Biosynthetic enzyme analysis identifies a protective role for TLR4-acting gut microbial sulfonolipids in inflammatory bowel disease.
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| Formato: | Artículo científico |
| Lenguaje: | en |
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Nature communications
2024
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| _version_ | 1868266284978798594 |
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| author | Older, Ethan A Zhang, Jian Ferris, Zachary E Xue, Dan Zhong, Zheng Mitchell, Mary K Madden, Michael Wang, Yuzhen Chen, Hexin Nagarkatti, Prakash Nagarkatti, Mitzi Fan, Daping Ellermann, Melissa Li, Yong-Xin Li, Jie |
| author_facet | Older, Ethan A Zhang, Jian Ferris, Zachary E Xue, Dan Zhong, Zheng Mitchell, Mary K Madden, Michael Wang, Yuzhen Chen, Hexin Nagarkatti, Prakash Nagarkatti, Mitzi Fan, Daping Ellermann, Melissa Li, Yong-Xin Li, Jie Older, Ethan A Zhang, Jian Ferris, Zachary E Xue, Dan Zhong, Zheng Mitchell, Mary K Madden, Michael Wang, Yuzhen Chen, Hexin Nagarkatti, Prakash Nagarkatti, Mitzi Fan, Daping Ellermann, Melissa Li, Yong-Xin Li, Jie |
| collection | PubMed - marine biology |
| contents | Biosynthetic enzyme analysis identifies a protective role for TLR4-acting gut microbial sulfonolipids in inflammatory bowel disease. Older, Ethan A Zhang, Jian Ferris, Zachary E Xue, Dan Zhong, Zheng Mitchell, Mary K Madden, Michael Wang, Yuzhen Chen, Hexin Nagarkatti, Prakash Nagarkatti, Mitzi Fan, Daping Ellermann, Melissa Li, Yong-Xin Li, Jie Toll-Like Receptor 4 Animals Gastrointestinal Microbiome Inflammatory Bowel Diseases Humans Mice Mice, Inbred C57BL Disease Models, Animal Lipopolysaccharides Macrophages Signal Transduction Metabolomics Male 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. |
| format | Artículo científico |
| id | pubmed_39477928 |
| institution | PubMed |
| language | en |
| publishDate | 2024 |
| publisher | Nature communications |
| record_format | pubmed |
| spellingShingle | Biosynthetic enzyme analysis identifies a protective role for TLR4-acting gut microbial sulfonolipids in inflammatory bowel disease. Older, Ethan A Zhang, Jian Ferris, Zachary E Xue, Dan Zhong, Zheng Mitchell, Mary K Madden, Michael Wang, Yuzhen Chen, Hexin Nagarkatti, Prakash Nagarkatti, Mitzi Fan, Daping Ellermann, Melissa Li, Yong-Xin Li, Jie Toll-Like Receptor 4 Animals Gastrointestinal Microbiome Inflammatory Bowel Diseases Humans Mice Mice, Inbred C57BL Disease Models, Animal Lipopolysaccharides Macrophages Signal Transduction Metabolomics Male Biosynthetic enzyme analysis identifies a protective role for TLR4-acting gut microbial sulfonolipids in inflammatory bowel disease. Older, Ethan A Zhang, Jian Ferris, Zachary E Xue, Dan Zhong, Zheng Mitchell, Mary K Madden, Michael Wang, Yuzhen Chen, Hexin Nagarkatti, Prakash Nagarkatti, Mitzi Fan, Daping Ellermann, Melissa Li, Yong-Xin Li, Jie Toll-Like Receptor 4 Animals Gastrointestinal Microbiome Inflammatory Bowel Diseases Humans Mice Mice, Inbred C57BL Disease Models, Animal Lipopolysaccharides Macrophages Signal Transduction Metabolomics Male 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. |
| title | Biosynthetic enzyme analysis identifies a protective role for TLR4-acting gut microbial sulfonolipids in inflammatory bowel disease. |
| topic | Toll-Like Receptor 4 Animals Gastrointestinal Microbiome Inflammatory Bowel Diseases Humans Mice Mice, Inbred C57BL Disease Models, Animal Lipopolysaccharides Macrophages Signal Transduction Metabolomics Male |
| url | https://pubmed.ncbi.nlm.nih.gov/39477928/ |