前体B细胞急性淋巴细胞白血病患儿肠道菌群功能失调的研究

Gut microbiota dysfunction in children with precursor B-cell acute lymphoblastic leukemia

摘要:

目的阐明前体B细胞急性淋巴细胞白血病(acute lymphoblastic leukemia, ALL)患儿肠道微生物酶的变化及其与宿主基因表达的潜在相互作用。 方法比较ALL患儿与健康对照组的肠道微生物酶丰度差异，并进行代谢网络和宿主基因表达数据分析，利用长双歧杆菌与ALL NALM6细胞共培养探究微生物调节宿主基因表达变化的关联。 结果与健康对照组相比，ALL患儿的多种肠道微生物酶丰度均表现出显著改变，如腺苷脱氨酶及二甲基精氨酸酶活性显著降低(P=0.0146，P=0.0119)。ALL患儿肠道菌群中与短链脂肪酸和葡萄糖相关的代谢通路(包括丙酮酸-苹果酸羧化酶等)出现失调。微生物酶丰度与宿主基因表达变化之间存在协同关系，微生物酶以及相应人类同工酶(包括ALDH、DDAH、ME2、ALDH7A1和ALDH1A1等多个基因)在ALL患者中同时变化。在与长双歧杆菌共培养时，ALL NALM6细胞中关键代谢酶ALDH7A1蛋白表达量显著降低(P=0.0407)。 结论前体B细胞ALL患儿存在肠道微生物酶失调，且与宿主基因表达改变相关，靶向肠道微生物组可能对ALL治疗干预有一定意义。

Abstract:

ObjectiveTo investigate the changes in gut microbial enzyme profiles and their potential interactions with host gene expression in children with precursor B-cell(pre-B) acute lymphoblastic leukemia(ALL). MethodsThe differences in gut microbial enzyme abundance between pre-B ALL children and healthy controls were compared. Metabolic network analysis and host gene expression data and co-culture experiments of Bifidobacterium longum with ALL NALM6 cells were used to explore the functional connections between altered microbial functions and host gene expression changes. ResultsSignificant alterations in gut microbial enzyme abundance were observed in ALL children compared to healthy controls, e.g. adenosine deaminase(P=0.0146) and dimethylargininase activity(P=0.0119). Metabolic pathways related to short-chain fatty acid and glucose metabolism, including pyruvate-malate carboxylase, were dysregulated in the gut microbiota of ALL children. Interestingly, a synergistic relationship was identified between altered microbial functions and host gene expression changes. Several microbial enzymes had corresponding human isoenzymes(including multiple genes such as ALDH, DDAH, ME2, ALDH7A1, and ALDH1A1) that exhibited synchronized upregulation in ALL children. In co-culture with Bifidobacterium longum, ALDH7A1 protein expression in ALL NALM6 cells was significantly reduced(P=0.0407). ConclusionGut microbial enzyme dysbiosis is associated with altered host gene expression in pre-B ALL children. These findings suggest that targeting the gut microbiome may hold therapeutic potential for ALL.