Hirschsprung disease (HSCR), one of several neurocristopathies in children, is characterized by nerve loss in the large intestine and is mainly treated by surgery, which causes severe complications. Enteric neural crest-derived cell (ENCC) transplantation is a potential therapeutic strategy; however, so far with poor efficacy. Here, we assessed whether and how fecal microbiota transplantation (FMT) could improve ENCC transplantation in a rat model of hypoganglionosis; a condition similar to HSCR, with less intestinal innervation. We found that the hypoganglionosis intestinal microenvironment negatively influenced the ENCC functional phenotype in vitro and in vivo. Combining 16S rDNA sequencing and targeted mass spectrometry revealed microbial dysbiosis and reduced short-chain fatty acid (SCFA) production in the hypoganglionic gut. FMT increased the abundance of Bacteroides and Clostridium, SCFA production, and improved outcomes following ENCC transplantation. SCFAs alone stimulated ENCC proliferation, migration, and supported ENCC transplantation. Transcriptome-wide mRNA sequencing identified MAPK signaling as the top differentially regulated pathway in response to SCFA exposure, and inhibition of MEK1/2 signaling abrogated the SCFA-mediated effects on ENCC. This study demonstrates that FMT improves cell therapy for hypoganglionosis via short-chain fatty acid metabolism-induced MEK1/2 signaling.

中文翻译：

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粪便微生物群移植通过 SCFA 诱导的 MEK1/2 信号通路增强神经节减退症大鼠模型的细胞治疗

先天性巨结肠症（HSCR）是儿童的几种神经嵴病之一，其特点是大肠神经丧失，主要通过手术治疗，会引起严重的并发症。肠神经嵴衍生细胞（ENCC）移植是一种潜在的治疗策略；但迄今为止效果不佳。在这里，我们评估了粪便微生物群移植 (FMT) 是否以及如何能够改善神经节减退症大鼠模型中的 ENCC 移植；与 HSCR 类似的情况，肠道神经支配较少。我们发现，神经节减退的肠道微环境对体外和体内的ENCC 功能表型产生负面影响。结合 16S rDNA 测序和靶向质谱分析揭示了下神经节肠道中的微生物失调和短链脂肪酸 (SCFA) 产生减少。FMT 增加了拟杆菌和梭菌的丰度、SCFA 的产量，并改善了 ENCC 移植后的结果。SCFA 单独刺激 ENCC 增殖、迁移并支持 ENCC 移植。全转录组 mRNA 测序发现 MAPK 信号传导是响应 SCFA 暴露的首要差异调节途径，而 MEK1/2 信号传导的抑制消除了 SCFA 介导的对 ENCC 的影响。这项研究表明，FMT 通过短链脂肪酸代谢诱导的 MEK1/2 信号传导改善神经节减退症的细胞治疗。