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Title: Maternal methyl-donor supplementation induces prolonged murine offspring colitis susceptibility in association with mucosal epigenetic and microbiomic changes

Author
item SCHAIBLE, TIFFANY - Baylor College Of Medicine
item HARRIS, R - Baylor College Of Medicine
item DOWD, SCOT - Research And Testing Laboratories, Llc
item SMITH, C - Children'S Nutrition Research Center (CNRC)
item KELLERMAYER, RICHARD - Baylor College Of Medicine

Submitted to: Human Molecular Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/31/2011
Publication Date: 2/4/2011
Citation: Schaible, T.D., Harris, R.A., Dowd, S.E., Smith, C.W., Kellermayer, R. 2011. Maternal methyl-donor supplementation induces prolonged murine offspring colitis susceptibility in association with mucosal epigenetic and microbiomic changes. Human Molecular Genetics. 20(9):1687-1696.

Interpretive Summary: It is now clear that certain dietary factors can influence the activity of some genes. In this study, we analyzed the effect of a diet rich in folic acid, vitamin B12, betaine, and choline (a diet referred to as a methyl-donor or MD diet) on the inflammation that occurs in the intestines when mice are caused to develop inflammatory bowel disease. This diet is known to alter the activity of a number of genes through what is referred to as epigenetic programing. The effect of maternal methyl-donor diet feeding was a strikingly increased severity of inflammatory bowel disease in their offspring. These findings underscore that epigenetic reprograming affecting susceptibility to inflammatory bowel disease can occur early in development in response to maternal dietary modifications.

Technical Abstract: Developmental epigenetic changes, such as DNA methylation, have been recognized as potential pathogenic factors in inflammatory bowel diseases, the hallmark of which is an exaggerated immune response against luminal microbes. A methyl-donor (MD) diet can modify DNA methylation at select murine genomic loci during early development. The components of the MDs are routinely incorporated into prenatal human supplements. Therefore, we studied the effects of maternal MD supplementation on offspring colitis susceptibility and colonic mucosal DNA methylation and gene expression changes in mice as a model. Additionally, we investigated the offspring mucosal microbiomic response to the maternal dietary supplementation. Colitis was induced by dextran sulfate sodium. Colonic mucosa from offspring of MD-supplemented mothers following reversal to control diet at weaning was interrogated by methylation-specific microarrays and pyrosequencing at postnatal days 30 (P30) and P90. Transcriptomic changes were analyzed by microarray profiling and real-time reverse transcription polymerase chain reaction. The mucosal microbiome was studied by high throughput pyrosequencing of 16S rRNA. Maternal MD supplementation induced a striking susceptibility to colitis in offspring. This phenotype was associated with colonic mucosal DNA methylation and expression changes. Metagenomic analyses did not reveal consistent bacteriomic differences between P30 and P90, but showed a prolonged effect of the diet on the offspring mucosal microbiome. In conclusion, maternal MD supplementation increases offspring colitis susceptibility that associates with persistent epigenetic and prolonged microbiomic changes. These findings underscore that epigenomic reprogramming relevant to mammalian colitis can occur during early development in response to maternal dietary modifications.