Early-life disruption of plasmalogen-positive anaerobic microbiota is linked to the aggravation of colitis

Abstract Objective The development of inflammatory bowel disease promotes increases in the aerobic and facultative anaerobic bacteria population but reduces the anaerobic bacteria population. Plasmalogens are widely present in anaerobic but absent from aerobic and facultative anaerobic bacteria. Herein, we hypothesized that the alteration of plasmalogen-producing bacteria might be involved in colitis development early in life. Design Abundances of plasmalogen-positive bacteria and dimethyl acetal (DMA, represent plasmalogens) were assessed via 16s microbiome and lipids analysis. Dextran sodium sulfate-induced colitis model, antibiotic-induced microbiota depletion, and metronidazole-induced anaerobic bacteria-eliminated model were utilized to analyze the role of early-life microbiota disruption. Fecal microbiota transplantation and plasmalogens administration were used for investigating the potential of plasmalogen-producing bacteria in colitis. Results Higher abundance of plasmalogen-positive bacteria and dimethyl-acetal were observed in young mice, but reduced abundance was observed in individuals with IBD. Early-life microbiota depletion exacerbated later colitis, while mid-life microbiota depletion showed partially reduced colitis. Besides, restitution of early-life microbiota confers protection against colitis. Of note, depletion of anaerobic bacteria resulted in reduced DMA levels, which underscored that anaerobic bacteria are the mainly microbial origin of colonic plasmalogens. Interestingly, plasmalogens treatment showed benefits against colitis in mice. Similarly, colonization with anaerobic microbiota from young mice suppressed colitis. On the contrary, early-life anaerobic bacteria elimination resulted in the aggravation of colitis, while this aggravation phenotype was reverted by plasmalogens administration. Conclusion Here, these data point to one of the mechanisms by which the gut microbiota controls susceptibility to colitis early in life via plasmalogens driven by anaerobic bacteria.

摘要 研究目的：炎症性肠病（IBD）的发生发展会伴随需氧菌与兼性厌氧菌种群数量升高，而厌氧菌种群数量降低。缩醛磷脂（plasmalogens）广泛存在于厌氧菌中，却不存在于需氧菌及兼性厌氧菌内。据此我们提出假说：生命早期产缩醛磷脂菌群的改变可能参与结肠炎的发生发展。
实验设计：本研究通过16S微生物组分析与脂质组分析，对缩醛磷脂阳性菌群的丰度以及二甲基缩醛（DMA，作为缩醛磷脂的代表标志物）水平进行检测。采用葡聚糖硫酸钠（DSS）诱导结肠炎模型、抗生素诱导菌群耗竭模型及甲硝唑诱导厌氧菌清除模型，分析生命早期菌群紊乱的生物学效应。通过粪便菌群移植与缩醛磷脂给药实验，探究产缩醛磷脂菌群在结肠炎中的潜在干预价值。
研究结果：幼龄小鼠体内缩醛磷脂阳性菌群与二甲基缩醛的丰度更高，而炎症性肠病患者体内二者丰度均显著下降。生命早期菌群耗竭会加重成年后的结肠炎症状，而中年时期菌群耗竭则会部分减轻结肠炎病情。此外，恢复生命早期菌群可对结肠炎起到保护作用。值得注意的是，厌氧菌清除会导致DMA水平降低，这证实厌氧菌是结肠缩醛磷脂的主要微生物来源。有趣的是，缩醛磷脂给药可有效缓解小鼠结肠炎症状。同样，移植幼龄小鼠的厌氧菌群也可抑制结肠炎的发生发展。与之相反，生命早期清除厌氧菌会加重结肠炎，而该加重表型可通过缩醛磷脂给药得到逆转。
结论：本研究结果揭示了肠道菌群通过厌氧菌驱动的缩醛磷脂途径，调控生命早期结肠炎易感性的潜在机制之一。