Stress ages bone marrow stem cells via the gut in mice

• Our understanding of the gut-brain axis has evolved and expanded to include the gut microbiome, immune system, and endocrine system.
• The gut-brain connection can be negatively impacted by mental health conditions like psychological stress.
• A new study finds a connection among gut, brain, and bone marrow.
• In this interconnection, psychological stress may alter the gut microbiome, potentially accelerating the aging process in bone marrow stem cells, as shown in a mouse model.

For some time now, we’ve known of a connection between the brain and the gut. Known as the gut-brain axis, it shows that what happens in the brain can directly affect the gastrointestinal system, and vice versa.

Past studies show that certain mental health conditions, such as depression, anxiety, and psychological stress, can negatively impact the gut-brain axis.

Now, a new study published in the journal Cell Stem Cell says there is also a gut-brain-bone marrow connection. In this interconnection, psychological stress may alter the gut microbiome, potentially accelerating the aging process in bone marrow stem cells, as shown in a mouse model.

At the study’s conclusion, Zhao said he and his team found that stress impaired HSC self-renewal and reduced the production of lymphocytes, a type of white blood cell.

While investigating the underlying mechanism, they unexpectedly discovered that the brain communicates with the bone marrow through sympathetic regulation of the intestinal environment and gut microbiota, ultimately altering microbiota-derived spermidine — naturally occurring organic molecules believed to promote healthy aging — and HSC function.

“When the brain experiences psychological stress, it sends signals through the sympathetic nervous system to the intestine,” Zhao detailed. “These signals alter the intestinal environment and the gut microbiota, reducing the availability of beneficial metabolites such as spermidine. Without sufficient spermidine, HSC gradually lose their ability to maintain healthy blood and immune cell production.”

“In other words, emotional stress in the brain can indirectly influence the body’s immune system through the gut. Because spermidine is a metabolite with broad biological functions, this mechanism may also influence other organs beyond the bone marrow.”
— Meng Zhao, PhD

“To our knowledge, this is the first direct functional evidence that specific brain regions regulate HSC function in the bone marrow,” Zhao said. “We found that suppressing these two stress-responsive brain regions was sufficient to reproduce many of the hematopoietic and immune defects caused by psychological stress.”

“These findings demonstrate that specific neural circuits actively regulate immune stem cell function rather than simply responding to stress. More importantly, identifying these brain regions provides potential targets for developing new strategies to preserve immune function under chronic psychological stress.”
— Meng Zhao, PhD

“Our next goal is to determine whether this brain–gut–bone marrow axis operates similarly in humans and whether it contributes to immune dysfunction in aging, cancer, and other chronic diseases,” Zhao added.

MNT spoke with Ashkan Farhadi, MD, a board certified gastroenterologist at MemorialCare Orange Coast Medical Center in Fountain Valley, CA, about this study, who commented it adds one more layer to our understanding about the role of stress and the whole body.

“We had some understanding regarding the brain-gut axis that we knew there is a strong bi-directional current connection between the brain and gut,” Farhadi, who was not involved in this study, explained. “This access has been recently extended into brain-gut microbiome access. And now we’re having this access extended into other organs, including bone marrow and the general health of the body.”

“So this study is very novel in a sense that it shows that stress can start working its way through the body by going through the gut and its microbiome,” he added.

MNT also spoke with Dung Trinh, MD, an internist for MemorialCare Medical Group and chief medical officer of the Healthy Brain Clinic in Irvine, CA, who agreed.

“This is a fascinating and important study because it connects several systems we often talk about separately: the brain, the gut microbiome, the immune system, and aging,” Trinh, who likewise was not involved in this study, said.

“What stood out to me is that the researchers did not just say ‘stress is bad for the body’; they mapped a plausible biological pathway in mice showing how psychological stress may alter specific brain regions, change gut bacteria, reduce a protective metabolite called spermidine, and contribute to aging-like dysfunction in blood-forming stem cells.”
— Dung Trinh, MD

“That makes the study especially compelling, though it is important to emphasize that this is still preclinical research in animals, not proof that the same mechanism works the same way in humans,” Trinh added.

For readers who may be looking for ways to lower their stress, MNT asked Rosario Ligresti, MD, FASGE, chief of the Division of Gastroenterology at Hackensack University Medical Center, medical director of The Pancreas Center at Hackensack University Medical Center, and associate professor of medicine at Hackensack Meridian School of Medicine in New Jersey, for his top tips.

Ligresti said one of the most powerful and simple tools you have for combating stress is your own breath. He suggested trying this simple deep breathing exercise, which can be done anywhere, at any time, to help calm your nervous system:

• Step 1: Find a comfortable position, either sitting or standing.
• Step 2: Inhale slowly and deeply through your nose for a count of four, allowing your belly to expand.
• Step 3: Hold your breath for a brief moment.
• Step 4: Exhale slowly through your mouth for a count of five, thinking the word “relax” as you do.
• Step 5: Repeat this cycle 5 to 10 times, focusing on the sensation of your breath.

“Another effective way to quickly reduce stress is to get moving,” Ligresti said. “You don’t need an intense workout; even a simple, 20-minute walk can work wonders for clearing your mind and reducing feelings of stress.”

He explained that physical activity helps release endorphins and other natural mood elevators.

“It also reduces the levels of stress hormones in your body. The next time you feel overwhelmed, try stepping outside for a brisk walk. You may be surprised at how much calmer and more focused you feel afterward,” he said.

Trinh also offered some stress-reducing tips, including prioritizing sleep and limiting stress accelerators like alcohol, caffeine, and even constant news or social media exposure, which he said can intensify stress responses.

“Loneliness and isolation can worsen stress,” Trinh continued. “Regular contact with friends, family, faith groups, support groups, or community activities can be protective.”

“Persistent anxiety, depression, trauma symptoms, caregiver strain, or feeling overwhelmed are good reasons to talk with a primary care clinician or mental health professional,” he added.