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

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.

Trehalose prevents neural tube defects by correcting maternal diabetes-suppressed autophagy and neurogenesis

“…These findings have important implications, as the only known effective prevention against NTDs, including those induced by maternal diabetes (50), is folic acid supplementation. Recently, it was reported that folic acid supplementations during pregnancies produce increased incidences of breast cancers in mouse models (27) and inflammatory bowel diseases in the offspring (39). Therefore, there is an urgent and critical need for alternate candidates for preventing NTDs.…”

“…Folate supplements are able to prevent about 70% of NTDs in human (47) and reduce maternal diabetes-induced NTDs in animal models (50). However, recent studies suggest that high maternal folate supplementation during pregnancy may increase the risk of breast cancer (27) and inflammatory bowel diseases (39) in offspring. Studies have shown that inositol can prevent some of the folate-resistant NTDs (16).…”

Colonic mucosal DNA methylation, immune response, and microbiome patterns in Toll-like receptor 2-knockout mice

“…This reconstitution is likely sensitive to the genetic background of the host and may be responsive to nutritional exposures (such as folate supplementation) during specific stages of development. 32 In summary, our manuscript emphasized the sophisticated network of molecular and cellular interactions that bridge genotype to phenotype in mammalian "superorganisms". This intercalating network has the capacity to overcome significant genetic/environmental insults (such as the homozygous absence of Tlr2 in mice) with no obvious phenotype change under usual environmental conditions.…”

“…This intricacy is probably most astounding in humans where the "superorganism" can be envisioned as the result of the multiorganic articLe addenduM articLe addenduM 1b). [30][31][32] Not surprisingly, plasma folate levels have been related to fecal bacterial composition changes in pregnant women recently. 33 These studies on one single vitamin/micronutrient model and illustrate the close to incomprehensible complexity of host-environment interactions in the human "superorganism".…”

Pathogenesis of Ulcerative Colitis and Crohn’s Disease: Similarities, Differences and a Lot of Things We Do Not Know Yet

“…Methyl-donors are abundant in human maternal dietary supplements. In mice, maternal methyl-donor supplementation augmented susceptibility to colitis in offspring, parallel to colonic mucosal DNA methylation and expression changes, followed by a sustained effect of the diet on colonic mucosal microbiota [185]. Although similar data in humans is missing, a study on ileal CD patients has found that several of the known CD risk gene loci were enriched in methylation compared to healthy controls, including the Th17 pathway and NOD2 [186].…”