Abstract
ABSTRACTBackgroundFolate and choline are essential methyl donor nutrients throughout the life span; however, the adverse effects of combined deficiency on early growth, intestinal epithelial morphology, and the gut microbiome remain only partially understood.ObjectivesWe investigated the effects of dietary folate and choline deficiency on early growth, small intestinal (SI) epithelial architecture, and the gut microbiota of mice. To explore potential mechanisms for adverse effects on gut epithelial morphology, we also evaluated gene expression and DNA methylation in mouse intestinal epithelial organoids (enteroids) maintained in methyl donor–deficient (MDD) conditions.MethodsPregnant dams were administered 1 of 4 diets: 1) control diet (CD−), 2) an isocaloric MDD− diet, or 3) CD+ and 4) MDD+ formulations containing 1% succinylsulfathiazole to inhibit folate-producing gut bacteria. We weaned pups to their dams’ diet at 3 wk of age and monitored body weight and tail length pre- and postweaning. We measured serum folate, SI crypt morphology, and microbiota composition at 7 wk of age.ResultsBoth MDD+ and MDD− diets impaired early ponderal and linear growth, lowered serum folate concentrations, and produced patchy areas of increased crypt depth throughout the SI. Succinylsulfathiazole increased crypt depth independently of diet. MDD or succinylsulfathiazole, alone or in combination, altered the gut microbiome, with decreased Bacteroidales and Clostridiales, increased Lactobacillales and Erysipelotrichaceae taxa, and decreased α-diversity indexes. Enteroids maintained in MDD media displayed dysmorphic crypt domains, altered expression of stem cell and secretory differentiation genes, and decreased DNA methylation of the glycosylation genes Beta-1,4-N-Acetyl-Galactosaminyltransferase-1 (B4galnt1) and Phosphoethanolamine/Phosphocholine-Phosphatase (Phospho1).ConclusionMDD impairs ponderal and linear growth in mice in association with dysmorphic SI crypts and reduced gut microbial diversity. In vitro methyl donor deficiency similarly induced dysmorphic crypts in mouse enteroids in conjunction with altered gene expression and DNA methylation.
Highlights
Despite declining rates of folate deficiency worldwide, folate insufficiency remains a significant public health issue [1,2,3]
Because folate is used as an adjunct therapy for tropical sprue and is important for DNA methylation, we hypothesized methyl donor deficiency (MDD) would induce the growth failure and crypt hypertrophy seen in EE by modulating intestinal stem cell dynamics [12,13,14]
Intestinal epithelial cell proliferation, and elongation of nuclei To determine the extent to which the body growth and systemic effects of MDD and antibiotic exposure were accompanied by enteropathy, we examined crypt/villus architecture, epithelial proliferation, and intestinal epithelial nuclear morphology along the length of the small intestinal (SI)
Summary
Despite declining rates of folate deficiency worldwide, folate insufficiency remains a significant public health issue [1,2,3]. Choline is abundant in common dietary constituents; ∼90% of individuals do not meet their adequate daily intake [4] Both folate and choline provide one-carbon units for the synthesis of the methyl donor S-adenosylmethionine, a ubiquitous component required for cell biosynthesis of a wide range of components that plays a key role in DNA methylation, a fundamental epigenetic mechanism [5, 6]. Both micronutrients are produced and consumed by gut microbiota; animals obtain folate and choline from dietary sources and share these nutrients with, and derive them from, resident gut microbes. Folate and choline are essential methyl donor nutrients throughout the life span; the adverse effects of combined deficiency on early growth, intestinal epithelial morphology, and the gut microbiome remain only partially understood
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