The gut-brain axis is crucial to microbial-host interactions. The neurotransmitter serotonin is primarily synthesized in the gastrointestinal (GI) tract, where it is secreted into the lumen and subsequently removed by the serotonin transporter, SERT. Here, we show that serotonin decreases virulence gene expression by enterohemorrhagic E. coli (EHEC) and Citrobacter rodentium, a murine model for EHEC. The membrane-bound histidine sensor kinase, CpxA, is a bacterial serotonin receptor. Serotonin induces dephosphorylation of CpxA, which inactivates the transcriptional factor CpxR controlling expression of virulence genes, notably those within the locus of enterocyte effacement (LEE). Increasing intestinal serotonin by genetically or pharmacologically inhibiting SERT decreases LEE expression and reduces C. rodentium loads. Conversely, inhibiting serotonin synthesis increases pathogenesis and decreases host survival. As other enteric bacteria contain CpxA, this signal exploitation may be engaged by other pathogens. Additionally, repurposing serotonin agonists to inhibit CpxA may represent a potential therapeutic intervention for enteric bacteria.

肠脑轴对于微生物与宿主之间的相互作用至关重要。神经递质5-羟色胺主要在胃肠道（GI）合成，然后被分泌到管腔中，随后被5-羟色胺转运蛋白SERT清除。在这里，我们显示5-羟色胺通过肠出血性大肠杆菌（EHEC）和啮齿类柠檬酸杆菌降低毒力基因表达，是EHEC的鼠模型。膜结合的组氨酸传感器激酶CpxA是细菌血清素受体。血清素诱导CpxA的去磷酸化，从而使控制毒力基因表达的转录因子CpxR失活，特别是在肠上皮细胞受损（LEE）位点的那些基因。通过遗传或药理学抑制SERT的方法增加肠道5-羟色胺会降低LEE表达并降低啮齿类念珠菌的负荷。相反，抑制5-羟色胺合成会增加发病机理并降低宿主存活率。由于其他肠道细菌含有CpxA，因此其他病原体可能参与了该信号的利用。另外，重新使用5-羟色胺激动剂抑制CpxA可能代表对肠细菌的潜在治疗干预。