Objective The specific breast milk-derived metabolites that mediate host–microbiota interactions and contribute to the onset of atopic dermatitis (AD) remain unknown and require further investigation. Design We enrolled 250 mother–infant pairs and collected 978 longitudinal faecal samples from infants from birth to 6 months of age, along with 243 maternal faecal samples for metagenomics. Concurrently, 239 corresponding breast milk samples were analysed for metabolomics. Animal and cellular experiments were conducted to validate the bioinformatics findings. Results The clinical findings suggested that a decrease in daily breastfeeding duration was associated with a reduced incidence of AD. This observation inspired us to investigate the effects of breast milk-derived fatty acids. We found that high concentrations of arachidonic acid (AA), but not eicosapentaenoic acid (EPA) or docosahexaenoic acid, induced gut dysbiosis in infants. Further investigation revealed that four specific bacteria degraded mannan into mannose, consequently enhancing the mannan-dependent biosynthesis of O-antigen and lipopolysaccharide. Correlation analysis confirmed that in infants with AD, the abundance of Escherichia coli under high AA concentrations was positively correlated with some microbial pathways (eg, ‘GDP-mannose-derived O-antigen and lipopolysaccharide biosynthesis’). These findings are consistent with those of the animal studies. Additionally, AA, but not EPA, disrupted the ratio of CD4/CD8 cells, increased skin lesion area and enhanced the proportion of peripheral Th2 cells. It also promoted IgE secretion and the biosynthesis of prostaglandins and leukotrienes in BALB/c mice fed AA following ovalbumin immunostimulation. Moreover, AA significantly increased IL-4 secretion in HaCaT cells costimulated with TNF-α and INF-γ. Conclusions This study demonstrates that AA is intimately linked to the onset of AD via gut dysbiosis. Data are available on reasonable request. Data may be obtained from a third party and are not publicly available. Metabolics data of breast milk is available from supplementary table 2.

中文翻译：

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母乳来源的花生四烯酸诱导的婴儿肠道菌群失调与特应性皮炎发病的关系


目的 介导宿主-微生物群相互作用并导致特应性皮炎 （AD） 发作的特定母乳衍生代谢物仍不清楚，需要进一步研究。设计 我们招募了 250 对母婴，收集了 978 份从出生到 6 个月大婴儿的纵向粪便样本，以及 243 份用于宏基因组学的母体粪便样本。同时，对 239 个相应的母乳样本进行了代谢组学分析。进行了动物和细胞实验以验证生物信息学结果。结果 临床发现表明，每日母乳喂养时间的减少与 AD 发病率的降低相关。这一观察激发了我们研究母乳衍生脂肪酸的影响。我们发现，高浓度的花生四烯酸 （AA），而不是二十碳五烯酸 （EPA） 或二十二碳六烯酸，会诱导婴儿肠道菌群失调。进一步的研究显示，四种特异性细菌将甘露聚糖降解为甘露糖，从而增强 O 抗原和脂多糖的甘露聚糖依赖性生物合成。相关性分析证实，在 AD 婴儿中，高 AA 浓度下大肠杆菌的丰度与一些微生物途径（例如，“GDP-甘露糖衍生的 O 抗原和脂多糖生物合成”）呈正相关。这些发现与动物研究的结果一致。此外，AA 而非 EPA 破坏了 CD4/CD8 细胞的比例，增加了皮肤病变面积并增加了外周 Th2 细胞的比例。它还促进了卵清蛋白免疫刺激后喂食 AA 的 BALB/c 小鼠的 IgE 分泌以及前列腺素和白三烯的生物合成。 此外，AA 显着增加了与 TNF-α 和 INF-γ 共刺激的 HaCaT 细胞中 IL-4 的分泌。结论 本研究证明，AA 通过肠道菌群失调与 AD 的发病密切相关。数据可应合理要求提供。数据可能从第三方获得，并且不会公开。母乳的代谢数据可从补充表 2 中获得。