Intestinal lipid metabolism controls molecular and behavioral immunity through NHR-68 and gut–brain signaling in Caenorhabditis elegans
- 1Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
- 2Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, United States of America
- 3Department of Microbiology and Molecular Genetics, McGovern Medical School at UTHealth, Houston, Texas, United States of America
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.
Mounting an immune response is energetically costly, and so host defenses are often influenced by internal metabolic states. This study identifies a gut-brain signaling mechanism in C. elegans wherein intestinal NHR-68 coordinates fatty acid homeostasis to shape pathogen avoidance and molecular immune responses.
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BibTeX
@article{ren2026intestinal,
title = {{Intestinal lipid metabolism controls molecular and behavioral immunity through NHR-68 and gut–brain signaling in Caenorhabditis elegans}},
author = {Jie Ren and Yu Sang and Young-Mo Kim and Ernesto S. Nakayasu and Alejandro Aballay},
journal = {PLOS Biology},
year = {2026},
month = sep,
doi = {10.1371/journal.pbio.3004026},
url = {https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3004026},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Intestinal lipid metabolism controls molecular and behavioral immunity through NHR-68 and gut–brain signaling in Caenorhabditis elegans
AU - Jie Ren
AU - Yu Sang
AU - Young-Mo Kim
AU - Ernesto S. Nakayasu
AU - Alejandro Aballay
PY - 2026
DA - 2026/09/29
JO - PLOS Biology
DO - 10.1371/journal.pbio.3004026
UR - https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3004026
AB - 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. Mounting an immune response is energetically costly, and so host defenses are often influenced by internal metabolic states. This study identifies a gut-brain signaling mechanism in C. elegans wherein intestinal NHR-68 coordinates fatty acid homeostasis to shape pathogen avoidance and molecular immune responses.
SN - 1545-7885
ER -