MIT discovers amino acid that helps the gut heal itself

This enhanced ability to regenerate could help the body heal damage caused by radiation, which is a common side effect of cancer treatments. Although the study was conducted in mice, scientists say that if similar results are seen in humans, cysteine from food or supplements might offer a new way to help the intestine recover faster after injury.

"The study suggests that if we give these patients a cysteine-rich diet or cysteine supplementation, perhaps we can dampen some of the chemotherapy or radiation-induced injury," says Omer Yilmaz, director of the MIT Stem Cell Initiative, an associate professor of biology at MIT, and a member of MIT's Koch Institute for Integrative Cancer Research. "The beauty here is we're not using a synthetic molecule; we're exploiting a natural dietary compound."

Earlier studies have shown that specific types of diets, including calorie restriction, can enhance the function of intestinal stem cells. However, this research is the first to pinpoint a single nutrient that directly boosts the gut's regenerative capacity.

Yilmaz is the senior author of the study, which was recently published in Nature. The paper's lead author is Koch Institute postdoctoral researcher Fangtao Chi.

Diet and Regeneration

It is well known that diet plays a major role in health. High-fat diets can contribute to obesity, diabetes, and other chronic conditions, while low-calorie diets have been linked to longer lifespans in many species. Yilmaz's lab has long studied how different dietary patterns influence stem cell regeneration and has previously shown that both high-fat diets and short-term fasting can boost stem cell activity in distinct ways.

"We know that macro diets such as high-sugar diets, high-fat diets, and low-calorie diets have a clear impact on health. But at the granular level, we know much less about how individual nutrients impact stem cell fate decisions, as well as tissue function and overall tissue health," Yilmaz says.

In their latest work, the MIT team fed mice diets high in one of 20 amino acids, which are the building blocks of proteins. They then analyzed how each amino acid affected stem cell growth in the intestine. Cysteine produced the strongest impact, greatly increasing both stem cells and progenitor cells (immature cells that develop into adult intestinal cells).

Further experiments revealed that cysteine sets off a chain reaction that activates immune cells known as CD8 T cells. When intestinal cells absorb cysteine from food, they convert it into CoA, a cofactor that moves into the mucosal lining of the intestine. There, CD8 T cells take up CoA, which triggers them to multiply and release a signaling molecule called IL-22.

IL-22 plays a key role in regulating intestinal stem cell regeneration, but until now, scientists did not know that CD8 T cells could produce it. Once activated, these IL-22-releasing T cells help protect and repair the intestinal lining whenever it is injured.

"What's really exciting here is that feeding mice a cysteine-rich diet leads to the expansion of an immune cell population that we typically don't associate with IL-22 production and the regulation of intestinal stemness," Yilmaz says. "What happens in a cysteine-rich diet is that the pool of cells that make IL-22 increases, particularly the CD8 T-cell fraction."

These T cells tend to cluster in the intestinal lining, placing them in the right location to respond quickly to damage. The researchers observed that the activation of CD8 T cells occurred mainly in the small intestine, not elsewhere in the digestive tract, likely because most dietary protein is absorbed there.

Repairing Radiation and Chemotherapy Damage

In the study, mice on a cysteine-rich diet showed improved repair of radiation damage to the intestinal lining. In additional, unpublished work, the team found that the same diet helped regeneration after treatment with 5-fluorouracil, a chemotherapy drug commonly used for colon and pancreatic cancers that can also harm intestinal tissue.

Cysteine occurs naturally in many protein-rich foods, including meat, dairy, legumes, and nuts. The body can also make cysteine by converting another amino acid, methionine, in the liver. However, the cysteine produced internally circulates throughout the body rather than concentrating in the intestine the way dietary cysteine does.

"With our high-cysteine diet, the gut is the first place that sees a high amount of cysteine," Chi says.

Beyond Antioxidants

Cysteine has long been known for its antioxidant properties, but this study is the first to show that it also helps intestinal stem cells regenerate. The researchers are now exploring whether cysteine can stimulate regeneration in other tissues as well. One ongoing project is testing whether cysteine can promote hair follicle regrowth.

They also plan to continue investigating other amino acids that may influence stem cell renewal and gut health.

"I think we're going to uncover multiple new mechanisms for how these amino acids regulate cell fate decisions and gut health in the small intestine and colon," Yilmaz says.

This research was supported by the National Institutes of Health, the V Foundation, the Kathy and Curt Marble Cancer Research Award, the Koch Institute-Dana-Farber/Harvard Cancer Center Bridge Project, the American Federation for Aging Research, the MIT Stem Cell Initiative, and the Koch Institute Support (core) Grant from the National Cancer Institute.