Intestinal fibrosis is the primary cause of disability in patients with Crohn's disease (CD), yet effective therapeutic strategies are currently lacking. Here, we report a multiomics analysis of gut microbiota and fecal/blood metabolites of 278 CD patients and 28 healthy controls, identifying characteristic alterations in gut microbiota (e.g., Lachnospiraceae, Ruminococcaceae, Muribaculaceae, Saccharimonadales) and metabolites (e.g., L-aspartic acid, glutamine, ethylmethylacetic acid) in moderate-severe intestinal fibrosis. By integrating multiomics data with magnetic resonance enterography features, putative links between microbial metabolites and intestinal fibrosis-associated morphological alterations were established. These potential associations were mediated by specific combinations of amino acids (e.g., L-aspartic acid), primary bile acids, and glutamine. Finally, we provided causal evidence that L-aspartic acid aggravated intestinal fibrosis both in vitro and in vivo. Overall, we offer a biologically plausible explanation for the hypothesis that gut microbiota and its metabolites promote intestinal fibrosis in CD while also identifying potential targets for therapeutic trials.

中文翻译：

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多组学揭示了微生物代谢物是克罗恩病肠道纤维化的关键因素。


肠道纤维化是克罗恩病 （CD） 患者残疾的主要原因，但目前缺乏有效的治疗策略。在这里，我们报告了对 278 名 CD 患者和 28 名健康对照者的肠道微生物群和粪便/血液代谢物的多组学分析，确定了肠道微生物群（例如，毛螺菌科、瘤胃球菌科、Muribaculaceae、Saccharimonadales）和代谢物（例如，L-天冬氨酸、谷氨酰胺、乙基甲基乙酸）的特征性改变中度至重度肠道纤维化。通过将多组学数据与磁共振小肠造影特征相结合，建立了微生物代谢物与肠道纤维化相关形态学改变之间的假定联系。这些潜在的关联是由氨基酸（例如 L-天冬氨酸）、伯酸胆汁酸和谷氨酰胺的特定组合介导的。最后，我们提供了 L-天冬氨酸在体外和体内加重肠纤维化的因果证据。总体而言，我们为肠道微生物群及其代谢物促进 CD 肠道纤维化的假设提供了生物学上合理的解释，同时也确定了治疗试验的潜在靶点。