克罗恩病静止期症状为何挥之不去?研究产硫微生物和硫代谢途径的影响

Jonathan Golob, Krishna Rao, Jeffrey A Berinstein, Prashant Singh, William Chey, Chung Owyang, Nobuhiko Kamada, Peter D.R. Higgins, Vincent Young, Shrinivas Bishu, Allen Lee
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引用次数: 0

摘要

导言:即使在没有炎症的情况下,克罗恩病(CD)患者也会出现持续性症状,并使生活质量下降。我们曾证实,在有持续性消化道症状(qCD+S)和无持续性消化道症状(qCD-S)的静止期克罗恩病患者中,硫化物微生物含量丰富。因此,我们假设硫代谢途径将在粪便中富集,而不同数量的微生物将与 qCD+S 中重要的硫代谢途径相关。研究方法我们在 SPARC IBD 中进行了一项多中心观察研究。根据粪便钙蛋白水平 < 150 mcg/g 来定义静止性炎症。持续性症状以 CD-PRO2 为标准。对照组包括活动性 CD(aCD)和非 IBD 腹泻为主的肠易激综合征(IBS-D)。研究结果39名qCD+S患者、274名qCD-S患者、21名aCD患者和40名IBS-D患者接受了配对猎枪元基因组测序和非靶向代谢组分析。qCD+S患者的粪便代谢组与qCD-S和IBS-D患者有显著差异,但与aCD患者无显著差异。qCD+S患者富含含硫氨基酸途径,包括半胱氨酸和蛋氨酸,以及丝氨酸、甘氨酸和苏氨酸。相对于 qCD-S,谷胱甘肽和烟酸/烟酰胺通路也在 qCD+S 中富集,这表明线粒体功能障碍,而线粒体功能障碍是 H2S 信号转导的下游目标。多组学整合表明,qCD+S 中富集的微生物与重要的硫代谢途径有关。包括 CTH、isfD、sarD 和 asrC 在内的细菌硫代谢基因在 qCD+S 中调控失调。最后,有无硫化物生成微生物的硫代谢物在预测 qCD+S 的存在方面表现出良好的准确性。讨论在 qCD+S 中,微生物衍生的硫途径和下游线粒体功能受到干扰,这表明 H2S 信号与该病症的发病机制有关。未来的研究将确定靶向 H2S 通路是否能改善 qCD+S 患者的生活质量。
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Why Symptoms Linger in Quiescent Crohn's Disease: Investigating the Impact of Sulfidogenic Microbes and Sulfur Metabolic Pathways
Introduction: Even in the absence of inflammation, persistent symptoms in patients with Crohn's disease (CD) are prevalent and worsen quality of life. We previously demonstrated enrichment in sulfidogenic microbes in quiescent CD patients with (qCD+S) vs. without persistent GI symptoms (qCD-S). Thus, we hypothesized that sulfur metabolic pathways would be enriched in stool while differentially abundant microbes would be associated with important sulfur-metabolic pathways in qCD+S. Methods: We performed a multi-center observational study nested within SPARC IBD. Quiescent inflammation was defined by fecal calprotectin level < 150 mcg/g. Persistent symptoms were defined by CD-PRO2. Active CD (aCD) and non-IBD diarrhea-predominant irritable bowel syndrome (IBS-D) were included as controls. Results: Thirty-nine patients with qCD+S, 274 qCD-S, 21 aCD, and 40 IBS-D underwent paired shotgun metagenomic sequencing and untargeted metabolomic profiling. The fecal metabolome in qCD+S was significantly different relative to qCD-S and IBS-D but not aCD. Patients with qCD+S were enriched in sulfur-containing amino acid pathways, including cysteine and methionine, as well as serine, glycine, and threonine. Glutathione and nicotinate/nicotinamide pathways were also enriched in qCD+S relative to qCD-S, suggestive of mitochondrial dysfunction, a downstream target of H2S signaling. Multi-omic integration demonstrated that enriched microbes in qCD+S were associated with important sulfur-metabolic pathways. Bacterial sulfur-metabolic genes, including CTH, isfD, sarD, and asrC, were dysregulated in qCD+S. Finally, sulfur metabolites with and without sulfidogenic microbes showed good accuracy in predicting presence of qCD+S. Discussion: Microbial-derived sulfur pathways and downstream mitochondrial function are perturbed in qCD+S, which implicate H2S signaling in the pathogenesis of this condition. Future studies will determine whether targeting H2S pathways results in improved quality of life in qCD+S.
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