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bioRxiv · 10.64898/2026.06.24.734305

Intestinal lipid metabolism controls immune response through NHR-68 and gut-brain signaling in C. elegans

Ren, J.·Sang, Y.·Nakayasu, E. S.·Kim, Y.-M.·Aballay, A.
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Abstract

Animals must allocate limited energetic resources across competing defense programs in response to infection. Here, we show that the conserved nuclear hormone receptor NHR-68 integrates fatty acid metabolism with the neural control of molecular and behavioral immunity in Caenorhabditis elegans. Acting in parallel with NHR-10, NHR-68 controls genes involved in polyunsaturated fatty acid (PUFA) metabolism. Loss of NHR-68 disrupts linoleic acid (LA) homeostasis, impairing pathogen avoidance behavior. Supplementation with LA restores avoidance, and fat-3 inhibition, which elevates LA, enhances pathogen avoidance, whereas loss of LA synthesis by fat-2 inhibition diminishes this behavior, indicating that LA promotes behavioral immunity. We further show that NHR-68 acts in the intestine to regulate linoleic acid homeostasis, and that changes in intestinal lipid metabolism influence an AWC-dependent pathogen-avoidance circuit through intestine-to-neuron communication. NHR-68 suppresses activation of the PMK-1/p38 MAPK and DAF-16/FOXO pathways, which mediate molecular immune responses. These findings identify a gut-brain transcriptional circuit that connects intestinal lipid metabolism to neural and immune outputs, revealing a mechanism by which the metabolic state coordinates behavioral and molecular defenses to optimize host protection.

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Ren, J., Sang, Y., Nakayasu, E. S., Kim, Y.-M., Aballay, A.. 2026-06-29. Intestinal lipid metabolism controls immune response through NHR-68 and gut-brain signaling in C. elegans. https://doi.org/10.64898/2026.06.24.734305

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