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ARS Home » Plains Area » Houston, Texas » Children's Nutrition Research Center » Research » Publications at this Location » Publication #365352
Title: Murin methyl donor deficiency impairs early growth in association with dysmorphic small intestinal crypts and reduced gut microbial community diversity

Author
item ALVES DA SILVA, ANTONIO - UNIVERSIDADE FEDERAL DO CEARA (UFC)
item DE CASTRO OLIVEIRA, STEPHANIE - CHILDREN'S HOSPITAL - CINCINNATI, OHIO
item DI RIENZI, SARA - BAYLOR COLLEGE OF MEDICINE
item LAUREN, DEHAN - CHILDREN'S HOSPITAL - CINCINNATI, OHIO
item ROOD, JILL - CHILDREN'S HOSPITAL - CINCINNATI, OHIO
item LE, HUNG - CHILDREN'S HOSPITAL - CINCINNATI, OHIO
item MAIER, ELIZABETH - UNIVERSIDADE FEDERAL DO CEARA (UFC)
item BETA, KRISTINA - UNIVERSIDADE FEDERAL DO CEARA (UFC)
item AIHARA, EITARO - UNIVERSITY OF CINCINNATI
item LEY, RUTH - MAX PLANCK INSTITUTE FOR BIOGEOCHEMISTRY
item PREIDIS, GEOFFREY - UNIVERSITY OF VIRGINIA SCHOOL OF MEDICINE
item SHEN, LANLAN - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC)
item MOORE, SEAN - UNIVERSITY OF VIRGINIA SCHOOL OF MEDICINE

Submitted to: Current Developments in Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/9/2018
Publication Date: 10/3/2018
Citation: Alves Da Silva, A.V., De Castro Oliveira, S.B., Di Rienzi, S.C., Lauren, D.M., Rood, J.K., Le, H., Maier, E.A., Beta, K.J., Aihara, E., Ley, R.E., Preidis, G.A., Shen, L., Moore, S.R. 2018. Murin methyl donor deficiency impairs early growth in association with dysmorphic small intestinal crypts and reduced gut microbial community diversity. Current Developments in Nutrition. 3(1):nzy070. https://doi.org/10.1093/cdn/nzy070
DOI: https://doi.org/10.1093/cdn/nzy070

Interpretive Summary: Folate and choline are essential methyl donor nutrients throughout the life span and the insufficiency of dietary methyl donor remains a significant public health issue worldwide. We designed mouse experiments to investigate the effects of combined dietary folate and choline deficiency, without macronutrient restriction, on prenatal and postnatal growth, intestinal epithelial structure and function, and the gut microbiome. In addition, we tested the effects of choline and folate deficiency on crypt morphology, gene expression, and DNA methylation in mouse small intestinal (SI) organoids. We found that methyl donor-deficient condition impairs the postnatal growth, intestinal morphology, and gut microbial diversity in mice. In addition, we found that methyl donor-deficiency modulates the expression of gene markers for intestinal stem cells and the DNA methylation of genes related to mucin production. Our findings provide important insight on how methyl donor nutrient based strategies may promote early gut health.

Technical Abstract: Folate 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. We 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. Pregnant 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. Both 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 a-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-alactosaminyltransferase-1 (B4galnt1) and Phosphoethanolamine/Phosphocholine-Phosphatase (Phospho1). MDD 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.