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Abstract

Inositol lipid production is phylogenetically restricted among bacteria but prevalent in host-associated Bacteroidetes. The inositol lipid metabolic pathway in the human symbiont Bacteroides thetaiotaomicron (BT) is similar to in mycobacteria and proceeds through a phosphatidylinositol-phosphate (PIP) intermediate. However, some Bacteroidota spp. lacking homology to the BT-like pathway for inositol lipid synthesis nevertheless produce inositol sphingolipids through a pathway we predicted to lack the PIP intermediate, instead generating CDP-inositol. Here, we characterize this alternative inositol lipid gene cluster via heterologous expression in BT and gene knockout in Phocaeicola dorei. We determine the activity of key enzymes in the gene cluster and characterize inositol lipid structural diversity in a panel of Bacteroidota, including novel inositol lipid structures present in abundant human symbionts. As inositol lipids are potent bioactive signaling molecules in humans, the inositol lipid contribution from gut- associated Bacteroidetes, via one of two metabolic pathways, offers future potential mechanisms for host-microbe interactions.