Abstract
ABSTRACTMice harboring a mutation in the gene encoding gastric intrinsic factor (Gif), a protein essential for the absorption of vitamin B12/cobalamin (Cbl), have potential as a model to explore the role of vitamins in infection. The levels of Cbl in the blood of Giftm1a/tm1a mutant mice were influenced by the maternal genotype, with offspring born to heterozygous (high Cbl, F1) mothers exhibiting a significantly higher serum Cbl level than those born to homozygous (low Cbl, F2) equivalents. Low Cbl levels correlated with susceptibility to an infectious challenge with Salmonella enterica serovar Typhimurium or Citrobacter rodentium, and this susceptibility phenotype was moderated by Cbl administration. Transcriptional and metabolic profiling revealed that Cbl deficient mice exhibited a bioenergetic shift similar to a metabolic phenomenon commonly found in cancerous cells under hypoxic conditions known as the Warburg effect, with this metabolic effect being exacerbated further by infection. Our findings demonstrate a role for Cbl in bacterial infection, with potential general relevance to dietary deficiency and infection susceptibility.
Highlights
Mice harboring a mutation in the gene encoding gastric intrinsic factor (Gif), a protein essential for the absorption of vitamin B12/cobalamin (Cbl), have potential as a model to explore the role of vitamins in infection
By exploiting a novel Gif mutant mouse line, we have demonstrated a critical role for Cbl in controlling susceptibility to infection by two different bacterial pathogens, C. rodentium and S
We link this severe phenotype to likely disruptions in glycolysis, fatty acid synthesis, and energy homeostasis processes in Cbl-defective mice [12, 14, 30, 31, 33], with infection susceptibility further being influenced by the genotype of mothers, a phenomenon linked to their ability to transfer Cbl to their offspring [35]
Summary
Mice harboring a mutation in the gene encoding gastric intrinsic factor (Gif), a protein essential for the absorption of vitamin B12/cobalamin (Cbl), have potential as a model to explore the role of vitamins in infection. Our findings demonstrate a role for Cbl in bacterial infection, with potential general relevance to dietary deficiency and infection susceptibility. We postulate that this model, along with vitamin deficient mice, could be used to further explore the mechanisms associated with micronutrients and susceptibility to diseases, thereby increasing our understanding of disease in the malnourished. Vitamin B12 (cobalamin [Cbl]) serves as an essential cofactor in the cellular growth of most prokaryotic organisms While bacterial species such as Escherichia coli and Salmonella enterica have the ability to produce Cbl de novo anaerobically, mammals obtain Cbl exclusively from animal protein dietary sources [7]. Characterize the susceptibility of this mouse line to different infection challenges, highlighting maternal and metabolic influences on serum Cbl levels and susceptibility
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