Early-life vitamin B12 orchestrates lipid peroxidation to ensure reproductive success via SBP-1/SREBP1 in Caenorhabditis elegans

The antidiabetic drug metformin aids bacteria in hijacking vitamin B12 from the environment through RcdA

“…Fecundity screen ( d ). The cartoons of sterile and fertile Δnhr-114 worms were adapted from our previous work 25 . The whole library was screened using Δnhr-114 worms treated with 2 mM phenformin and 0.05 nM B12.…”

“…Metformin and phenformin promote bacterial B12 accumulation. To investigate whether biguanides can change the level of B12 in bacteria, we employed the nhr-114 loss-of-function (hereafter abbreviated as Δnhr-114) worm model, which is a newly proposed B12-deficient model developed by us and others 25,27 . Phenotypically, these animals exhibit fertility in a B12 dose-dependent manner.…”

“…High-throughput screens for genes mediating the action of biguanides in bacteria. To identify the genetic machinery responsible for bacterial B12 accumulation by biguanides, we set up genetic screens using Δnhr-114 animals whose reproduction could be fully restored by B12 25,27 and the B12 sensor worm strain Pacdh-1::GFP. To better design the screens, we compared the sensitivities of these two worm models upon supplementation with various doses of B12 and found that the Δnhr-114 readout showed higher sensitivity to the low dose of B12 than the GFP sensor strain, especially when 0.05 nM B12 was co-administered with phenformin to the bacteria (Fig.…”

“…Unlike the symbiotic relationship between humans and gut microbes, C. elegans directly eats bacteria as a source of food, making it a suitable tool to detect B12 levels in bacteria 25 , 26 . In the present study, through functional analysis of B12 activity in worms and direct measurement of bacterial B12 levels, we demonstrated that biguanides significantly increased the amount of B12 in multiple E. coli strains.…”

“…Mechanistically, we found that both biguanides could increase the expressions of certain vital B12 transporter genes in E. coli, especially tonB, suggesting a possible mechanism by which biguanides promote B12 accumulation in bacteria. Through a genome-wide screen with the E. coli Keio collection library for genes responsible for biguanide action using B12-sensing worm models [25][26][27] , among which the tonB mutant bacterial clone was included as a positive control, we revealed that the biofilm formation process and transmembrane transport were the top enriched pathways. Knockout of genes from those enriched pathways significantly impaired the effect of phenformin in elevating bacterial B12 levels.…”