December 9, 2022

Antibiotics that deplete the gut microbiome can make it worse

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A mouse study found that antibiotics that deplete the gut microbiome can make melanoma worse. Douglas Sacha/Getty Images
  • The researchers studied melanoma-induced tumor growth in the bones of mice treated with antibiotics that depleted the gut microbiome.
  • They found that the number of bone tumor cells was higher in antibiotic-treated, microbiome-depleted mice than in controls without antibiotics.
  • The researchers also revealed that the gut microbiome is associated with the migration of immune cells from the gut to the bone marrow of tumor-bearing bones, thereby limiting the growth of bone tumors.
  • The accelerated growth of bone tumors in mice due to antibiotic-induced microbiome depletion suggests that antibiotics can potentially negatively affect melanoma patients.

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

Melanoma is a form of cancer that develops when cells in the skin that produce the skin-darkening pigment melanin, called melanocytes, mutate and start dividing rapidly.

Melanoma can spread to distant organs, such as the bones, lungs, 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 metastases, too much bone is broken down, leading to 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. 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 by researchers at Emory University in Atlanta sheds light on how the gut microbiome stunts the growth of bone tumors and warns of the potentially harmful consequences of microbiome-depleting antibiotic treatments in melanoma patients .

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

To study the effect of gut microbiome-depleting antibiotics on the growth of melanoma bone tumors, the researchers injected luminescent mouse melanoma cells into the hearts and bones of 12-week-old mice. Beginning two weeks before injection of melanoma cells, researchers administered broad-spectrum antibiotics (1 mg/mL ampicillin, 0.5 mg/mL vancomycin, 1 mg/mL neomycin sulfate, 1 mg/mL metronidazole) to mice for four weeks.

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

Dr. Subhashis Pal, 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 inhibits the progression of melanoma bone lesions in mice by promoting the expansion of intestinal natural killer (NK) cells and helper T cells (Th1) and enhancing their migration to the tumor site.

The use of oral antibiotics depleted the gut microbiome and reduced the population of gut NK cells and Th1 cells. 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, researchers determined the frequency of NK and Th1 immune cells in Peyer’s patches (clusters of lymphoid follicles in the mucous membrane lining the gut). hail) 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 noticeable 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. In contrast, 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.

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

Through further experiments, the researchers discovered 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 that block the receptors, the NK and Th1 cells did not migrate to 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 CXCL9 or CXCR3, the frequency of NK and Th1 cells in the bone marrow decreased and tumor growth accelerated.

Considering the study results, Dr. Pal remarked, “We need to be very careful about our gut microbiome and the unintended adverse consequences of antibiotic regimens. Conversely, probiotics can play a major role in maintaining a healthy gut microbiome and better overall health.

DTM also spoke with Teacher. Natalie Sims, Ph.D., head of the bone cell and disease biology unit and deputy director of St. Vincent’s Institute of Medical Research in Australia, who was not involved in the study. Dr Sims said DTM that the new research is “an interesting early-stage study, but […] it is far too early to suggest that melanoma patients avoid antibiotics!

She pointed out that “the model used does not really mimic the way melanoma spreads (metastasizes) in the body. [but] tests for melanoma growth when it has already reached the skeleton”, and “high doses of multiple antibiotics were used to almost completely eliminate normal gut bacteria”, making this “a pretty extreme model”.

“It is also important to know that, although the study shows some changes in the skeleton, it is not known how these occur – there is no histology showing the tumor in the bone marrow. , nor how the bone is destroyed. Nevertheless, this suggests that the gut microbiota may play a role in protecting melanoma patients, but what this means for [patients] is unclear and will take a few years to establish.

– Teacher. Natalie Sims