Nociceptors are known to directly recognize bacterial cell wall components or secreted toxins, thereby leading to pain induced by bacterial infection. However, direct activation of nociceptors by bacterial metabolites remains unclear although bacteria produce numerous metabolites related to health and disease. In this study, we investigated whether and how a common bacterial metabolite, indole, which is produced by normal microflora of the gastrointestinal tract and oral cavity, can directly activate nociceptive sensory neurons. We found that indole elicits calcium response and evokes inward currents in subsets of dorsal root ganglia (DRG) neurons. Intraplantar (i.pl.) injection of indole produced nocifensive behaviors in adult mice, which were enhanced in complete Freund’s adjuvant–induced chronic inflammatory condition. Indole increased calcitonin gene-related peptide release in DRG neurons, and i.pl. injection of indole increased hind paw thickness, suggesting its role in generation of neurogenic inflammation. These in vitro and in vivo indole-induced responses were pharmacologically blocked by transient receptor potential ankyrin 1 (TRPA1) antagonist, HC-030031, and significantly abolished in TRPA1 knockout (KO) mice, indicating that indole targets TRPA1 for its action in DRG neurons. Nocifensive licking behavior induced by the injection of live Escherichia coli was significantly decreased in tryptophanase mutant (TnaA KO) E. coli-injected mice that lack indole production, further supporting the idea that bacteria-derived indole can induce pain during infection. Identifying the mechanism of action of indole through TRPA1 provides insights into bacteria–neuron interactions and the role of bacterial metabolites in pain signaling, especially in inflammation-accompanied bacterial infection.

已知伤害感受器直接识别细菌细胞壁成分或分泌的毒素，从而导致细菌感染引起的疼痛。然而，尽管细菌产生大量与健康和疾病相关的代谢物，但细菌代谢物对伤害感受器的直接激活仍不清楚。在这项研究中，我们研究了胃肠道和口腔正常微生物群产生的常见细菌代谢物吲哚是否以及如何直接激活伤害性感觉神经元。我们发现吲哚会引起钙反应并在背根神经节（DRG）神经元亚群中引起内向电流。足底内（i.pl.）注射吲哚会在成年小鼠中产生伤害行为，这种行为在完全弗氏佐剂诱导的慢性炎症条件下得到增强。吲哚增加 DRG 神经元中降钙素基因相关肽的释放，并且 i.pl。注射吲哚增加后爪厚度，表明其在神经源性炎症的产生中发挥作用。这些体外和体内吲哚诱导的反应可被瞬时受体电位锚蛋白 1 (TRPA1) 拮抗剂 HC-030031 药理学阻断，并在 TRPA1 敲除 (KO) 小鼠中显着消除，表明吲哚在 DRG 神经元中的作用以 TRPA1 为目标。在缺乏吲哚产生的色氨酸酶突变体（TnaA KO）大肠杆菌注射小鼠中，注射活大肠杆菌诱导的伤害性舔舐行为显着减少，这进一步支持了细菌来源的吲哚可以在感染期间引起疼痛的观点。通过 TRPA1 识别吲哚的作用机制可以深入了解细菌-神经元相互作用以及细菌代谢物在疼痛信号传导中的作用，特别是在炎症伴随的细菌感染中。