Pediatrics Research Institute of Hunan Province, Hunan Children's Hospital, Changsha, China.
Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China.
Microbiol Spectr. 2024 Apr 2;12(4):e0523022. doi: 10.1128/spectrum.05230-22. Epub 2024 Mar 6.
Altered gut microbiota and metabolites are important for non-alcoholic fatty liver disease (NAFLD) in children. We aimed to comprehensively examine the effects of gut metabolites on NAFLD progression. We performed integrative metabolomics (untargeted discovery and targeted validation) analysis of non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), and obesity in children. Fecal samples were collected from 75 subjects in the discovery cohort (25 NAFL, 25 NASH, and 25 obese control children) and 145 subjects in an independent validation cohort (53 NAFL, 39 NASH, and 53 obese control children). Among 2,491 metabolites, untargeted metabolomics revealed a complete NAFLD metabolic map containing 318 increased and 123 decreased metabolites. Then, machine learning selected 65 important metabolites that can distinguish the severity of the NAFLD. Furthermore, precision-targeted metabolomics selected 5 novel gut metabolites from 20 typical metabolites. The functionality of candidate metabolites was validated in hepatocyte cell lines. In the end, this study annotated two novel elevated pathogenic metabolites (dodecanoic acid and creatinine) and a relationship between depleted protective gut microbiota ( and ), increased inflammation (IL-1β), lipid metabolism (TG), and liver function (ALT and AST). This study demonstrates the role of novel gut metabolites (dodecanoic acid and creatinine), as the fatty acid metabolism regulator contributing to NAFLD development through its influence on inflammation and liver function.
Altered gut microbiota and metabolites are a major cause of non-alcoholic fatty liver disease (NAFLD) in children. This study demonstrated a complete gut metabolic map of children with NAFLD, containing 318 increased and 123 decreased metabolites by untargeted metabolomic. Multiple validation approaches (machine learning and targeted metabolomic) selected five novel gut metabolites for targeted metabolomics, which can distinguish NAFLD status and severity. The gut microbiota ( and ) and metabolites (creatinine and dodecanoic acid) were novel biomarkers associated with impaired liver function and inflammation and validated by experiments of hepatocyte cell lines. The data provide a better understanding of the importance of gut microbiota and metabolite alterations in NAFLD, which implies that the altered gut microbiota and metabolites may represent a potential target to prevent NAFLD development.
肠道微生物群和代谢物的改变对儿童非酒精性脂肪性肝病（NAFLD）很重要。我们旨在全面研究肠道代谢物对 NAFLD 进展的影响。我们对儿童非酒精性脂肪肝（NAFL）、非酒精性脂肪性肝炎（NASH）和肥胖进行了综合代谢组学（非靶向发现和靶向验证）分析。从发现队列的 75 名受试者（25 名 NAFL、25 名 NASH 和 25 名肥胖对照组儿童）和独立验证队列的 145 名受试者（53 名 NAFL、39 名 NASH 和 53 名肥胖对照组儿童）中收集粪便样本。在 2491 种代谢物中，非靶向代谢组学揭示了包含 318 种增加和 123 种减少代谢物的完整 NAFLD 代谢图谱。然后，机器学习选择了 65 种可区分 NAFLD 严重程度的重要代谢物。此外，精确靶向代谢组学从 20 种典型代谢物中选择了 5 种新型肠道代谢物。候选代谢物的功能在肝细胞系中得到验证。最后，本研究注释了两种新升高的致病性代谢物（十二烷酸和肌酸）和一种耗竭的保护性肠道微生物群（和）之间的关系，增加了炎症（IL-1β）、脂质代谢（TG）和肝功能（ALT 和 AST）。这项研究表明，新型肠道代谢物（十二烷酸和肌酸）通过影响炎症和肝功能，作为脂肪酸代谢调节剂，在 NAFLD 发展中起作用。
肠道微生物群和代谢物的改变是儿童非酒精性脂肪性肝病（NAFLD）的主要原因。本研究通过非靶向代谢组学显示了包含 318 种增加和 123 种减少代谢物的儿童 NAFLD 完整肠道代谢图谱。多种验证方法（机器学习和靶向代谢组学）选择了 5 种新型肠道代谢物进行靶向代谢组学分析，可区分 NAFLD 状态和严重程度。肠道微生物群（和）和代谢物（肌酸和十二烷酸）是通过肝细胞系实验验证的与肝功能和炎症受损相关的新型生物标志物。数据提供了对肠道微生物群和代谢物改变在 NAFLD 中重要性的更好理解，这意味着改变的肠道微生物群和代谢物可能代表预防 NAFLD 发展的潜在目标。
