The use of broad-spectrum antibiotics in mice with malignant melanoma, an aggressive type of skin cancer, accelerated their metastatic bone growth, according to a recent study by researchers at Emory University in Atlanta.
This most likely occurred as a result of the medications’ effects on the mice’s immune system and intestinal flora.
According to one of the study’s authors, Subhashis Pal, Ph.D., a postdoctoral fellow in endocrinology at the Emory University School of Medicine, the findings highlight the significance of the gut microbiome in overall health and suggest that physicians should carefully consider the gastrointestinal effects when using antibiotic therapies to treat cancer or other diseases.
Dr. Pal, who presented the study today at the annual meeting of the American Society of Bone and Mineral Research in Austin, Texas, the United States, warned that “any disease or therapy that affects the gut microbiome could have a severe influence on our health.”
According to Dr. Pal’s research, the gut microbiota helps intestinal natural killer (NK) cells and T helper (Th1) cells grow and migrate to the tumour site, which slows the spread of melanoma bone lesions in mice. “Oral antibiotic use lowered the number of intestinal NK cells and Th1 cells and depleted the gut microbiome. The mice were now more susceptible to the development of tumours. In comparison to control mice with healthy gut microbiomes, they had more melanoma tumours.”
Malignant melanoma complications include osteolytic bone metastases. The scientists reasoned that depleting the gut microbiota of mice with antibiotics would disrupt their intestinal immune cells, modify their immunological response, and hasten bone metastases. Mice given broad-spectrum antibiotic treatment had their hearts and bones injected with B16-F10 melanoma cells. Contrary to control mice who had not gotten the injections, the antibiotic injections in those mice accelerated bone metastasis growth.
The study identified the melanoma’s metastatic growth mechanism. Intestinal NK and Th1 cells’ growth in response to melanoma and their migration from the gut to tumor-bearing bones were both blocked by microbiome removal, according to a flow cytometric examination of Peyer’s patches and bone marrow cells within tumour lesions. Antibiotics significantly reduced the migration of NK and Th1 cells from the gut to the tumour site, as measured directly by NK and Th1 cell migration in Kaede mice, a type that expresses a photo-convertible fluorescent protein that enables direct tracking of intestinal lymphocytes.
S1PR5 and S1PR1 receptors play a role in the immunological response of the body when NK cells and Th1 cells exit the gut. Antibiotic effects were duplicated by pharmacologically blocking the cells’ movement through the receptors, which involved S1PR5 with NK cells or S1PR1 with Th1 cells. The blockage enhanced the formation of bone metastases by preventing NK cell and Th1 cell expansion in the bone marrow.
The chemokine ligand CXCL9, which is expressed by bone marrow cells, and CXCR3, which is expressed by NK and Th1 cells, control the influx of circulating NK and Th1 cells to the tumour site. The frequency of tumour NK and Th1 cells was lowered and tumour growth was accelerated by either global ablation of CXCR3 or antibody-mediated neutralisation of CXCL9.
According to Dr. Pal, this data strongly suggests that antibiotic-induced microbiome alterations may have detrimental clinical effects on a variety of illnesses, not just melanoma. “For instance, inflammatory bowel disease and other gastrointestinal disorders that cause inflammation can increase the amount of TNF-producing Th17 cells in the gut, which has a detrimental effect on the health of our bones. Similar to this, we’ve seen that lower oestrogen levels make it easier for bacterial byproducts to cross the intestinal barrier and activate the immune system in a mouse model of surgical menopause. As a result, more intestine and bone marrow T cells produce cytokines, which greatly aids in the progression of bone loss.”
Dr. Pal continued: “We should be extremely cautious when it comes to our gut flora and the unanticipated negative effects of antibiotic regimens. Probiotics, on the other hand, can significantly contribute to greater overall health by maintaining a healthy gut flora.”