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bioRxiv · 10.1101/2025.08.28.672769

Diacylglycerol metabolism drives host-pathogen responses during enteric infection in Drosophila

Li, X.·Mlih, M.·Karpac, J.
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Abstract

Lipid metabolism is fundamental to cellular homeostasis, supporting energy storage, membrane architecture, and cellular signaling. Beyond these canonical roles, lipids have emerged as critical regulators of host immunity. Here, we define a lipid-driven mechanism that governs host-pathogen interactions by impacting pathogen clearance and thus infection outcomes. Exploiting Drosophila, we show that enteric infection triggers robust accumulation of neutral lipids, and specifically 1,2-diacylglycerols (DAGs), in the midgut. Disruption of DAG biosynthesis or lipid transport in midgut enterocytes (ECs) impairs lipid accumulation and reduces host survival. Conversely, dietary lipid supplementation enhances lipid storage and improves survival. Mechanistically, these lipid-dependent responses regulate defecation, thereby controlling bacterial clearance from the midgut. DAGs can act as signaling lipids that activate protein kinase C (PKC), and DAG accumulation in ECs correlates with elevated PKC activity and calcium signaling in midgut visceral muscle (VM), promoting VM contraction, midgut motility, and expulsion of pathogens via defecation. Together, our findings reveal a previously unrecognized role for DAG metabolism in shaping host defenses.

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Li, X., Mlih, M., Karpac, J.. 2025-09-02. Diacylglycerol metabolism drives host-pathogen responses during enteric infection in Drosophila. https://doi.org/10.1101/2025.08.28.672769

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