The intestinal microbiome releases a plethora of small molecules. Here, we show that the Ruminococcaceae metabolite isoamylamine (IAA) is enriched in aged mice and elderly people, whereas Ruminococcaceae phages, belonging to the Myoviridae family, are reduced. Young mice orally administered IAA show cognitive decline, whereas Myoviridae phage administration reduces IAA levels. Mechanistically, IAA promotes apoptosis of microglial cells by recruiting the transcriptional regulator p53 to the S100A8 promoter region. Specifically, IAA recognizes and binds the S100A8 promoter region to facilitate the unwinding of its self-complementary hairpin structure, thereby subsequently enabling p53 to access the S100A8 promoter and enhance S100A8 expression. Thus, our findings provide evidence that small molecules released from the gut microbiome can directly bind genomic DNA and act as transcriptional coregulators by recruiting transcription factors. These findings further unveil a molecular mechanism that connects gut metabolism to gene expression in the brain with implications for disease development.

肠道微生物组释放大量小分子。在这里，我们发现，瘤胃球菌科代谢物异戊胺（IAA）在老年小鼠和老年人中富集，而属于肌病毒科的瘤胃球菌科噬菌体则减少。口服 IAA 的年轻小鼠表现出认知能力下降，而肌病毒科小鼠则表现出认知能力下降噬菌体给药可降低 IAA 水平。从机制上讲，IAA 通过将转录调节因子 p53 招募到 S100A8 启动子区域来促进小胶质细胞凋亡。具体而言，IAA 识别并结合 S100A8 启动子区域，以促进其自互补发夹结构的解旋，从而随后使 p53 能够接近 S100A8 启动子并增强 S100A8 表达。因此，我们的研究结果提供了证据，证明肠道微生物组释放的小分子可以直接结合基因组 DNA，并通过招募转录因子充当转录共调节剂。这些发现进一步揭示了一种将肠道代谢与大脑基因表达联系起来的分子机制，并对疾病的发展产生影响。