After prolonged chemotherapy, gut microbes promote the production of neutrophils

The results of a study by researchers at Hokkaido University School of Medicine show that the composition of the gut microbiome is crucial for driving a process known as granulogenesis, which can replenish the number of
neutrophils in the blood of mice after undergoing treatments such as hematopoietic stem cell transplantation (SCT) or chemotherapy.
The mechanism was found to rely on T cells producing IL-17
.
The team suggests that future work could investigate the development of antibiotics that do not affect the gut flora that promote particle production, or probiotics that may support granule
production after SCT or chemotherapy.

Under the leadership of Dr.
Daigo Hashimoto and Dr.
Takanori Teshima, the authors published a paper
in the Proceedings of the National Academy of Sciences (PNAS) titled "Reactive granulogenesis relies on T cells producing IL-17A and neutrophil-related alterations in the gut microbiota.
" 。 In their report, the researchers noted the possible clinical implications of their results, concluding that "our findings are potentially clinically relevant because the rapid recovery of neutrophils after SCT and chemotherapy ensures the safety of these treatment modalities by reducing the risk of
infection.
"

White blood cells or granulocytes are part of the
innate immune system.
The most common type of granulocytes is neutrophils, which are phagocytes that destroy microorganisms
in the body.
A low neutrophil count in the blood is called neutropenia; This condition is common in leukemia or after
chemotherapy.
Neutropenia is known to induce granulocyte production, forming granulocytes such as neutrophils
.

The authors explain that the process of increasing granulocyte production above homeostatic levels can be divided into emergency granulogenesis, which is driven by bacterial infection, or reactive granulogenesis, which increases granulocyte production in the absence of infection by viable microorganisms, but which may be caused
by inflammatory stimulation or neutropenia after hematopoietic stem cell transplantation (SCT) or cancer chemotherapy.
However, they note that the exact mechanisms by which neutropenia drives granulogenesis are not fully understood
.
"While emergency granulogenesis relies on pathogen-associated molecular patterns to promote endothelial cell production of granulocyte colony-stimulating factor (G-CSF), the mechanism by which neutropenia induces granulopoiesis remains to be clarified
.
"

The Hokkaido University team wanted to understand the mechanism
by which neutropenia triggers reactive neutropogenesis in both cases.
In their study, they induced prolonged neutropenia in a mouse model and looked at levels of cytokines (cell signaling molecules), which are known to be involved in
particle production.
The results showed that two cytokines, G-CSF and interleukin 17A (IL-17A), were significantly elevated
.
Further studies showed that IL-17A is essential for neutrophil recovery and confirmed that T cells are the main source of
IL-17A.

The researchers then examined whether the gut microbiome influences granule production on the basis of previous research showing that gut microbiome and bone marrow hematopoiesis can influence
each other.
They found that the gut microbiome did upregulate reactive granule production through IL-17A secreted by T cells, and also found that prolonged neutropenia altered the gut microbiome
.

"Our data suggest that after long-term neutropenia, the gut microbiota plays a key role in enhancing IL-17A production in T cells.
.
.
In the current study, neutropenia after SCT or chemotherapy led to significant changes
in the gut microbiota.
"Further experiments confirmed that it is this change in microbiome composition that enhances reactive particle production
.
" In summary, we found that the reduction of neutrophils stimulated T cells to produce IL-17A in a microbiota-dependent manner, thereby enhancing reactive granule production
.
”

The comprehensive results showed that the change of the gut microbiome caused by neutropenia stimulates reactive neutrophil production in the bone marrow through IL-17A secreted by T cells, promoting neutrophil recovery
.
"Our results show that there is an interaction between gut microbiota and particle production in prolonged neutropenia, providing a new prospect
for reactive particle production," the scientists wrote.
Future work will focus on clinical trials to test whether such crosstalk exists in humans; Other avenues include developing antibiotic formulations that leave the bacteria that support particle formation intact
.
"Our findings may pave the way for future clinical studies in which the benefits
of new strategies for antibiotic use in which the retention of particles after SCT support bacterial or FMT (fecal microbiota transplantation) or probiotics that support granule production will be tested.
"