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

Author

Listed:
  • 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
    Academy of Scientific and Innovative Research (AcSIR))

  • Shivani Chitkara

    (Academy of Scientific and Innovative Research (AcSIR))

  • Tripti Nair

    (Aruna Asaf Ali Marg
    University of Southern California)

  • Rachamadugu Sai Keerthana

    (Aruna Asaf Ali Marg)

  • Shantanu Sengupta

    (CSIR-Institute of Genomics and Integrative Biology
    Academy of Scientific and Innovative Research (AcSIR))

  • Arnab Mukhopadhyay

    (Aruna Asaf Ali Marg)

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.

Suggested Citation

  • Sabnam Sahin Rahman & Shreya Bhattacharjee & Simran Motwani & Govind Prakash & Rajat Ujjainiya & Shivani Chitkara & Tripti Nair & Rachamadugu Sai Keerthana & Shantanu Sengupta & Arnab Mukhopadhyay, 2025. "Methionine cycle in C. elegans serotonergic neurons regulates diet-dependent behaviour and longevity through neuron-gut signaling," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60475-0
    DOI: 10.1038/s41467-025-60475-0
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    References listed on IDEAS

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    3. Javier Apfeld & Cynthia Kenyon, 1999. "Regulation of lifespan by sensory perception in Caenorhabditis elegans," Nature, Nature, vol. 402(6763), pages 804-809, December.
    4. Michael P. O’Donnell & Bennett W. Fox & Pin-Hao Chao & Frank C. Schroeder & Piali Sengupta, 2020. "A neurotransmitter produced by gut bacteria modulates host sensory behaviour," Nature, Nature, vol. 583(7816), pages 415-420, July.
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