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Diet-induced remission in chronic enteropathy is associated with altered microbial community structure and synthesis of secondary bile acids.
Microbiome ( IF 15.5 ) Pub Date : 2019-08-31 , DOI: 10.1186/s40168-019-0740-4
Shuai Wang 1 , Rene Martins 2 , Megan C Sullivan 1 , Elliot S Friedman 3 , Ana M Misic 1 , Ayah El-Fahmawi 1 , Elaine Cristina Pereira De Martinis 4 , Kevin O'Brien 1 , Ying Chen 1 , Charles Bradley 1 , Grace Zhang 1 , Alexander S F Berry 1, 5 , Christopher A Hunter 1 , Robert N Baldassano 5 , Mark P Rondeau 2 , Daniel P Beiting 1
Affiliation  

BACKGROUND The microbiome has been implicated in the initiation and persistence of inflammatory bowel disease. Despite the fact that diet is one of the most potent modulators of microbiome composition and function and that dietary intervention is the first-line therapy for treating pediatric Crohn's disease, the relationships between diet-induced remission, enteropathy, and microbiome are poorly understood. Here, we leverage a naturally-occurring canine model of chronic inflammatory enteropathy that exhibits robust remission following nutritional therapy, to perform a longitudinal study that integrates clinical monitoring, 16S rRNA gene amplicon sequencing, metagenomic sequencing, metabolomic profiling, and whole genome sequencing to investigate the relationship between therapeutic diet, microbiome, and disease. RESULTS We show that remission induced by a hydrolyzed protein diet is accompanied by alterations in microbial community structure marked by decreased abundance of pathobionts (e.g., Escherichia coli and Clostridium perfringens), reduced severity of dysbiosis, and increased levels of the secondary bile acids, lithocholic and deoxycholic acid. Physiologic levels of these bile acids inhibited the growth of E. coli and C. perfringens isolates, in vitro. Metagenomic analysis and whole genome sequencing identified the bile acid producer Clostridium hiranonis as elevated after dietary therapy and a likely source of secondary bile acids during remission. When C. hiranonis was administered to mice, levels of deoxycholic acid were preserved and pathology associated with DSS colitis was ameliorated. Finally, a closely related bile acid producer, Clostridium scindens, was associated with diet-induced remission in human pediatric Crohn's disease. CONCLUSIONS These data highlight that remission induced by a hydrolyzed protein diet is associated with improved microbiota structure, an expansion of bile acid-producing clostridia, and increased levels of secondary bile acids. Our observations from clinical studies of exclusive enteral nutrition in human Crohn's disease, along with our in vitro inhibition assays and in vivo studies in mice, suggest that this may be a conserved response to diet therapy with the potential to ameliorate disease. These findings provide insight into diet-induced remission of gastrointestinal disease and could help guide the rational design of more effective therapeutic diets.

中文翻译:

饮食引起的慢性肠病缓解与微生物群落结构的改变和继发性胆汁酸的合成有关。

背景技术微生物组与炎症性肠病的发生和持续有关。尽管饮食是微生物组组成和功能的最有效调节剂之一,而饮食干预是治疗小儿克罗恩病的一线疗法,但饮食引起的缓解,肠病和微生物组之间的关系知之甚少。在这里,我们利用天然存在的慢性炎性肠病的犬模型进行营养治疗,该模型在营养治疗后表现出明显的缓解,以进行整合了临床监测,16S rRNA基因扩增子测序,宏基因组测序,代谢组学分析和全基因组测序的纵向研究治疗饮食,微生物组和疾病之间的关系。结果我们表明,水解蛋白饮食诱导的缓解伴随着微生物群落结构的改变,其特征在于病原菌数量减少(例如大肠杆菌和产气荚膜梭状芽胞杆菌),营养不良的程度降低以及次生胆汁酸,石胆酸的水平增加和脱氧胆酸。这些胆汁酸的生理水平在体外抑制了大肠杆菌和产气荚膜梭菌分离株的生长。荟萃基因组学分析和全基因组测序确定,饮食治疗后胆汁酸产生者平梭菌(Clostridium hiranonis)升高,并且在缓解期间可能是次生胆汁酸的来源。当将C. hiranonis施用给小鼠时,脱氧胆酸的水平得以保持,并且与DSS结肠炎有关的病理得以改善。最后,一个密切相关的胆汁酸生产商,梭状芽孢杆菌与饮食引起的人类小儿克罗恩病缓解有关。结论这些数据表明,水解蛋白饮食诱导的缓解与微生物群结构的改善,产胆汁酸梭状芽胞杆菌的扩大和次生胆汁酸水平的提高有关。我们从人类克罗恩病独家肠内营养的临床研究中观察到的结果,以及我们在小鼠中进行的体外抑制测定和体内研究表明,这可能是对饮食疗法的保守反应,具有改善疾病的潜力。这些发现提供了饮食引起的胃肠道疾病缓解的见解,并可能有助于指导更有效的治疗性饮食的合理设计。的疾病。结论这些数据表明,水解蛋白饮食诱导的缓解与微生物群结构的改善,产胆汁酸梭状芽胞杆菌的扩大和次生胆汁酸水平的提高有关。我们从人类克罗恩病独家肠内营养的临床研究中观察到的结果,以及我们在小鼠中进行的体外抑制测定和体内研究表明,这可能是对饮食疗法的保守反应,具有改善疾病的潜力。这些发现提供了饮食引起的胃肠道疾病缓解的见解,并可能有助于指导更有效的治疗性饮食的合理设计。的疾病。结论这些数据表明,水解蛋白饮食诱导的缓解与微生物群结构的改善,产胆汁酸梭状芽胞杆菌的扩大和次生胆汁酸水平的提高有关。我们从人类克罗恩病独家肠内营养的临床研究中观察到的结果,以及我们在小鼠中进行的体外抑制测定和体内研究表明,这可能是对饮食疗法的保守反应,具有改善疾病的潜力。这些发现提供了饮食引起的胃肠道疾病缓解的见解,并可能有助于指导更有效的治疗性饮食的合理设计。产生胆汁酸的梭状芽胞杆菌扩大,继发性胆汁酸水平升高。我们从人类克罗恩病独家肠内营养的临床研究中观察到的结果,以及我们在小鼠中进行的体外抑制测定和体内研究表明,这可能是对饮食疗法的保守反应,具有改善疾病的潜力。这些发现提供了饮食引起的胃肠道疾病缓解的见解,并可能有助于指导更有效的治疗性饮食的合理设计。产生胆汁酸的梭状芽胞杆菌扩大,继发性胆汁酸水平升高。我们从人类克罗恩病独家肠内营养的临床研究中观察到的结果,以及我们在小鼠中进行的体外抑制测定和体内研究表明,这可能是对饮食疗法的保守反应,具有改善疾病的潜力。这些发现提供了饮食引起的胃肠道疾病缓解的见解,并可能有助于指导更有效的治疗性饮食的合理设计。提示这可能是对饮食疗法的保守反应,有可能改善疾病。这些发现提供了饮食引起的胃肠道疾病缓解的见解,并可能有助于指导更有效的治疗性饮食的合理设计。提示这可能是对饮食疗法的保守反应,有可能改善疾病。这些发现提供了饮食引起的胃肠道疾病缓解的见解,并可能有助于指导更有效的治疗性饮食的合理设计。
更新日期:2019-08-31
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