Methionine cycle in C. elegans serotonergic neurons regulates diet-dependent behaviour and longevity through neuron-gut signaling

The folate and methionine cycles (Met-C) are regulated by vitamin B12 (B12), obtained exclusively from diet and microbiota. Met-C supports amino acid, nucleotide, and lipid biosynthesis and provides one-carbon moieties for methylation reactions. While B12 deficiency and polymorphisms in Met-C genes are clinically attributed to neurological and metabolic disorders, less is known about their cell-non-autonomous regulation of systemic physiological processes. Using a B12-sensitive Caenorhabditis elegans mutant, we show that the neuronal Met-C responds to differential B12 content in diet to regulate p38-MAPK activation in the intestine, thereby modulating cytoprotective gene expression, osmotic stress tolerance, behaviour and longevity. Mechanistically, our data suggest that B12-driven changes in the metabolic flux through the Met-C in the mutant’s serotonergic neurons increase serotonin biosynthesis. Serotonin activates its receptor, MOD-1, in the post-synaptic interneurons, which then secretes the neuropeptide FLR-2. FLR-2 binding to its intestinal receptor, FSHR-1, induces the phase transition of the SARM domain protein TIR-1, thereby activating the p38-MAPK pathway. Together, we reveal a dynamic neuron-gut signalling axis that helps an organism modulate life history traits based on the status of neuronal Met-C, determined by B12 availability in its diet.