Psychological stress is increasingly recognized as a risk factor for certain health conditions including cardiovascular disease and diabetes, especially when paired with an impaired immune response. In a study in the Cell Press journal Cell Stem Cell publishing on July 2, researchers describe a mechanism in mice that explains this association: psychological stress speeds up aging-like changes in the body's blood-forming stem cells in the bone marrow—called hematopoietic stem cells—by altering the intestinal microbiota.
"Our research shows how stress-responsive brain regions regulate the balance of the intestinal microbiota, which ultimately affects the function of hematopoietic stem cells," says senior author Meng Zhao of Sun Yat-sen University in Guangzhou, China.
Previous studies have shown that chronic stress influences immune function and the formation of immune cells in the bone marrow largely through inflammatory pathways and adrenergic receptors, which drive the body's "fight-or-flight" response. But how these stress signals were transmitted from the brain to the bone marrow was unclear.
In the new study, the researchers used four different mouse models of stress to study interactions among the brain, intestine, and bone marrow. They confirmed that chronic stress reduced activity in two brain regions—the medial prefrontal cortex and the periaqueductal gray. This in turn induced a number of changes in the physiology of the mice, including loss of hematopoietic stem cells and reduced lymphocyte production.
Importantly, the team also observed changes in the signals sent to the intestines. Specifically, the stressed mice had a loss of Lactobacillus reuteri—a species important for maintaining a healthy balance of gut microbes—and lowered levels of spermidine—a naturally occurring compound that plays a crucial role in clearing out damaged cells.
"One surprising finding of our study was that suppression of only two specific brain regions was sufficient to produce many of the hematopoietic defects caused by psychological stress," says co-corresponding author Linjia Jiang, also of Sun Yat-sen University.
"Alternations in the gut microbiota and in the microbial metabolite spermidine played a crucial role in mediating communication between the brain and the bone marrow," says Jiang.
Several important questions remain, including how psychological stress alters the neural circuits in different disease settings and whether similar mechanisms operate in humans. This is something the researchers plan to study. They are also looking at whether interventions could be developed to improve bone marrow function in aging or during times of chronic stress.
"Although substantial work is needed before clinical translation, these findings provide a conceptual framework for developing new approaches to mitigate immune aging and stress-associated immune dysfunction," Zhao says.
"More broadly, our findings raise the possibility that managing psychological stress may not only improve mental well-being but also help preserve immune function and promote healthy aging," Jiang adds.
