Researchers have found that inflammation in the gut can have lasting effects on intestinal stem cells (ISCs), impairing their ability to heal the intestine even after the inflammation has subsided. This discovery is crucial as it influences how ISCs respond to future challenges.
A team of researchers from Baylor College of Medicine, the University of Michigan, and other collaborating institutions has revealed that gut inflammation leaves enduring effects on intestinal stem cells (ISCs), hampering their healing capacity even after the inflammation resolves. This finding is significant because it impacts the future responses of ISCs to various challenges. The research has been published in Cell Stem Cell.
“We focus on graft-vs-host disease (GVHD), a serious condition that can lead to death following bone marrow transplantation, which is a potential cure for several blood disorders. One of our objectives is to deepen our understanding of GVHD and explore ways to control it,” explained Dr. Pavan Reddy, the corresponding author, professor, and director of the Dan L Duncan Comprehensive Cancer Center at Baylor, who previously worked at the University of Michigan.
“GVHD occurs when immune T cells from the donor’s bone marrow attack the gut cells of the host, particularly targeting ISCs,” said Dr. Dongchang Zhao, the first author working in Reddy’s lab.
Although many ISCs die during GVHD, some do survive. What remains unclear is whether these surviving ISCs are fully functional or whether they can regain their full functionality after GVHD has resolved. This has significant implications for the body’s ability to recover and stay resilient.
“In our current study, we explored the effects of inflammation on ISCs using well-defined clinical models of GVHD,” Reddy noted.
“Through cellular and animal studies, we discovered that inflammation caused ISCs to modify their metabolism, leading to the buildup of succinate, a byproduct of cellular activity. This shift in metabolism then reprogrammed the epigenome,” Zhao explained.
The epigenome refers to the chemical modifications on DNA that control gene expression within a cell. The reprogramming of the epigenome due to inflammation altered the expression of genes responsible for cell proliferation. As a result, the reprogrammed ISCs were less capable of regenerating, which is the initial step necessary for healing the intestine.
“We then examined whether ISCs could restore their regenerative abilities once the inflammation had subsided,” Reddy continued. “Our findings indicated that ISCs did not recover from their initial exposure to inflammation. Even after 28 days of reduced GVHD inflammation, ISCs maintained a diminished regenerative capacity, which resulted in ineffective recovery and increased mortality in response to challenges like non-lethal radiation exposure in animal models. We aim to conduct further research to devise methods that could help ISCs ‘forget’ their inflammation exposure and improve their resilience against immune responses.”
Other contributors to this research include Visweswaran Ravikumar, Tyler J. Leach, Daniel Kraushaar, Emma Lauder, Lu Li, Yaping Sun, Katherine Oravecz-Wilson, Evan T. Keller, Fengju Chen, Laure Maneix, Robert R. Jenq, Robert Britton, Katherine Y. King, Ana E. Santibanez, Chad J. Creighton, and Arvind Rao, all of whom are affiliated with Baylor College of Medicine, the University of Michigan, and the University of Texas MD Anderson Cancer Center in Houston.
This research was made possible through support from various NIH grants (P01CA039542, P01HL149633, R01CA203542, R01HL152605, R01CA217156, R01AI165563, and CA125123) as well as a grant from the Cancer Prevention and Research Institute of Texas (CPRIT) (RR220033).
