The results of a study by researchers at Hokkaido University’s Faculty of Medicine have shown how composition of the gut microbiome is crucial to driving a process known as granulopoiesis that replenishes neutrophil counts in the blood of mice following treatments such as hematopoietic stem cell transplants (SCT) or chemotherapy. The mechanism was found to depend on T cell production of IL-17. The team suggests that future work could investigate the development of antibiotics that don’t affect those gut microbiota that promote granulopoiesis, or probiotics that might support granulopoiesis after SCT or chemotherapy.

Led by Associate Professor Daigo Hashimoto, PhD, and Professor Takanori Teshima, PhD, the authors reported on their study in Proceedings of the National Academy of Sciences (PNAS) in a paper titled “Reactive granulopoiesis depends on T-cell production of IL-17A and neutropenia-associated alteration of gut microbiota.” In their report the researchers noted the possible clinical implications of their results, concluding, “Our finding is potentially clinically relevant, because rapid recovery of neutrophils after SCT and chemotherapy ensures safety of these treatment modalities by reducing risk of infections.”

White blood cells, or granulocytes, are cells that are part of the innate immune system. The most common type of granulocyte is the neutrophil, a phagocyte that destroys microbes in the body. Low neutrophil counts in the blood is called neutropenia; this condition is commonly seen in cases of leukemia or following chemotherapy. It is known that neutropenia induces granulopoiesis, the process that forms granulocytes such as neutrophils.

The process of increasing granulopoiesis above a homeostatic level can be categorized as either emergency granulopoiesis, which is driven by the presence of bacterial infection, or reactive granulopoiesis, where granulopoiesis is increased in the absence of active microbial infections, but which might be induced by inflammatory stimuli or neutropenia after hematopoietic stem cell transplantation (SCT) or cancer chemotherapy, the authors explained. However, they noted, the exact mechanisms by which neutropenia drives granulopoiesis are not fully understood. “While emergency granulopoiesis depends on granulocyte-colony stimulating factor (G-CSF) production from endothelial cells promoted by pathogen-associated molecular patterns, the mechanism by which neutropenia induces granulopoiesis remains to be clarified.”

The Hokkaido University team wanted to understand the mechanisms by which neutropenia triggered reactive granulopoiesis in these two scenarios. For their studies they induced prolonged neutropenia in mice models, and observed the levels of cytokines—cell signalling molecules—which are known to be associated with granulopoiesis. The results showed that two cytokines, G-CSF an interleukin 17A (IL-17A) were significantly elevated. Further studies then showed that IL-17A was critical for neutrophil recovery, and confirmed that T cells are the primary source of IL-17A.

Under normal conditions (steady state) neutrophils regulate the gut microbiota. When the number of neutrophils drops (neutropenia), the composition of the gut microbiota changes, stimulating T cells to produce IL-17A. IL-17-A in turn stimulates the production of neutrophils in the bone marrow (reactive granulopoiesis). [Daigo Hashimoto]

The investigators then examined if the gut microbiome influenced granulopoiesis, building on prior research suggesting that the gut microbiome and bone marrow haematopoiesis could affect each other. They found that the gut microbiome does upregulate reactive granulopoiesis via the IL-17A secreted by T cells, and also found that prolonged neutropenia alters the gut microbiome.

“Our data indicated that the gut microbiota plays a critical role in the enhanced production of IL-17A in T cells after prolonged neutropenia … In the current study, prolonged neutropenia after SCT or chemotherapy led to significant alteration of the gut microbiota,” they stated. Further experiments determined that it was this change in microbiome composition that enhanced reactive granulopoiesis. “In conclusion, we found that depletion of neutrophils stimulated T cell production of IL-17A in a microbiota-dependent manner, that enhanced reactive granulopoiesis.”

The study’s combined results indicated that the changes in intestinal microbiome induced by neutropenia stimulate reactive granulopoiesis in the bone marrow via IL-17A secreted by T cells, promoting neutrophil recovery. “Our results reveal a cross talk between the intestinal microbiota and granulopoiesis during prolonged neutropenia, providing a new prospect in reactive granulopoiesis,” the scientists wrote. Future work will focus on clinical trials to test if this crosstalk is found in humans; other avenues include the development of antibiotic formulations that leave granulopoiesis-supporting bacteria intact. “Our findings may pave the way for the future clinical studies in which benefits of novel strategies for antibiotic usage sparing granulopoiesis-supporting bacteria or FMT [fecal microbiota transplatation] or probiotics supporting granulopoiesis after SCT will be tested.”

Previous articleLung Cancer Progression Predicted by Tumor Matrix
Next articleOrganoid Framework Facilitates Engineering of Self-Organizing Tissues