Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina, 29208, USA.
Department of Chemistry and The Swire Institute of Marine Science, The University of Hong Kong, Pokfulam Road, Hong Kong, China.
Nat Commun. 2024 Oct 30;15(1):9371. doi: 10.1038/s41467-024-53670-y.
The trillions of microorganisms inhabiting the human gut are intricately linked to human health. While specific microbes have been associated with diseases, microbial abundance alone cannot reveal the molecular mechanisms involved. One such important mechanism is the biosynthesis of functional metabolites. Here, we develop a biosynthetic enzyme-guided disease correlation approach to uncover microbial functional metabolites linked to disease. Applying this approach, we negatively correlate the expression of gut microbial sulfonolipid (SoL) biosynthetic enzymes to inflammatory bowel disease (IBD). Targeted chemoinformatics and metabolomics then confirm that SoL abundance is significantly decreased in IBD patient data and samples. In a mouse model of IBD, we further validate that SoL abundance is decreased while inflammation is increased in diseased mice. We show that SoLs consistently contribute to the immunoregulatory activity of different SoL-producing human microbes. We further reveal that sulfobacins A and B, representative SoLs, act on Toll-like receptor 4 (TLR4) and block lipopolysaccharide (LPS) binding, suppressing both LPS-induced inflammation and macrophage M1 polarization. Together, these results suggest that SoLs mediate a protective effect against IBD through TLR4 signaling and showcase a widely applicable biosynthetic enzyme-guided disease correlation approach to directly link the biosynthesis of gut microbial functional metabolites to human health.
栖息在人类肠道中的数万亿微生物与人类健康有着错综复杂的联系。虽然特定的微生物与疾病有关，但微生物的丰度并不能揭示涉及的分子机制。其中一个重要机制是功能性代谢物的生物合成。在这里，我们开发了一种基于生物合成酶的疾病相关性方法，以揭示与疾病相关的微生物功能性代谢物。应用这种方法，我们将肠道微生物磺内酯（SoL）生物合成酶的表达与炎症性肠病（IBD）负相关。然后，靶向化学生物信息学和代谢组学证实 SoL 在 IBD 患者数据和样本中的丰度显著降低。在 IBD 的小鼠模型中，我们进一步验证了在患病小鼠中 SoL 的丰度降低，而炎症增加。我们表明 SoLs 一致有助于不同产生 SoL 的人类微生物的免疫调节活性。我们进一步揭示了磺基丁二酸 A 和 B，代表性的 SoLs，作用于 Toll 样受体 4（TLR4）并阻断脂多糖（LPS）结合，抑制 LPS 诱导的炎症和巨噬细胞 M1 极化。总之，这些结果表明 SoLs 通过 TLR4 信号传导介导对 IBD 的保护作用，并展示了一种广泛适用的基于生物合成酶的疾病相关性方法，可直接将肠道微生物功能性代谢物的生物合成与人类健康联系起来。
