Aberrant changes in the gut microbiota are implicated in many diseases, including inflammatory bowel disease (IBD). Gut microbes produce diverse metabolites that can shape the immune system and impact the intestinal barrier integrity, indicating that microbe-mediated modulation may be a promising strategy for preventing and treating IBD. Although fecal microbiota transplantation and probiotic supplementation are well-established IBD therapies, novel chemical agents that are safe and exert strong effects on the gut microbiota are urgently needed. Herein, we report the total synthesis of heudelotinone and the discovery of 5-heudelotinone (an enantiomer) as a potent agent against experimental colitis that acts by modulating the gut microbiota. 5-Heudelotinone alters the diversity and composition of the gut microbiota and increases the concentration of short-chain fatty acids (SCFAs); thus, it regulates the intestinal immune system by reducing proinflammatory immune cell numbers, and maintains intestinal mucosal integrity by modulating tight junctions (TJs). Moreover, 5-heudelotinone () ameliorates colitis-associated colorectal cancer (CAC) in an azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced carcinoma model. Together, these findings reveal the potential of a novel natural product, namely, 5-heudelotinone, to control intestinal inflammation and highlight that this product is a safe and effective candidate for the treatment of IBD and CAC.

中文翻译：

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5S-Heudelotinone 通过以肠道微生物群依赖性方式塑造免疫系统和增强肠道屏障来缓解实验性结肠炎

肠道微生物群的异常变化与许多疾病有关，包括炎症性肠病（IBD）。肠道微生物产生多种代谢物，这些代谢物可以塑造免疫系统并影响肠道屏障的完整性，这表明微生物介导的调节可能是预防和治疗 IBD 的一种有前途的策略。尽管粪便微生物群移植和益生菌补充剂是成熟的 IBD 疗法，但仍迫切需要安全且对肠道微生物群产生强烈影响的新型化学制剂。在此，我们报告了 heudelotinone 的全合成，并发现了 5-heudelotinone（一种对映体）作为一种有效的实验性结肠炎药物，通过调节肠道微生物群发挥作用。5-Heudelotinone 改变肠道微生物群的多样性和组成，并增加短链脂肪酸 (SCFA) 的浓度；因此，它通过减少促炎免疫细胞数量来调节肠道免疫系统，并通过调节紧密连接（TJ）来维持肠粘膜完整性。此外，在氧化偶氮甲烷 (AOM)/硫酸葡聚糖钠 (DSS) 诱导的癌症模型中，5-heudelotinone () 可改善结肠炎相关结直肠癌 (CAC)。总之，这些发现揭示了一种新型天然产物，即 5-heudelotinone，在控制肠道炎症方面的潜力，并强调该产品是治疗 IBD 和 CAC 的安全有效的候选药物。