An intestinal sphingolipid promotes neuronal health across generations

Maternal diet and environment can influence the neuronal health of offspring. Here, we report that diet-induced intestinal sphingolipid biosynthesis reduces adult-onset neurodegeneration intergenerationally inCaenorhabditis elegans. FeedingC. eleganswith ursolic acid (UA), a natural plant product, provides neuroprotection by enhancing maternal provisioning of sphingosine-1-phosphate (S1P) - a bioactive sphingolipid. S1P promotes neuronal health across generations by upregulating transcription of the acid ceramidase-1 (asah-1) gene in the intestine. Intergenerational intestine-to-oocyte S1P transfer is essential for promoting neuronal health and is dependent on the lipoprotein yolk receptor RME-2 (Receptor-Mediated Endocytosis-2). Spatially regulating sphingolipid biosynthesis is critical, as inappropriateasah-1neuronal expression causes developmental axon outgrowth defects. Our results reveal that sphingolipid homeostasis impacts the development and intergenerational health of the nervous system.