Antibiotic tolerance, the ability of a typically susceptible microorganism to survive extended periods of exposure to antibiotics, has a critical role in chronic and recurrent bacterial infections, and facilitates the evolution of antibiotic resistance. However, the physiological factors that contribute to the development of antibiotic tolerance, particularly in vivo, are not fully known. Despite the fact that a high-fat diet (HFD) is implicated in several human diseases, the relationship between HFD and antibiotic efficacy is still poorly understood. Here, we evaluated the efficacy of multiple clinically relevant bactericidal antibiotics in HFD-fed mice infected with methicillin-resistant Staphylococcus aureus (MRSA) or Escherichia coli. We found that HFD-fed mice had higher bacterial burdens and these bacteria displayed lower susceptibility to bactericidal antibiotic treatment compared with mice that were fed a standard diet, while microbiota-depleted standard-diet- or HFD-fed mice showed similar susceptibility. Faecal microbiota transplantation from HFD-fed mice impaired antibiotic activity in mice fed a standard diet, indicating that alteration of the gut microbiota and related metabolites in HFD-fed mice may account for the decreased antibiotic activity. 16S rRNA sequencing and metabolomics analysis of faecal samples revealed decreased microbial diversity and differential metabolite profiles in HFD-fed mice. Notably, the tryptophan metabolite indole-3-acetic acid (IAA) was significantly decreased in HFD-fed mice. Further in vitro studies showed that IAA supplementation inhibited the formation of bacterial persisters and promoted the elimination of persisters in combination with antibiotic treatment, potentially through the activation of bacterial metabolic pathways. In vivo, the combination of IAA and ciprofloxacin increased the survival rate of HFD-fed mice infected with MRSA persisters. Overall, our data reveal that a HFD has an antagonistic effect on antibiotic treatment in a mouse model, and this is associated with the alteration of the gut microbiota and IAA production.

抗生素耐受性是一种典型易感微生物在长时间接触抗生素后存活的能力，在慢性和复发性细菌感染中起关键作用，并促进抗生素耐药性的演变。然而，导致抗生素耐受性发展的生理因素，特别是在体内，尚不完全清楚。尽管高脂肪饮食 (HFD) 与多种人类疾病有关，但人们对 HFD 与抗生素疗效之间的关系仍然知之甚少。在这里，我们评估了多种临床相关杀菌抗生素对感染耐甲氧西林金黄色葡萄球菌(MRSA) 或大肠杆菌的 HFD 喂养小鼠的疗效. 我们发现，与喂食标准饮食的小鼠相比，喂食 HFD 的小鼠具有更高的细菌负荷，并且这些细菌对杀菌抗生素治疗的敏感性较低，而用标准饮食或 HFD 喂养的微生物群耗尽的小鼠表现出相似的敏感性。来自 HFD 喂养小鼠的粪便微生物群移植损害了喂食标准饮食的小鼠的抗生素活性，这表明 HFD 喂养小鼠肠道微生物群和相关代谢物的改变可能是抗生素活性降低的原因。粪便样本的 16S rRNA 测序和代谢组学分析显示，HFD 喂养小鼠的微生物多样性和差异代谢物谱降低。值得注意的是，在喂食 HFD 的小鼠中，色氨酸代谢物吲哚-3-乙酸 (IAA) 显着降低。进一步的体外研究表明，IAA 补充剂可抑制细菌持久性的形成，并与抗生素治疗相结合促进持久性的消除，可能是通过激活细菌代谢途径。在体内，IAA 和环丙沙星的组合提高了感染 MRSA 持续菌的 HFD 喂养小鼠的存活率。总体而言，我们的数据显示，HFD 在小鼠模型中对抗生素治疗具有拮抗作用，这与肠道微生物群和 IAA 产生的改变有关。IAA 和环丙沙星的组合增加了感染 MRSA 持续菌的 HFD 喂养小鼠的存活率。总体而言，我们的数据显示，HFD 在小鼠模型中对抗生素治疗具有拮抗作用，这与肠道微生物群和 IAA 产生的改变有关。IAA 和环丙沙星的组合增加了感染 MRSA 持续菌的 HFD 喂养小鼠的存活率。总体而言，我们的数据显示，HFD 在小鼠模型中对抗生素治疗具有拮抗作用，这与肠道微生物群和 IAA 产生的改变有关。