A hormone best known for triggering hunger pangs may hold the key to protecting the gut after radiation exposure, according to new research that pinpoints exactly how that protection works and what can shut it down.
The study, published in the International Journal of Molecular Sciences, comes from researchers at the Center for Immunology and Inflammation at the Feinstein Institutes for Medical Research and the Zucker School of Medicine at Hofstra/Northwell in Manhasset, New York. The team investigated ghrelin, a hormone produced in the stomach, as a potential treatment for gastrointestinal acute radiation syndrome (GI-ARS), a severe and currently untreatable complication of high-dose radiation exposure that destroys the lining of the intestines.
GI-ARS occurs at higher radiation doses, 6 Gy or more, delivered to the body at once, the kind of exposure associated with a nuclear detonation, a reactor accident, or a radiological weapon, rather than routine medical imaging (a chest X-ray, by comparison, delivers a tiny fraction of that dose). It is especially dangerous because it strikes the gut directly. The intestinal lining breaks down, allowing bacteria to leak from the gut into the bloodstream, which can trigger sepsis and organ failure. The Food and Drug Administration has approved several treatments for the blood-related form of radiation sickness, but despite GI-ARS’s high death toll, no treatment yet exists for it. That gap has become a priority for military and civilian planners preparing for scenarios like nuclear accidents, radiological terrorism, or nuclear conflict.
The researchers exposed mice to partial body irradiation and then gave them either ghrelin or a placebo at 24, 48, and 72 hours afterward. To test whether ghrelin’s benefits depend on the vagus nerve, the primary communication line between the brain and the gut, some mice had this nerve surgically severed before irradiation. Tissue and blood samples were collected four days after exposure to measure intestinal damage, inflammation, and the activity of two types of intestinal stem cells responsible for regenerating the gut lining.
Ghrelin substantially improved every measure of gut health the team tracked. It preserved the finger-like villi that absorb nutrients, increased the number of regenerative crypts, and cut radiation-induced cell death nearly in half. It also sharply reduced gut permeability and the leakage of bacteria into the liver and surrounding tissue, the process that drives sepsis in irradiated patients. Mice given ghrelin showed dramatic increases in two stem cell populations essential to intestinal repair: fast-dividing Lgr5-positive stem cells, which normally replenish the gut lining but are highly vulnerable to radiation, and a reserve population called Clu-positive revival stem cells, which activate specifically after severe injury to rebuild the depleted Lgr5 pool.
Cutting the vagus nerve reversed nearly all of these benefits. In vagotomized mice, ghrelin’s protective effects on villus height, crypt survival, and a blood marker of gut damage called citrulline were reduced by roughly one quarter to nearly two thirds. The hormone’s ability to shield cells from radiation-induced death and to preserve the intestinal barrier was similarly undercut, with gut permeability in nerve-severed mice ending up worse than in untreated, irradiated animals. The stem cell effects were hit hardest of all: the vagus nerve cut eliminated more than half of ghrelin’s boost to Lgr5-positive stem cells and roughly a third to a half of its effect on Clu-positive revival stem cells.
The findings point to a previously undescribed communication loop in which the brain, acting through the vagus nerve, directly regulates stem cell behavior in the gut following injury. That mechanistic detail matters for regulators as much as for scientists. Ghrelin has already passed through more than 100 early-phase human safety trials with a favorable track record, can be manufactured at scale, and is simple to inject in the field, all of which make it an appealing candidate for a mass-casualty countermeasure. Because drugs for radiation injuries are typically approved under the FDA’s Animal Rule, which requires human testing to be impractical and relies instead on a well-understood mechanism of action in animal studies, demonstrating precisely how ghrelin works strengthens its case for future development.
The authors note that the study used only male mice to limit hormonal variability, so ghrelin’s effects in females remain to be tested, and the vagus nerve was cut surgically rather than verified through direct nerve-conduction testing. Measurements were also taken at a single time point four days after irradiation, leaving open questions about how the stem cell response evolves over a longer recovery window.
This article was researched and sourced by Global Biodefense editors and reported with Claude AI assistance for drafting and editing.
Sources and further reading
Zhang F, Jin H, Ma G, et al. Ghrelin Induces Clu+ Revival Stem Cells and Regenerates Lgr5+ Stem Cells via the Vagus Nerve to Mitigate Gastrointestinal Acute Radiation Syndrome. International Journal of Molecular Sciences. 29 July 2026.