Commonly used non-antibiotic drugs have been associated with changes in gut microbiome composition, paving the way for the possibility of repurposing FDA-approved molecules as next-generation microbiome therapeutics. Herein, we developed and validated an ex vivo high-throughput screening platform─the mini gut model─to underpin human gut microbiome response to molecular modulators. Ten FDA-approved compounds, selected based on maximum structural diversity of molecular fingerprints, were screened against the gut microbiome of five healthy subjects to characterize the ability of human-targeted drugs to modulate the human gut microbiome network. Three compounds, THIP hydrochloride, methenamine, and mesna, have shown promise as novel gut microbiome therapeutics in light of their capability of promoting health-associated features of the gut microbiome. Our findings provide a resource for future research on drug–microbiome interactions and lay the foundation for a new era of more precise gut microbiome modulation through drug repurposing, aimed at targeting specific dysbiotic events.

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通过药物再利用方法寻找新的微生物组靶向疗法

常用的非抗生素药物与肠道微生物组组成的变化有关，为将 FDA 批准的分子重新用作下一代微生物组疗法的可能性铺平了道路。在此，我们开发并验证了一种离体高通量筛选平台——迷你肠道模型——支持人类肠道微生物组对分子调节剂的反应。根据分子指纹的最大结构多样性选择十种 FDA 批准的化合物，针对五名健康受试者的肠道微生物组进行筛选，以表征人类靶向药物调节人类肠道微生物组网络的能力。三种化合物，THIP 盐酸盐、甲氧胺和美司钠，鉴于它们促进肠道微生物组健康相关特征的能力，已显示出作为新型肠道微生物组治疗剂的前景。我们的研究结果为未来药物-微生物组相互作用的研究提供了资源，并为通过药物再利用来更精确地调节肠道微生物组的新时代奠定了基础，旨在针对特定的菌群失调事件。