Cysteine may be the secret to repairing gut damage
A new MIT study finds that the amino acid initiates the regeneration of the intestinal lining by activating intestinal stem cells
When we eat anything, from nutritious vegetables to our favorite junk foods, the gastrointestinal (GI) tract is responsible for absorbing nutrients from our diet. Its lesser known function, however, is immunity.
The GI tract is lined with immune and stem cells. Stem cells are unspecialized cells that can develop into indefinitely more cells of the same type, which work together with immune cells to inform nearby cells of intestinal injury and respond by initiating tissue repair. Injury to these tissues is a common side effect of many infectious diseases and cancer treatments, including radiation and chemotherapy. Given the GI tract’s dual functions, researchers and doctors alike have previously suspected that diets could be modified to affect intestinal repair, but they didn’t quite know how.
New research from MIT’s Yilmaz Lab has demonstrated that a single amino acid, cysteine, initiates intestinal repair by interacting with immune and stem cells in the gut.
Cysteine is one of the twenty amino acids — the building blocks of proteins. Amino acids are often classified as micronutrients. As the name suggests, micronutrients are both small in size and required in “micro” amounts for various bodily functions. In contrast, macronutrients (e.g., proteins, carbohydrates, and fats) are needed in large amounts.
In the past, Associate Professor of Biology Ömer H. Yilmaz had focused his research on how different macronutrient-based diets, like keto and low-calorie diets, impact health and disease. The problem was that very little was known about the mechanisms by which micronutrients, like individual amino acids, impact those same biological processes.
Dr. Fangtao Chi, a researcher in the Yilmaz Lab, recognized this knowledge gap and sought to address it during his postdoctoral fellowship: “Fangtao became very interested in moving the lab in a new direction,” Yilmaz said.
Chi began by feeding diets rich in each amino acid to mice and noticed that a cysteine-rich diet caused increased levels of HMGCS2, a key protein associated with intestinal stem cells. He knew that this amino acid had to be explored further.
One day, a lab member approached Chi, trying to get rid of a surplus of immune-cell-deficient mice. When he fed those mice a cysteine-rich diet, he was shocked by the result: “The cysteine-rich diet didn’t have any effect on those mice, which directly pushed me to think about immune cell contribution,” Chi recalled with a smile. “So this link really opened a new door in this project.”
In the end, Chi’s experiments revealed that immune cells are a major intermediate in the intestinal stem cell pathway. The study identified a pathway that begins with the conversion of cysteine to coenzyme A (CoA), an essential protein for metabolism. High levels of CoA stimulate the activity of immune cells called CD8+ T cells. These T cells release signaling molecules known as IL-22 cytokines, which tell intestinal stem cells that it’s time to get working.
Yilmaz and Chi found an answer to their questions regarding the importance of micronutrients: cysteine repairs gut damage by activating intestinal stem cells.
For Dr. Christopher Duggan, this finding could be invaluable for his patients. As the senior gastroenterologist at Boston Children’s Hospital and medical director of the Center for Advanced Intestinal Rehabilitation, Duggan specializes in developing nutrition interventions for children with chronic gastrointestinal diseases. Though this research seems promising for treating such diseases, Chi and Duggan agree that this finding cannot yet be used as justification for recommending cysteine-rich diets to human patients. Instead, Duggan suggested that the next steps would be to test the diet in bioengineered human intestine models (called enteroids) and then eventually in clinical trials.
For Yilmaz, the study answered two main questions from his own postdoctoral fellowship — how stem cells sense their environment and how they adapt to different dietary conditions. While this finding reveals new information about how stem cells react to other biological products, there is still much to be discovered about these cells, which are believed to give rise to both specialized cells and cancer cells. “After 25 years of research, we have a much better understanding of what makes a stem cell different from a non-stem cell at the molecular level,” Yilmaz said. “What we know a lot less about is how stem cells incorporate cues from their microenvironment and from the overall physiology of an organism to regulate tissue homeostasis. Diet is one part of that.”
Because of their restorative ability, understanding stem cells opens doors to new ways of healing the body by using its own functions. “[An] area of biological research that’s going to be critical is regenerative medicine: our ability to repair damaged organs, engineer tissues, and transplant those engineered tissues back into patients. The building block for that is going to be a comprehensive understanding of stem cells, and how stem cells interact with their environment.” Yilmaz said. Now director of the MIT Stem Cell Initiative, Yilmaz leads a group of principal investigators who seek to understand stem cell biology in a variety of different tissues. He hopes that their combined research will enable innovations in treatments from tissue repair to cancer metastasis suppression.
As a health researcher, Chi is skeptical of the diets that influencers tout as “good for you,” encouraging people to ask how the diets are beneficial and compared to what benchmarks. It’s this mindset that led him to unearth a complex biological pathway that couples coenzyme biosynthesis, immune cell signalling, and intestinal stem cells, all initiated by a single micronutrient — cysteine. There is still much more to discover about micronutrient effects and stem cell function, but Yilmaz and Chi’s research has shed a much-needed light on gastrointestinal injury, unlocking the possibility of a clinically simple treatment for a biologically complex problem.