Writing in Genome Biology, the study implies that the suckling period during infancy is critical for defining the way that genes are expressed gut stem cells – and that this programmed stem cell gene activity plays a role in lifelong health through modulation of the intestine and gut microbiota.
Led by researchers at the USDA/ARS Children's Nutrition Research Center at Baylor College of Medicine and Texas Children's Hospital, the team suggested that while many recent studies demonstrate that the gut microbiome has a significant and long-term impact on gastrointestinal health, this new work provides a clue about how this works.
"Using mouse models, we were able to isolate and study a pure stem cell population," said study senior author Dr Lanlan Shen – who revealed that when her team used whole genome sequencing to study these cells during the suckling and weaning periods, they found that DNA methylation plays a regulatory role in intestinal stem cells.
In fact, they found that methylation of CpG islands (CGIs) turns on important genes involved in the development of these cells, and that in many cases, this epigenetic development depends on some of the bacteria that make up the gut microbiome.
"Cells are continually being replaced in the intestinal epithelium. They only last around four days and then new cells are formed," commented Dr Robert Waterland, who was also involved in the study. "It's a very dynamic process.”
“These stem cells are essentially the control centre of the gut. These are the cells that are going to regulate your gut physiology for your entire life."
DNA methylation
The team noted that DNA methylation is an epigenetic mechanism central to development and maintenance of complex mammalian tissues, but noted that our understanding of its role in intestinal development is limited.
Using whole genome bisulfite sequencing, the team found that differentiation of mouse colonic intestinal stem cells to intestinal epithelium is not associated with major changes in DNA methylation.
“However, we detect extensive dynamic epigenetic changes in intestinal stem cells and their progeny during the suckling period, suggesting postnatal epigenetic development in this stem cell population,” said Shen and colleagues.
Indeed, they reported that postnatal DNA methylation increases at CGIs correlate with transcriptional activation of glycosylation genes responsible for intestinal maturation – adding that postnatal CGI methylation and associated gene activation in intestinal epithelial cells are significantly altered by intestinal microbes and germ-free conditions.
“Our results demonstrate that the suckling period is critical for epigenetic development of intestinal stem cells, with potential important implications for lifelong gut health, and that the gut microbiome guides and/or facilitates these postnatal epigenetic processes,” said the team.
Probiotic potential
They concluded that future studies will be needed to determine how microbial–host metabolite interactions contribute to the epigenetic effects.
“Given the profound effects of the gut microbiome in human health and disease, it will be important to determine whether specific bacterial species are involved and whether there is a critical developmental period for the microbiota to influence ISC developmental epigenetics,” the team stated. “If so, this may open the possibility for developmentally targeted probiotic therapies to provide lifelong protection against intestinal disease.”
In addition, researchers suggested that it may be possible to use markers identified in the study and see if they can translate the findings to humans, and perhaps even develop an epigenetic maturation index in infants to guide optimal gut health.
"This promises some exciting opportunities to understand how we might be able to tailor one's microbiome exposure during infancy to maximize health and reduce gastrointestinal disease throughout life," added Waterland.
Source: Genome Biology
Published online, Open Access, doi: 10.1186/s13059-015-0763-5
“Postnatal epigenetic regulation of intestinal stem cells requires DNA methylation and is guided by the microbiome”
Authors: Da-Hai Yu, et al