The composition of gut bacteria is critical to restoring the number of neutrophils in the blood of mice after procedures such as stem cell transplants or chemotherapy.
White blood cells, or granulocytes, are cells that are part of the innate immune system. The most common type of granulocytes are neutrophils, phagocytes that destroy microbes in the body. A low level of neutrophils in the blood is called neutropenia; this disease is usually seen in cases of leukemia or after chemotherapy. Neutropenia is known to induce granulopoiesis, the process of granulocyte formation. However, the exact mechanisms by which neutropenia drives granulopoiesis are not fully understood.
A team of researchers led by Associate Professor Daigo Hashimoto and Professor Takanori Teshima from Hokkaido University’s Faculty of Medicine found that the gut microbiome plays an important role in controlling granulopoiesis in mouse models. Their results were published in the journal Proceedings of the National Academy of Sciences.
The process of increasing granulopoiesis above the homeostatic level can be divided into emergency granulopoiesis, due to the presence of bacteria, and reactive granulopoiesis, where granulopoiesis increases in the absence of active microbial infections. Reactive granulopoiesis has been known to occur after neutropenia caused by hematopoietic stem cell (HSC) transplantation or cancer chemotherapy. The team wanted to understand the mechanisms by which neutropenia triggers reactive granulopoiesis in these two scenarios.
The team induced prolonged neutropenia in mouse models and observed levels of cytokines, cell signaling molecules known to be associated with granulopoiesis. They found that two cytokines were significantly elevated: granulocyte colony-stimulating factor (G-CSF) and interleukin 17A (IL-17A). They showed that IL-17A is critical for neutrophil recovery. They confirmed that T cells are the main source of IL-17A.
They were interested in investigating whether the gut microbiome affects granulopoiesis, building on other studies that have shown that the gut microbiome and hematopoiesis in the bone marrow can influence each other. They found that the gut microbiome does increase reactive granulopoiesis through IL-17A released by T cells, and they also found that prolonged neutropenia alters the gut microbiome. They determined that it is this change in the composition of the microbiome that enhances reactive granulopoiesis.
This study showed that neutropenia-induced changes in the gut microbiome stimulate reactive granulopoiesis in the bone marrow via IL-17A released by T cells, promoting neutrophil recovery. Future work will focus on clinical trials to test whether this cross-talk is detectable in humans; other avenues include the development of antibiotics that leave the bacteria that support granulopoiesis intact.