Melanoma: Antibiotics that damage the gut microbiome can make it worse

Melanoma: Antibiotics that damage the gut microbiome can make it worse

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A study in mice found that antibiotics that harm the gut microbiome can make melanoma worse. Douglas Sacha/Getty Images
  • The researchers examined the growth of melanoma-induced tumors in the bones of mice treated with antibiotics that harm the gut microbiome.
  • They found that the number of bone tumor cells was greater in antibiotic-treated mice and microbiome-deprived mice than in antibiotic-free controls.
  • The researchers also revealed that the gut microbiome is linked to the migration of immune cells from the gut to the bone marrow of tumor-bearing bones, thus limiting bone tumor growth.
  • Accelerated bone tumor growth in mice due to antibiotic-induced microbiome depletion suggests that antibiotics may potentially negatively affect melanoma patients.

According to the American Cancer Society, melanoma accounts for only 1% of skin cancers, yet it causes many skin cancer deaths.

Melanoma is a form of cancer that develops when skin cells that produce the pigment melanin, known as melanocytes, undergo a mutation and begin to divide rapidly.

Melanoma can spread to distant organs such as the bones, lungs, liver, and brain. When tumor cells migrate to the bone (bone metastases), stimulate the overproduction of bone-destroying osteoclast cells. In healthy individuals, bone is constantly breaking down and reforming. In patients with melanoma and osteolytic bone metastases, too much bone is broken down, resulting in bone pain, fractures, and other complications.

According to research, immune cells regulate the growth of tumor cells. Natural killer (NK) cells and T helper 1 (Th1) cells are among those involved in the immune response to melanoma. Both NK and Th1 immune cells are abundant in the gut and studies demonstrated that their activity is regulated by commensal bacteria living in the intestine – the intestinal microbiome.

A study led by researchers at Emory University in Atlanta sheds light on how the gut microbiome limits bone tumor growth and warns of the potentially harmful consequences of microbiome-damaging antibiotic therapy in melanoma patients.

The results of this study were published in Journal of Clinical Investigation and recently presented at the American Society for Bone and Mineral Research (ASBMR) 2022 Annual Meeting.

To examine the effect of gut microbiome-damaging antibiotics on melanoma bone tumor growth, the researchers injected luminescent mouse melanoma cells into the hearts and bones of 12-week-old mice. Starting two weeks before injecting the melanoma cells, the researchers administered broad-spectrum antibiotics (1 mg/ml ampicillin, 0.5 mg/ml vancomycin, 1 mg/ml neomycin sulfate, 1 mg/ml metronidazole) to the mice for four weeks.

When the researchers assessed bone tumor growth in mice using luminescence, they found that the number of bone tumor cells was greater in mice treated with antibiotics than in mice without antibiotics.

Dr. Subhashis Pal, Ph.D., co-author of the study and a postdoctoral fellow in endocrinology at Emory University School of Medicine, explained the findings Medical News Today:

“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.

The use of oral antibiotics depleted the gut microbiome and reduced gut NK cell and Th1 cell populations. This made the mice more vulnerable to tumor growth. They had a higher melanoma tumor burden than control mice whose gut microbiomes were intact.

To understand how depletion of the gut microbiome by antibiotics affects immune cell activity, the researchers used flow cytometry to determine the frequency of NK and Th1 immune cells in Peyer’s patches (a collection of lymphoid follicles in the mucous membrane lining the small intestine) and in the bone marrow.

They found that when they injected melanoma cells into the bones of control mice without antibiotics, there was a significant increase in NK and Th1 cells in the bone marrow. This indicates that NK and Th1 cells migrated from the gut to the bone marrow in response to tumor cell injection. Conversely, in mice treated with antibiotics, the frequency of immune cells in the bone marrow did not increase in response to the injection of tumor cells.

Because antibiotic treatment prevented the migration of NK and Th1 cells from the gut to the bone marrow, the researchers hypothesized that this migration of immune cells must depend on the gut microbiome.

Through further experiments, the researchers found that the migration of NK and Th1 cells from the intestine to the bone marrow is mediated by the cell receptors S1PR5 and S1PR1, respectively. When the researchers injected the mice with drugs blocking the receptors, NK and Th1 cells did not migrate into the bone marrow after the injection of tumor cells, and the bone tumor grew faster.

The researchers also found that the CXCL9 protein, secreted by bone marrow cells, and the CXCR3 receptor on NK and Th1 cells control the influx of NK and Th1 cells into the bone marrow. When they inhibited either CXCL9 or CXCR3, the frequency of NK and Th1 cells in the bone marrow decreased and tumor growth accelerated.

Due to the results of the study Dr. Pal noted, “We should be very careful with our gut microbiome and the unanticipated adverse consequences of antibiotic regimens. Conversely, probiotics can play a major role in maintaining a healthy gut microbiome and better overall health.

MNT also spoke with Prof. Natalie Sims, Ph.D., chief of the Division of Bone Cell Biology and Disease and Associate Director of the Institute of Medical Research at St. Vincent in Australia, which was not involved in the study. said Dr. Sims MNT that the new research is “an interesting early-stage study, but […] it is too early to suggest that melanoma patients should avoid antibiotics!”

She pointed out that “the model used does not actually mimic how melanoma spreads (metastasizes) in the body [but] tests how melanoma grows once it has reached the skeleton, and “high doses of several antibiotics were used to almost completely eliminate normal gut bacteria,” making it “a pretty extreme model.”

“It’s also important to know that although the study shows some changes in the skeleton, it’s not clear how they occur – there’s no histology showing a tumor in the bone marrow or how the bone is destroyed.” However, this suggests that the gut microbiome could play a role in protecting melanoma patients, but what does this mean for [patients] is unclear and will take several years to resolve.”

– Prof. Natalie Sims

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