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

In the human gut, the growth of Clostridioides difficile 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 C. difficile to clinically relevant antibiotics using bottom-up assembly of human gut communities. We discover two classes of microbial interactions that alter C. 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 Desulfovibrio piger increases metronidazole tolerance of C. difficile. Competition with species that display higher sensitivity to the antibiotic than C. difficile leads to enhanced growth of C. difficile 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 C. difficile’s response to antibiotics, which could inform therapeutic interventions.

人类肠道内，艰难梭菌（Clostridioides difficile）的生长会受到其与人类肠道菌群成员之间复杂的种间相互作用网络的影响。本研究通过自下而上组装人类肠道菌群群落，探究了种间相互作用对艰难梭菌应答临床相关抗生素的调控作用。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：高抗生素浓度下罕见出现的耐受性提升，以及低抗生素浓度下频繁出现的生长增强效应。基于全基因组转录谱数据，我们证实：常见肠道菌种拜氏脱硫弧菌（Desulfovibrio piger）通过产生硫化氢引发金属螯合作用，可提升艰难梭菌对甲硝唑的耐受性。与对该抗生素敏感性高于艰难梭菌的菌种发生竞争，会在低抗生素浓度下促进艰难梭菌的生长。本研究借助动态计算模型，明确了驱动该效应的生态设计原则。本研究结果加深了我们对调控艰难梭菌抗生素应答的生态与分子机制的理解，可为相关治疗干预手段提供理论参考。