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Biosynthetic enzyme analysis identifies a protective role for TLR4-acting gut microbial sulfonolipids in inflammatory bowel disease

Author

Listed:
  • Ethan A. Older

    (University of South Carolina)

  • Jian Zhang

    (The University of Hong Kong
    Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou))

  • Zachary E. Ferris

    (University of South Carolina)

  • Dan Xue

    (University of South Carolina)

  • Zheng Zhong

    (The University of Hong Kong
    Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou))

  • Mary K. Mitchell

    (University of South Carolina)

  • Michael Madden

    (University of South Carolina)

  • Yuzhen Wang

    (University of South Carolina)

  • Hexin Chen

    (University of South Carolina)

  • Prakash Nagarkatti

    (University of South Carolina)

  • Mitzi Nagarkatti

    (University of South Carolina)

  • Daping Fan

    (University of South Carolina)

  • Melissa Ellermann

    (University of South Carolina)

  • Yong-Xin Li

    (The University of Hong Kong
    Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou))

  • Jie Li

    (University of South Carolina)

Abstract

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.

Suggested Citation

  • Ethan A. Older & Jian Zhang & Zachary E. Ferris & Dan Xue & Zheng Zhong & Mary K. Mitchell & Michael Madden & Yuzhen Wang & Hexin Chen & Prakash Nagarkatti & Mitzi Nagarkatti & Daping Fan & Melissa El, 2024. "Biosynthetic enzyme analysis identifies a protective role for TLR4-acting gut microbial sulfonolipids in inflammatory bowel disease," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53670-y
    DOI: 10.1038/s41467-024-53670-y
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    References listed on IDEAS

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