We should be extremely cautious when it comes to our gut flora and the unanticipated negative effects of antibiotic regimens, warn the experts.

A new study by researchers at Emory University in Atlanta found that giving mice with malignant melanoma, an aggressive form of skin cancer, broad-spectrum antibiotics sped up their metastatic bone growth. This is likely because the drugs wiped out the mice’s intestinal flora and weakened their immune response.

One of the study’s authors, Subhashis Pal, Ph.D., a postdoctoral fellow in endocrinology at Emory University School of Medicine, said that the results show how important the gut microbiome is to overall health and that doctors should think carefully about the effects of antibiotic therapies on the gut when treating 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 harms the gut microbiome could have a negative impact 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 tumor site, which slows the spread of melanoma bone lesions in mice. 

“Using oral antibiotics depleted the gut microbiome and reduced the population of intestinal NK cells and Th1 cells. This made the mice more vulnerable for tumor growth. They had a higher melanoma tumor burden than control mice whose gut microbiomes were intact .”

Melanoma can cause osteolytic bone metastases. The researchers expected that depleting the gut microbiota of mice with antibiotics would disrupt their intestinal immune cells, hence altering their immune response and accelerating bone metastases. They gave mice that had received broad-spectrum antibiotic treatment injections of B16F10 melanoma cells into their hearts and bones. As expected, the antibiotic injections accelerated the growth of bone metastases in these mice compared to mice that did not get the shots (control mice).

The study found out how melanoma spreads to other parts of the body. Flow cytometric analysis of Peyer’s patches and bone-marrow cells in tumor lesions showed that microbiome depletion stopped melanoma from causing intestinal NK and Th1 cells to grow and move from the gut to bones with tumors. This also stopped the cells from moving from the gut to bones with tumors. Antibiotics significantly reduced the migration of NK and Th1 cells from the gut to the tumor site, as measured directly by NK and Th1 cell migration in Kaede mice, a type that expresses a photoconvertible fluorescent protein that enables direct tracking of intestinal lymphocytes.

As part of the body’s immune response, S1PR5 and S1PR1 receptors help NK cells and Th1 cells move out of the gut. Antibiotic-like effects were seen when the receptors, S1PR5 with NK cells or S1PR1 with Th1 cells, were used to stop the cells from moving. As a result of the blockage, bone metastases developed more quickly and NK cells and Th1 cells did not have time to expand 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 tumor site. Global deletion of CXCR3 or blocking of CXCL9 with an antibody decreased the number of NK and Th1 cells in tumors and made them grow faster.

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 example, inflammatory bowel disease, or other gut conditions that create inflammation, can lead to increased Th17 cells, TNF producing cell numbers in the gut, which ultimately has a negative impact on our bone health. Similarly, we have seen that in a murine model of surgical menopause, reduced levels of estrogen cause bacterial metabolites to pass more easily through the gut barrier and hyperactivate the immune system. As a result, the number of intestinal and bone marrow cytokine producing T cells rises, largely contributing to the development of bone loss.”

Dr. Pal continued: “We should be very much careful with our gut microbiome, and of the unforeseen adverse consequence of antibiotic regimens. Conversely, probiotics can play a major role to maintain a healthy gut microbiome, and better overall health.”

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