Inflammation-Induced Epigenetic Changes Limit Intestinal Stem Cell Regeneration

Researchers from the University of Michigan, Baylor College of Medicine, and other affiliated institutions have found that intestinal stem cells (ISCs) are permanently altered by inflammation in the gut, which limits the cells' capacity to repair the gut even after the inflammation has subsided. This matters because it influences how ISCs will react to upcoming difficulties. The research was published in the journal Cell Stem Cell.

We study graft-vs-host disease (GVHD), a major cause of mortality after bone marrow transplantation, a potentially curative therapy for many blood diseases. One of our goals is to better understand GVHD and identify strategies to control it.”

Dr. Pavan Reddy, Professor and Study Corresponding Author, Baylor College of Medicine

GVHD is an inflammatory reaction in which immune T cells from the bone marrow transplant donor attack the host gut cells, mainly ISCs.”

Dr. Dongchang Zhao, Study First Author, Baylor College of Medicine

Although many ISCs die during GVHD, some survive. The resolution of GVHD has significant consequences for host resilience and repair; however, it is unknown if they are totally functional or can regain full functionality.

“In the current study, we investigated the consequences of inflammation on ISCs in well-defined clinically relevant models of GVHD,” Reddy said.

Zhao said, “Using cellular and animal models, we found that exposure to inflammation drove ISCs to change their metabolism in ways that resulted in the accumulation of succinate, a product of cellular processes, which in turn reprogramed the epigenome.”

The system of chemical markers on DNA called the epigenome controls which genes are expressed by the cell. Inflammation-induced epigenome reprogramming changes the expression of genes involved in cell reproduction. Reprogrammed ISCs are often less capable of renewing, which is a prerequisite for intestinal repair.

We then investigated whether ISCs would be able to recuperate their regenerative ability after inflammation had resolved. We found that ISCs had not overcome their initial exposure to inflammation. Despite mitigating GVHD inflammation for 28 days, ISCs retained a reduced regenerative capacity that led to poor recovery and increased mortality from challenges, such as non-lethal radiation exposure, in animal models.”

Dr. Dongchang Zhao, Study First Author, Baylor College of Medicine

Zhao added, “More research is on the way to design strategies to help ISCs ‘forget’ their encounter with inflammation and enhance their resilience against immune attacks.”