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Abstract:
Inositol lipid production is phylogenetically restricted among bacteria but prevalent in host-associated Bacteroidota. The inositol lipid metabolic pathway in the human gut symbiont Bacteroides thetaiotaomicron (BT) is similar to the mycobacterial pathway for phosphatidylinositol synthesis and proceeds through a phosphatidylinositol-phosphate (PIP-DAG) 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-DAG intermediate, instead generating an array of soluble inositol intermediates leading to inositol sphingolipid synthesis. Here, we characterize this alternative inositol lipid gene cluster via heterologous expression in BT and gene knockout in Phocaeicola dorei. We define the activity of key enzymes in the gene cluster in vitro and describe inositol lipid structural diversity in a panel of 29 Bacteroidota species. As inositol lipids are potent bioactive signaling molecules in humans, the inositol lipid contribution from gut-associated Bacteroidota, via one of two metabolic pathways, offers future potential mechanisms for host-microbe interactions.
