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Infection Susceptibility in Gastric Intrinsic Factor (Vitamin B12)-Defective Mice Is Subject to Maternal Influences.

ABSTRACT: UNLABELLED: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. The levels of Cbl in the blood of Gif(tm1a/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. IMPORTANCE:Malnutrition continues to be a major public health problem in countries with weak infrastructures. In communities with a high prevalence of poor diet, malnourishment and infectious disease can impact vulnerable individuals such as pregnant women and children. Here, we describe a highly flexible murine model for monitoring maternal and environmental influences of vitamin B12 metabolism. We also demonstrate the potential importance of vitamin B12 in controlling susceptibility to bacterial pathogens such as C. rodentium and S Typhimurium. We postulate that this model, along with similarly 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.

SUBMITTER: Mottram L

PROVIDER: S-EPMC4916386 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Infection Susceptibility in Gastric Intrinsic Factor (Vitamin B12)-Defective Mice Is Subject to Maternal Influences.

Mottram Lynda L Speak Anneliese O AO Selek Reza M RM Cambridge Emma L EL McIntyre Zoe Z Kane Leanne L Mukhopadhyay Subhankar S Grove Carolyn C Colin Amy A Brandt Cordelia C Duque-Correa Maria A MA Forbester Jessica J Nguyen Tu Anh Pham TA Hale Christine C Vasilliou George S GS Arends Mark J MJ Wren Brendan W BW Dougan Gordon G Clare Simon S

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<h4>Unlabelled</h4>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. The levels of Cbl in the blood of Gif(tm1a/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) equ ...[more]

PMID: 27329747

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Project description:BackgroundVitamin B12 deficiency during pregnancy has been associated with adverse maternal and infant health outcomes. Few prospective studies have investigated vitamin B12 status early in pregnancy, and its links to infant vitamin B12 status, particularly in India where the burden of vitamin B12 deficiency is estimated to be the highest globally. The objective of this study was to examine the associations of maternal vitamin B12 biomarkers with neonatal vitamin B12 status.MethodsPregnant women (~12 weeks' gestation) were enrolled in a perinatal cohort study in Bangalore, India. Total vitamin B12, methylmalonic acid (MMA), and homocysteine concentrations were evaluated in maternal samples at enrollment and in neonates at birth using cord blood. Linear and binomial regression models were used to evaluate the associations of maternal vitamin B12 biomarkers with neonatal vitamin B12 status and perinatal outcomes.ResultsA total of 63.2% of women had vitamin B12 deficiency (<148 pmol/L), 87.2% had vitamin B12 insufficiency (<221 pmol/L), and 47.3% had impaired vitamin B12 status (vitamin B12<148 pmol/L and MMA>0.26μmol/L) at enrollment; 40.8% of neonates had vitamin B12 deficiency, 65.6% were insufficiency, and 38.1% had impaired vitamin B12 status at birth. Higher maternal vitamin B12 concentrations at enrollment were associated with increased neonatal vitamin B12 concentrations (β(SE): 0.40 (0.05); p<0.0001) and lower risk of neonatal vitamin B12 deficiency (Risk Ratio [RR]: 0.53; 95% CI: [0.43, 0.65]; p<0.0001). Maternal vitamin B12 deficiency (RR: 1.97 [1.43, 2.71]; p<0.001), insufficiency (RR: 2.18 [1.23, 3.85]; p = 0.007), and impaired vitamin B12 status (RR: 1.49 [1.13, 1.97]; p = 0.005) predicted a two-fold increase in the risk of neonatal vitamin B12 deficiency at birth.ConclusionsThe prevalence of vitamin B12 deficiency was high early in pregnancy and predicted neonatal vitamin B12 status. Future research is needed to determine the role of vitamin B12 in the development of pregnancy and infant outcomes, and to inform screening and interventions to improve maternal and child health.

Project description:Folate, vitamin B12, and homocysteine concentrations during pregnancy are important factors for early development and may persistently influence kidney function in the offspring. We examined the associations of folate, vitamin B12, and homocysteine concentrations during pregnancy with kidney outcomes in school-aged children.Population-based prospective cohort study from fetal life onward.This study was performed among 4,226 pregnant women and their children.Folate, vitamin B12, and homocysteine blood concentrations measured in early pregnancy (median gestational age, 13.2 [IQR, 12.2-14.8] weeks) and at birth (cord blood).At the median age of 6.0 (IQR, 5.9-6.3) years, we measured combined kidney volume with ultrasound, estimated glomerular filtration rate based on creatinine (eGFRcr) and cystatin C (eGFRcys) concentrations, and microalbuminuria.We observed that higher maternal folate concentrations were associated with larger childhood combined kidney volume, whereas higher maternal vitamin B12 concentrations were associated with higher childhood eGFRcys (P for both <0.05). These associations were independent of homocysteine concentrations. Higher maternal homocysteine concentrations were associated with smaller combined kidney volume and lower childhood eGFRcys (P for both < 0.05). The association of maternal homocysteine concentrations with childhood eGFRcys was largely explained by combined kidney volume. Higher cord blood homocysteine concentrations were associated with larger combined kidney volume and lower eGFRcys (P for both < 0.05). Folate, vitamin B12, or homocysteine concentrations were not associated with microalbuminuria.Observational study, so causality cannot be established.Our findings suggest that folate, vitamin B12, and homocysteine concentrations during fetal life are associated with offspring kidney development. However, effect sizes are small. Further studies to replicate these findings and assess the causality and consequences for kidney health in later life are needed.

Dataset Information

Infection Susceptibility in Gastric Intrinsic Factor (Vitamin B12)-Defective Mice Is Subject to Maternal Influences.

Publications

Infection Susceptibility in Gastric Intrinsic Factor (Vitamin B12)-Defective Mice Is Subject to Maternal Influences.

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