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

Sabnam Sahin Rahman, Shreya Bhattacharjee, Simran Motwani, Govind Prakash, Rajat Ujjainiya, Shivani Chitkara, Tripti Nair, Rachamadugu Sai Keerthana, Shantanu Sengupta and Arnab Mukhopadhyay ()
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Sabnam Sahin Rahman: Aruna Asaf Ali Marg
Shreya Bhattacharjee: Aruna Asaf Ali Marg
Simran Motwani: Aruna Asaf Ali Marg
Govind Prakash: Aruna Asaf Ali Marg
Rajat Ujjainiya: CSIR-Institute of Genomics and Integrative Biology
Shivani Chitkara: Academy of Scientific and Innovative Research (AcSIR)
Tripti Nair: Aruna Asaf Ali Marg
Rachamadugu Sai Keerthana: Aruna Asaf Ali Marg
Shantanu Sengupta: CSIR-Institute of Genomics and Integrative Biology
Arnab Mukhopadhyay: Aruna Asaf Ali Marg

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-60475-0

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