Microbiome-derived bacterial lipodipeptides directly regulate systemic monocyte responses by controlling gene expression of TLR/NF-κB pathway inhibitors.

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B109
Abstract ID: 4152

Presenting Author:
Saki Mihori , Graduate Student at UConn Hlth.

Abstract:

Microbiome regulation of innate immunity is poorly understood. Serine-glycine lipodipeptides (S/G lipids), derived from the microbiome phylum Bacteroidota, are TLR2 ligands that access the systemic circulation. We postulated that these lipids play a role in homeostatic regulation of systemic innate immune cells and previously documented that administering S/G lipids to autoimmune mice diminished systemic TLR2 responses and mitigated disease. Our present aim was to interrogate the effects of decreasing systemic S/G lipid levels on splenic monocytes. Decreasing microbiome Bacteroidota using oral antibiotics in C57BL/6 mice decreased GI and plasma S/G lipid levels and was associated with enhanced proinflammatory TLR2 responses. Administration of the S/G lipid family member, Lipid 654 (L654), to antibiotic-treated mice replenished plasma S/G lipid levels and normalized TLR2 responses. To understand the enhanced monocyte responses associated with decreased S/G lipids, transcriptomic analysis followed by gene ontology and pathway analyses revealed that decreasing S/G lipids significantly downregulated a subset of TLR/NF-κB pathway inhibitors. Consistent with its normalization of TLR2 responses, administering L654 normalized the gene expression of these inhibitors. Overall, our results confirm a role for microbiome-derived S/G lipids in regulating systemic innate immune responses and identify gene expression of TLR/NF-κB pathway inhibitors as a major target of S/G lipid regulation.