PDF(Pubmed)
Abstract：
Opioid crisis is an ongoing epidemic since the past several decades in the United States. Opioid use-associated microbial dysbiosis is emerging as a key regulator of intestinal homeostasis and behavioral responses to opioid. However, the mechanistic insight into the role of microbial community in modulating host response is unavailable. To uncover the role of opioid-induced dysbiosis in disrupting intestinal homeostasis we utilized whole genome sequencing, untargeted metabolomics, and mRNA sequencing to identify changes in microbiome, metabolome, and host transcriptome respectively. Morphine treatment resulted in significant expansion of Parasuterella excrementihominis, Burkholderiales bacterium 1_1_47, Enterococcus faecalis, Enterorhabdus caecimuris and depletion of Lactobacillus johnsonii. These changes correlated with alterations in lipid metabolites and flavonoids. Significant alteration in microbial metabolism (metabolism of lipids, amino acids, vitamins and cofactors) and increased expression of virulence factors and biosynthesis of lipopolysaccharides (LPS) and lipoteichoic acid (LTA) were observed in microbiome of morphine-treated animals. In concurrence with changes in microbiome and metabolome extensive changes in innate and adaptive immune response, lipid metabolism, and gut barrier dysfunction were observed in the host transcriptome. Microbiome depleted mice displayed lower levels of inflammation, immune response and tissue destruction compared to mice harboring a dysbiotic microbiome in response to morphine treatment, thus establishing dysbiotic microbiome as mediator of morphine gut pathophysiology. Integrative analysis of multi-omics data highlighted the associations between Parasutterella excrementihominis, Burkholderiales bacterium 1_1_47, Enterococcus faecalis, Enterorhabdus caecimuris and altered levels of riboflavin, flavonoids, and lipid metabolites including phosphocholines, carnitines, bile acids, and ethanolamines with host gene expression changes involved in inflammation and barrier integrity of intestine. Omic analysis also highlighted the role of probiotic bacteria Lactobacillus johnsonii, metabolites flavonoids and riboflavin that were depleted with morphine as important factors for intestinal homeostasis. This study presents for the first time ever an interactive view of morphine-induced changes in microbial metabolism, strain level gut microbiome analysis and comprehensive view of changes in gut transcriptome. We also identified areas of potential therapeutic interventions to limit microbial dysbiosis and present a unique resource to the opioid research community.
摘要：
阿片类药物危机是美国过去几十年来持续的流行病。阿片类药物使用相关的微生物菌群失调正在成为肠道稳态和阿片类药物行为反应的关键调节因子。然而,对微生物群落在调节宿主反应中的作用的机制见解尚不清楚.为了揭示阿片类药物诱导的生态失调在破坏肠道稳态中的作用，我们利用了全基因组测序，非靶向代谢组学，和mRNA测序来识别微生物组的变化，代谢组，和宿主转录组分别。吗啡治疗导致排泄物寄生虫显著扩张，伯氏杆菌1_1_47，粪肠球菌，盲肠和约氏乳杆菌的消耗。这些变化与脂质代谢物和类黄酮的变化有关。微生物代谢的显著改变(脂质代谢，氨基酸,维生素和辅因子）以及在吗啡处理的动物的微生物组中观察到毒力因子的表达增加以及脂多糖（LPS）和脂磷壁酸（LTA）的生物合成。伴随着微生物组和代谢组的变化，先天和适应性免疫反应发生了广泛的变化，脂质代谢，在宿主转录组中观察到肠屏障功能障碍。微生物耗尽的小鼠表现出更低水平的炎症，免疫反应和组织破坏相比，小鼠具有响应吗啡治疗的生态失调微生物组，从而建立了生态失调的微生物组作为吗啡肠道病理生理学的介体。对多组学数据的综合分析强调了排泄物旁之间的关联，伯氏杆菌1_1_47，粪肠球菌，肠背盲肠和核黄素水平改变，黄酮类化合物，和脂质代谢物，包括磷酸胆碱，肉碱,胆汁酸，与宿主基因表达变化有关的乙醇胺和肠道炎症和屏障完整性。Omic分析还强调了益生菌约氏乳杆菌的作用，代谢物类黄酮和核黄素被吗啡耗尽，是肠道稳态的重要因素。这项研究首次提出了吗啡诱导的微生物代谢变化的互动观点，菌株水平的肠道微生物组分析和肠道转录组变化的综合观点。我们还确定了潜在的治疗干预措施，以限制微生物菌群失调，并为阿片类药物研究界提供了独特的资源。
