 <i>Acetobacter</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月12日

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  • Dianshu Zhao,
  • Russel T. Shiga,
  • Zhangrong Song,
  • Runhang Shu,
  • Lipin Loo,
  • Adam Chun Nin Wong

摘要

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.