Excess Vitamins or Imbalance of Folic Acid and Choline in the Gestational Diet Alter the Gut Microbiota and Obesogenic Effects in Wistar Rat Offspring

Abstract

Excess vitamin intake during pregnancy leads to obesogenic phenotypes, and folic acid accounts for many of these effects in male, but not in female, offspring. These outcomes may be modulated by another methyl nutrient choline and attributed to the gut microbiota. Pregnant Wistar rats were fed an AIN-93G diet with recommended vitamin (RV), high 10-fold multivitamin (HV), high 10-fold folic acid with recommended choline (HFol) or high 10-fold folic acid without choline (HFol-C) content. Male and female offspring were weaned to a high-fat RV diet for 12 weeks post-weaning. Removing choline from the HFol gestational diet resulted in obesogenic phenotypes that resembled more closely to HV in male and female offspring with higher body weight, food intake, glucose response to a glucose load and body fat percentage with altered activity, concentrations of short-chain fatty acids and gut microbiota composition. Gestational diet and sex of the offspring predicted the gut microbiota differences. Differentially abundant microbes may be important contributors to obesogenic outcomes across diet and sex. In conclusion, a gestational diet high in vitamins or imbalanced folic acid and choline content contributes to the gut microbiota alterations consistent with the obesogenic phenotypes of in male and female offspring.

Modification of the serotonergic systems and phenotypes by gestational micronutrients

“…These results are consistent with the previous study that examined macronutrient selection where protein energy intake was lower in offspring from the control dams but not from HV-fed dams (Szeto, et al 2010). Our observed alterations were consistent with long-term food intake and body weight changes from weaning to 12 weeks postweaning, body composition and glucose concentrations representative of the obesogenic phenotypes, as well as our previous evidence of unregulated energy balance (Mjaaseth et al 2021). Male offspring of dams fed a diet devoid of choline but high in folic acid were not different from the RV group in their response to mCPP, even though the obesogenic phenotypes were evident, suggesting that consequences of an imbalance created between folic acid and choline may not contribute to central 5-HT effects.…”

“…Male offspring of dams fed a diet devoid of choline but high in folic acid were not different from the RV group in their response to mCPP, even though the obesogenic phenotypes were evident, suggesting that consequences of an imbalance created between folic acid and choline may not contribute to central 5-HT effects. In female offspring, only those from dams fed a diet high in folic acid with the recommended choline content displayed higher responsiveness to mCPP, consistent with their absence of the obesogenic phenotypes in the current study as well as previous reports (Huot, et al 2013;Mjaaseth et al 2021). Differences in food intake response to mCPP across sex of the offspring, where food intake suppression was less in males whereas it was more in females, may explain their contrasting outcomes to the high folic acid gestational diet.…”

“…Second, we have not identified specific bacterial species responsible for altering colon 5-HT concentrations. Our previous data showed that an imbalance between folic acid and choline led to lower Bifidobacterium, Allobaculum and Lactobacillus vaginalis toward increased energy harvest (Mjaaseth et al 2021), but further studies are needed to examine specific gut microbial communities as well as gut-derived factors such as short-chain fatty acids (Reigstad, et al 2015) as molecular targets in linking colon 5-HT and metabolic health. Third, we cannot ignore potential maternal influences on establishment of the gut microbiota and serotonergic functions, as many studies indicate the role of maternal gut microbiota being transferred to offspring as the basis of programming effects (Walker, et al 2017) although other studies distinctly show that diets during pregnancy can independently influence the gut microbiota of offspring (Chu, et al 2016).…”

“…Whereas excess folic acid intakes are commonly observed (Bailey et al 2019;Moore et al 2020), only small proportions of the populations meet the Adequate Intake requirement for choline (Lewis, et al 2014;Moore et al 2020;Fulgoni 2016, 2017), and such imbalances between folic acid and choline may have potential adverse outcomes. We have recently shown that choline acts as a strong modulator of the effects of the high folic acid gestational diet with changes in the gut microbiota composition toward obesity that differed in a sex-dependent manner (Mjaaseth, et al 2021). However, the mechanisms underlying differences in the metabolic phenotypes including body composition and glucose concentrations have not been established.…”

Folate and Choline: Does It Take Two to Tango in Early Programming of Disease?

“…As the link between gut microbiota and health is being uncovered [78], the end-products of microbial metabolism are increasingly appreciated as determinants of host health. Recent work demonstrates that altered gut microbiota composition and gutderived profiles of short-chain fatty acids and serotonin in offspring of dams fed excess vitamins or imbalanced folate-choline may account for the obesogenic phenotypes [60,79]. Lastly, sexually dimorphic responses to gestational intakes of folic acid [80,81] or choline [82] have been observed that reflect biased DNA methylation patterns.…”