Melanoma: Gut microbiome-depleting antibiotics may make it worse

• Researchers investigated melanoma-induced tumor growth in the bones of mice treated with gut microbiome-depleting antibiotics.
• They found that the number of bone tumor cells was greater in antibiotic-treated, microbiome-depleted mice than in the antibiotic-free controls.
• The researchers also revealed that the gut microbiome is associated with migrating immune cells from the gut to the bone marrow of tumor-bearing bones, thereby restraining bone tumor growth.
• The accelerated bone tumor growth in the 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 the skin cells that produce the skin-darkening pigment melanin, known as melanocytes, undergo a mutation and start to divide rapidly.

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

According to research, immune cells regulate tumor cell growth. 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 have shown that their activity is regulated by commensal bacteria living in the gut — the gut microbiome.

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

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

Antibiotics and melanoma mouse study

To investigate the effect of gut microbiome-depleting 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 the melanoma cell injection, 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 the mice by luminescence, they found that the number of bone tumor cells was greater in the antibiotic-treated mice than in the antibiotic-free mice.

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

“In our study we found that the gut microbiome restrains 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.

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.”

Gut microbiome depletion and bone cells

To understand how gut microbiome depletion by antibiotics impacts immune cell activity, the researchers determined the frequency of NK and Th1 immune cells in Peyer’s patches (groupings of lymphoid follicles in the mucus membrane lining the small intestine) and in the bone marrow using flow cytometry.

They found that when they injected melanoma cells into the bones of antibiotic-free control mice, there was a notable increase in NK and Th1 cells in the bone marrow. This indicates that NK and Th1 cells migrated from the intestine to the bone marrow in response to the injection of tumor cells. Contrastingly, in antibiotic-treated mice, the frequency of immune cells in the bone marrow did not increase in response to tumor cell injection.

Since antibiotic treatment prevented NK and Th1 cell migration from the intestine to the bone marrow, the researchers hypothesized that this immune cell migration 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 S1PR5 and S1PR1 cell receptors, respectively. When the researchers injected the mice with receptor-blocking drugs, the NK and Th1 cells did not migrate to the bone marrow following tumor cell injection, and the bone tumor grew faster.

The researchers also found that the protein CXCL9, 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.

Implications of early findings

Given the study findings, Dr. Pal remarked: “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 healthy gut microbiome, and better overall health.”

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

She pointed out that “the model used does not really mimic how melanoma spreads (metastasizes) in the body [but] tests how the melanoma grows when it has already reached the skeleton,” and “high doses of multiple antibiotics were used to almost completely remove the normal intestinal bacteria,” making it “a fairly extreme model.”

“It’s also important to know that, while the study shows some changes in the skeleton, it’s not clear how these happen – there is no histology showing the tumor in the bone marrow, nor how the bone is destroyed. Nevertheless, this does suggest that the gut microbiome could play a role in protecting patients with melanoma, but what this means for [patients] is unclear and will take some years to work out.”

– Prof. Natalie Sims

Source: Read Full Article