The gut microbiome is a malleable microbial community that can remodel in response to various factors, including diet, and contribute to the development of several chronic diseases, including atherosclerosis. We devised an in vitro screening protocol of the mouse gut microbiome to discover molecules that can selectively modify bacterial growth. This approach was used to identify cyclic d,l-α-peptides that remodeled the Western diet (WD) gut microbiome toward the low-fat-diet microbiome state. Daily oral administration of the peptides in WD-fed LDLr^−/− mice reduced plasma total cholesterol levels and atherosclerotic plaques. Depletion of the microbiome with antibiotics abrogated these effects. Peptide treatment reprogrammed the microbiome transcriptome, suppressed the production of pro-inflammatory cytokines (including interleukin-6, tumor necrosis factor-α and interleukin-1β), rebalanced levels of short-chain fatty acids and bile acids, improved gut barrier integrity and increased intestinal T regulatory cells. Directed chemical manipulation provides an additional tool for deciphering the chemical biology of the gut microbiome and might advance microbiome-targeted therapeutics.

肠道微生物组是一个具有延展性的微生物群落，可以根据包括饮食在内的各种因素进行重塑，并有助于包括动脉粥样硬化在内的多种慢性疾病的发展。我们设计了一种小鼠肠道微生物组的体外筛选方案，以发现可以选择性地改变细菌生长的分子。该方法用于识别将西方饮食 (WD) 肠道微生物群改造成低脂饮食微生物群状态的环状d,l -α-肽。每日口服 WD 喂养的LDLr中的肽^-/-小鼠降低血浆总胆固醇水平和动脉粥样硬化斑块。用抗生素消耗微生物组消除了这些影响。肽治疗重编程微生物组转录组，抑制促炎细胞因子（包括白细胞介素 6、肿瘤坏死因子 α 和白细胞介素 1β）的产生，重新平衡短链脂肪酸和胆汁酸的水平，改善肠道屏障完整性并增加肠道调节性 T 细胞。定向化学操作为破译肠道微生物组的化学生物学提供了额外的工具，并可能推进微生物组靶向治疗。