Prenatal Methyl-Donor Supplementation Augments Colitis in Young Adult Mice

Abstract

Inflammatory bowel diseases (IBD) have become highly prevalent in developed countries. Environmentally triggered exaggerated immune responses against the intestinal microbiome are thought to mediate the disorders. The potential dietary origins of the disease group have been implicated. However, the effects of environmental influences on prenatal developmental programming in respect to orchestrating postnatal microbiome composition and predilection towards mammalian colitis have not been examined. We tested how transient prenatal exposure to methyl donor micronutrient (MD) supplemented diets may impact predilection towards IBD in a murine dextran sulfate sodium (DSS) colitis model. Prenatal MD supplementation was sufficient to modulate colonic mucosal Ppara expression (3.2 fold increase; p=0.022) and worsen DSS colitis in young adulthood. The prenatal dietary exposure shifted the postnatal colonic mucosal and cecal content microbiomes. Transfer of the gut microbiome from prenatally MD supplemented young adult animals into germ free mice resulted in increased colitis susceptibility in the recipients compared to controls. Therefore, the prenatal dietary intervention induced the postnatal nurturing of a colitogenic microbiome. Our results show that prenatal nutritional programming can modulate the mammalian host to harbor a colitogenic microbiome. These findings may be relevant for the nutritional developmental origins of IBD.

DNA methylation-associated colonic mucosal immune and defense responses in treatment-naïve pediatric ulcerative colitis

“…Epigenetic maturation relevant for intestinal immune regulation continues beyond infancy in mammals, indicating that even postnatally occurring DNA methylation changes may be important in IBD pathogenesis 14 . Furthermore, maternal micronutrient supplementation can induce colonic mucosal DNA methylation modification relevant for murine colitis susceptibility, implicating this epigenetic process in the developmental origins of IBD 13 , 15 …”

Inflammatory Bowel Disease

“…Extension of these studies revealed that methyl donor supplementation during the prenatal period alone was sufficient to augment IBD risk, highlighting gestation as the critical developmental period for epigenetic changes that imprint sensitivity to mucosal injury, at least in this DSS model. 57 Interestingly, prenatal methyl donor exposure was also shown to induce changes in gut microbial composition independent of postnatal maternal colonization, resulting in a colitogenic microbiome. This microbial dysbiosis is attributed, at least in part, to methyl donor-derived epigenetic changes in the host that modulate mucosal immune development and function.…”

“…This microbial dysbiosis is attributed, at least in part, to methyl donor-derived epigenetic changes in the host that modulate mucosal immune development and function. 57 While this work has intriguing implications for the developmental origins of nutritional imprinting and IBD risk, further studies are needed to unravel how host genetics, environment and the microbiota interact to shape the mucosal epigenetic landscape over time.…”

“…Furthermore, fecal microbial transfer from methyl donor-exposed offspring potentiates susceptibility to DSS-induced colitis in germ-free recipients. 57 Several gene-targeted mouse models also demonstrate indigenous microbial dysbiosis characteristic of human IBD. Intestinal epithelial VDR knockout mice were found to harbor increased levels of Bacteroides and Escherichia coli and reduced abundance of butyrate-producing microorganisms.…”

Linking Immunity, Epigenetics, and Cancer in Inflammatory Bowel Disease

“…173 Thus, prenatal nutritional programming can modulate the mammalian host to harbor a colitogenic microbiome. 174 These studies provide important insights into microbespecific immunity through epigenetic regulation. They highlight the intimate interrelationship between expression of immunerelated genes and immunity pathways in the host with compositional and functional differences of the microbiome.…”