Salmonella Typhimurium vitamin B12-dependent methionine metabolism regulates Caenorhabditis elegans development and vitellogenesis

Host-microbe interactions extend beyond infection, involving microbial metabolites, such as short-chain fatty acids, vitamins, and other bioactive compounds, that influence host physiology and development. Using Caenorhabditis elegans , an excellent model organism for host-microbe interactions, we demonstrate that Salmonella Typhimurium significantly accelerates C. elegans growth through a vitamin B12-dependent mechanism affecting methionine metabolism. We measured the reproductive maturity of C. elegans via embryo and oocyte production in response to various Salmonella virulence factor mutants and Salmonella strains deficient in cobalamin, folate, and methionine synthesis pathways. We found that the Salmonella cbiB and metH genes are essential for rapid development in C. elegans . Moreover, the C. elegans metr-1 mutant, which lacks functional methionine synthase, did not exhibit increased reproductive maturity when fed on S . Typhimurium or Escherichia coli OP50 supplemented with vitamin B12. However, methionine supplementation rescued this phenotype, indicating that C. elegans obtains vitamin B12 from S . Typhimurium, enhancing the methionine/S-adenosylmethionine (MET/SAM) cycle. We further observed that the C. elegans sams-1 mutant, deficient in SAM synthase, showed growth defects and reduced oocyte production when fed on Salmonella or OP50 supplemented with vitamin B12 or methionine, respectively. Thus, SAM emerges as a key link between bacterial vitamin B12 metabolism and host reproduction. Additionally, Salmonella increases vitellogenin-2 expression, reduces glutathione S-transferase activity, and decreases mitochondrial function. However, Δ cbiB and Δ metH reversed the beneficial effects of vitamin B12-dependent methionine on vitellogenesis and oxidative stress, suggesting that Salmonella promotes vitellogenesis and reduces oxidative stress through vitamin B12-dependent mitochondrial regulation, linking microbial metabolism to host development.