Antibiotics can make melanoma worse in mice by accelerating metastatic bone growth, likely because the drugs deplete the mice’s gut flora and weaken their immune response, according to a new study by researchers at Emory University in Atlanta, US.
The findings underscore the importance of the gut microbiome for overall health and suggest that physicians should carefully weigh gastrointestinal effects when using antibiotic therapies while treating cancer or other diseases, said one of the study’s authors, Dr. Subhashis Pal.
“Any disease or therapy that affects the gut microbiome could have a negative impact on our health,” said Dr Pal, who presented the paper at the annual meeting of the American Society for Bone and Mineral Research in Austin, Texas, US
Antibiotics can make melanoma worse
“In our study, we found that the gut microbiome limits the progression of melanoma bone lesions in mice by promoting the expansion of intestinal natural killer (NK) cells and T helper (Th1) cells and enhancing their migration to the tumor site,” said Dr. Pal .
“Antibiotics can worsen melanoma by depleting the gut microbiome and reducing the population of gut NK cells and Th1 cells. This made the mice more vulnerable to tumor growth. They had a higher tumor burden than control mice whose gut microbiomes were intact,” the researcher added.
Osteolytic bone metastasis is a complication of malignant melanoma. The researchers hypothesized that using antibiotics to deplete the mice’s gut microbiome could damage their gut immune cells and thus alter their immune response, leading to accelerated bone metastases.
The mouse experiment
The scientists injected B16-F10 melanoma cells into the hearts and bones of mice that had been treated with broad-spectrum antibiotics. As they predicted, the antibiotic injections accelerated metastatic bone growth in those mice, compared to control mice that didn’t get the injections, they write Medical Xpress.
The study revealed the mechanism of metastatic growth of melanoma. Flow cytometric analysis of Peyer’s patches and bone marrow cells from tumor lesions showed that microbiome depletion prevented melanoma-induced expansion of intestinal NK and Th1 cells and their migration from the intestine to tumor-bearing bone.
Direct measurement of NK and Th1 cell migration using Kaede mice, a strain expressing a photoconvertible fluorescent protein that allows direct tracking of intestinal lymphocytes, showed that antibiotics decreased NK and Th1 cell migration from the intestine to the tumor site approximately eightfold.
The mechanism of action of antibiotics, in detail
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 the 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 decreased the frequency of NK and Th1 tumor cells and resulted in tumor growth.
This study strongly indicates that antibiotic-induced changes in the microbiome could have negative clinical consequences not only in melanoma but also in other diseases, Dr. Pal said.
Antibiotics can make melanoma worse, which should make us all more careful about our treatments
“For example, inflammatory bowel disease, or other gut conditions that create inflammation, can lead to an increase in Th17 cells, the number of TNF-producing cells in the gut, which ultimately has a negative impact on our bone health,” explains the man of science.
“Similarly, we saw that in a model of surgical menopause, reduced estrogen levels cause bacterial metabolites to cross the gut barrier more easily and hyperactivate the immune system. As a result, the number of cytokine-producing T cells in the gut and bone marrow increases, contributing greatly to bone loss,” he added.
“We should be very careful with our gut microbiome and the unintended adverse consequences of antibiotic regimens. Instead, probiotics can play a major role in maintaining a healthy gut microbiome and overall better health,” concluded Dr. Pal.