Human Gut Microbial Sulfonolipids are linked to Inflammatory Bowel Diseases through Toll-Like Receptor 4 Signaling.

The trillions of microorganisms inhabiting the human gut are intricately linked to human health. At the species abundance level, correlational studies have connected specific bacterial taxa to various diseases. While the abundances of these bacteria in the gut serve as good indicators for disease progression, understanding the functional metabolites they produce is critical to decipher how these microbes influence human health. Here, we leverage multi-omics big data analysis to directly establish a negative correlation between sulfonolipid (SoL) biosynthesis in the human gut microbiome and inflammatory bowel disease (IBD). We experimentally validate this informatic correlation in a mouse model of IBD, showing that SoLs are produced in higher abundance in non-IBD mice compared to IBD mice. We determine that SoLs consistently contribute to the immunoregulatory activity of SoL-producing human gut commensal strains. We further reveal that sulfobacin A (SoL A), a representative member of SoLs, primarily mediates its dual immunomodulatory activity through Toll-like receptor 4 (TLR4). We also demonstrate that SoL A interacts with TLR4 via direct binding to myeloid differentiation factor 2 and that SoL A competes with the natural ligand, lipopolysaccharide, for binding. Together, these results suggest that SoLs mediate a protective effect against IBD through TLR4 signaling and also showcase a widely applicable informatics-based approach to directly linking the biosynthesis of functional metabolites to human health.