The Combined Escherichia coli Nissle 1917 and Tryptophan Treatment Modulates Immune and Metabolome Responses to Human Rotavirus Infection in a Human Infant Fecal Microbiota-Transplanted Malnourished Gnotobiotic Pig Model.
The Combined Escherichia coli Nissle 1917 and Tryptophan Treatment Modulates Immune and Metabolome Responses to Human Rotavirus Infection in a Human Infant Fecal Microbiota-Transplanted Malnourished Gnotobiotic Pig Model.
复制标题
大肠杆菌Nissle 1917和色氨酸联合治疗调节人婴儿粪便微生物菌群移植营养不良的无菌猪模型中对人轮状病毒感染的免疫和代谢组反应。
作者：
人类轮状病毒（HRV）是发展中国家儿童腹泻的主要原因，在这些国家，普遍的营养不良导致口服疫苗功效下降和其他肠道感染患病率增加，这是全球健康的主要问题。新生儿无菌 (Gn) 仔猪在解剖学、生理学和远交状态方面与人类婴儿非常相似，为研究营养不良、补充剂和 HRV 感染提供了独特的模型。为了了解大肠杆菌 Nissle 1917 (EcN) 和色氨酸 (TRP) 与免疫增强和减轻腹泻严重程度相关的分子特征，我们对移植了人类婴儿粪便微生物群并感染有毒 (Vir) HRV 的营养不良猪的血浆和粪便内容物进行了免疫反应和整体非靶向代谢组学和脂质组学方法的研究。总体而言，EcN + TRP 组合（而不是单独的补充作用）可促进更大且平衡的免疫调节/免疫刺激反应，从而更好地保护营养不良的人源化仔猪免受 HRV 感染和疾病的影响。此外，EcN + TRP 治疗上调了几种具有免疫调节/免疫刺激特性的代谢物的产生：氨基酸（N-乙酰血清素、甲基乙酰乙酰辅酶A）、脂质（γ-丁甜菜碱、类二十烷酸、硫酸胆固醇、鞘氨醇/植物鞘氨醇、白三烯）、有机化合物（胆绿素）、苯类化合物（龙胆酸、氨基苯甲酸）和核苷酸（次黄嘌呤/肌苷/黄嘌呤、胞苷-5'-单磷酸）。此外，EcN + TRP 治疗后，多种促炎性有机化合物代谢物（腺苷高半胱氨酸、苯乙酰甘氨酸、尿胆素原/粪卟啉原）和氨基酸（苯丙氨酸）的水平降低。这些结果表明，EcN + TRP 对减少新生 Gn 猪 HRV 腹泻的作用至少部分归因于代谢物的改变，这些代谢物涉及脂质、氨基酸、苯类、有机化合物和核苷酸代谢。 EcN/TRP 预防 HRV 腹泻的这些重要机制的鉴定为治疗开发提供了新的靶标。重要性 人类轮状病毒 (HRV) 是儿童病毒性胃肠炎的最常见原因，尤其是在发展中国家，口服 HRV 疫苗的功效会降低。大肠杆菌 Nissle 1917 (EcN) 用于治疗肠道感染和溃疡性结肠炎，而色氨酸 (TRP) 是营养不良的生物标志物，补充色氨酸可以减轻营养不良宿主的肠道炎症并使肠道微生物群正常化。向营养不良的人源化无菌仔猪补充 EcN + TRP 可增强免疫反应，并更好地预防 HRV 感染和腹泻。此外，EcN + TRP 补充剂增加了免疫调节/免疫刺激代谢物的水平，同时减少了血浆和粪便样本中促炎代谢物的产生。分析与 HRV 扰动相关的免疫调节和促炎生物标志物将有助于确定针对营养不良儿童的 HRV 和其他肠道疾病的治疗方法。
Human rotavirus (HRV) is a major cause of childhood diarrhea in developing countries where widespread malnutrition contributes to the decreased oral vaccine efficacy and increased prevalence of other enteric infections, which are major concerns for global health. Neonatal gnotobiotic (Gn) piglets closely resemble human infants in their anatomy, physiology, and outbred status, providing a unique model to investigate malnutrition, supplementations, and HRV infection. To understand the molecular signatures associated with immune enhancement and reduced diarrheal severity by Escherichia coli Nissle 1917 (EcN) and tryptophan (TRP), immunological responses and global nontargeted metabolomics and lipidomics approaches were investigated on the plasma and fecal contents of malnourished pigs transplanted with human infant fecal microbiota and infected with virulent (Vir) HRV. Overall, EcN + TRP combined (rather than individual supplement action) promoted greater and balanced immunoregulatory/immunostimulatory responses associated with greater protection against HRV infection and disease in malnourished humanized piglets. Moreover, EcN + TRP treatment upregulated the production of several metabolites with immunoregulatory/immunostimulatory properties: amino acids (N-acetylserotonin, methylacetoacetyl-CoA), lipids (gamma-butyrobetaine, eicosanoids, cholesterol-sulfate, sphinganine/phytosphingosine, leukotriene), organic compound (biliverdin), benzenoids (gentisic acid, aminobenzoic acid), and nucleotides (hypoxathine/inosine/xanthine, cytidine-5′-monophosphate). Additionally, the levels of several proinflammatory metabolites of organic compounds (adenosylhomocysteine, phenylacetylglycine, urobilinogen/coproporphyrinogen) and amino acid (phenylalanine) were reduced following EcN + TRP treatment. These results suggest that the EcN + TRP effects on reducing HRV diarrhea in neonatal Gn pigs were at least in part due to altered metabolites, those involved in lipid, amino acid, benzenoids, organic compounds, and nucleotide metabolism. Identification of these important mechanisms of EcN/TRP prevention of HRV diarrhea provides novel targets for therapeutics development. IMPORTANCE Human rotavirus (HRV) is the most common cause of viral gastroenteritis in children, especially in developing countries, where the efficacy of oral HRV vaccines is reduced. Escherichia coli Nissle 1917 (EcN) is used to treat enteric infections and ulcerative colitis while tryptophan (TRP) is a biomarker of malnutrition, and its supplementation can alleviate intestinal inflammation and normalize intestinal microbiota in malnourished hosts. Supplementation of EcN + TRP to malnourished humanized gnotobiotic piglets enhanced immune responses and resulted in greater protection against HRV infection and diarrhea. Moreover, EcN + TRP supplementation increased the levels of immunoregulatory/immunostimulatory metabolites while decreasing the production of proinflammatory metabolites in plasma and fecal samples. Profiling of immunoregulatory and proinflammatory biomarkers associated with HRV perturbations will aid in the identification of treatments against HRV and other enteric diseases in malnourished children.
登录
查看更多内容
影响因子：
3.7
作者：
Guerrant RL;Leite AM;Pinkerton R;Medeiros PH;Cavalcante PA;DeBoer M;Kosek M;Duggan C;Gewirtz A;Kagan JC;Gauthier AE;Swann J;Mayneris-Perxachs J;Bolick DT;Maier EA;Guedes MM;Moore SR;Petri WA;Havt A;Lima IF;Prata MM;Michaleckyj JC;Scharf RJ;Sturgeon C;Fasano A;Lima AA
通讯作者：
Lima AA
影响因子：
4.5
作者：
Flanagan JL;Simmons PA;Vehige J;Willcox MD;Garrett Q
通讯作者：
Garrett Q
影响因子：
5.8
作者：
GREENE, S;WATANABE, K;LOU, L
通讯作者：
LOU, L
影响因子：
5.4
作者：
Azevedo, MSP;Yuan, L;Saif, LJ
通讯作者：
Saif, LJ
影响因子：
3
作者：
Brundige DR;Maga EA;Klasing KC;Murray JD
通讯作者：
Murray JD