Gut microbiota inter-species interactions shape the response of Clostridioides difficile to clinically relevant antibiotics

In the human gut, the growth of <em>Clostridioides difficile </em>is impacted by a complex web of inter-species interactions with members of human gut microbiota. We investigate the contribution of inter-species interactions on the antibiotic response of <em>C. difficile </em>to clinically relevant antibiotics using bottom-up assembly of human gut communities. We discover two classes of microbial interactions that alter <em>C. </em>difficile’s antibiotic susceptibility: infrequent increases in tolerance at high antibiotic concentrations and frequent growth enhancements at low antibiotic concentrations. Based on genome-wide transcriptional profiling data, we demonstrate that metal sequestration due to hydrogen sulfide production by the prevalent gut species <em>Desulfovibrio piger </em>increases metronidazole tolerance of <em>C. difficile</em>. Competition with species that display higher sensitivity to the antibiotic than <em>C. difficile </em>leads to enhanced growth of <em>C. difficile </em>at low antibiotic concentrations. A dynamic computational model identifies the ecological design principles driving this effect. Our results provide a deeper understanding of ecological and molecular principles shaping <em>C. difficile</em>’s response to antibiotics, which could inform therapeutic interventions.人体肠道内，艰难梭菌（Clostridioides difficile）的生长受到其与肠道菌群成员间复杂种间相互作用网络的影响。本研究采用人类肠道菌群自下而上组装的实验策略，探究种间相互作用对艰难梭菌应答临床相关抗生素的调控贡献。我们发现两类可改变艰难梭菌抗生素敏感性的微生物相互作用模式：一类是在高抗生素浓度下罕见的耐受性提升，另一类是在低抗生素浓度下频发的生长增强效应。基于全基因组转录组分析数据，我们证实：由常见肠道菌株脱硫弧菌（Desulfovibrio piger）产生硫化氢所介导的金属螯合作用，可提升艰难梭菌对甲硝唑（metronidazole）的耐受性。相较于艰难梭菌，对该抗生素敏感性更高的物种与之竞争时，会在低抗生素浓度下促进艰难梭菌的生长。本研究通过动态计算模型，揭示了驱动该效应的生态学设计原则。本研究结果加深了人们对调控艰难梭菌抗生素应答的生态学与分子机制的认知，可为相关治疗干预策略提供理论指导。