“Any disease or therapy that harms the gut microbiome can have a negative impact on our health,” said Dr. Pell, who presented the report today at the American Society for Bone and Mineral Research’s annual meeting in Austin, Texas, US.
“In our study, we found that the gut microbiome inhibits the progression of melanoma bone lesions in mice by promoting the expansion of intestinal natural killer (NK) and T-helper (Th1) cells and enhancing their migration to the tumor site,” said Dr. Skaz Pal. “Use of oral antibiotics depleted the gut microbiome and reduced intestinal NK and Th1 cell populations. This made the mice more vulnerable to tumor growth. They had a higher melanoma burden per tumor than control mice whose gut microbiomes were intact.”
Osteolytic bone metastases are a complication of malignant melanoma. The researchers hypothesized that using antibiotics to deplete the mice’s gut microbiome would affect the immune cells in their gut and thus alter their immune response, leading to accelerated bone metastasis. They injected B16-F10 melanoma cells into the hearts and bones of mice treated with broad-spectrum antibiotics. As predicted, the antibiotic injections accelerated the growth of bone metastases in these mice compared to control mice that did not receive the inoculation.
Metastatic growth of melanoma: new information
The study revealed the mechanism of metastatic melanoma growth. Flow cytometric analysis of Peyer’s patches and bone marrow cells in tumor lesions showed that microbiome depletion prevented melanoma-induced expansion of intestinal NK and Th1 cells and their migration from the gut to tumor-bearing bone. Direct measurement of NK and Th1 cell migration using Kaede mice, a strain that expresses a photoconvertible fluorescent protein that allows direct tracking of intestinal lymphocytes, showed that antibiotics reduced NK and Th1 cell migration from the intestine to the tumor site approximately eightfold.
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When NK cells and Th1 cells leave the gut as part of the body’s immune response, the process is mediated by the S1PR5 and S1PR1 receptors. Pharmacological blockade of cell migration through receptors – involving S1PR5 with NK cells or S1PR1 with Th1 cells – mimicked the effects of antibiotics. The blockade prevented the expansion of NK cells and Th1 cells in the bone marrow and caused accelerated growth of bone metastases. The influx of circulating NK and Th1 cells to the tumor site is directed by the chemokine ligand CXCL9, which is expressed by bone marrow cells, and CXCR3, which is expressed by NK and Th1 cells. Global deletion of CXCR3 or antibody neutralization of CXCL9 reduced the frequency of tumor NK and Th1 cells and increased tumor growth.
“For example, inflammatory bowel disease or other gut diseases that cause inflammation can lead to an increase in the number of Th17 cells, TNF producing cells in the gut, which ultimately has a negative impact on our bone health. Similarly, we have seen that in a mouse model of surgical menopause, decreased estrogen levels make bacterial metabolites more easily pass through the intestinal barrier and hyperactivate the immune system. As a result, the number of cytokine-producing T cells in the gut and bone marrow increases, which in a significant degree contributes to the development of bone loss.”
Dr. Pell added: “We have to be very careful about the gut microbiome and the unintended adverse effects of taking antibiotics. Conversely, probiotics can play an important role in maintaining a healthy gut microbiome and improving overall health.”
Source: Eurekalert
