Antibiotics may increase melanoma growth in bone by depleting the microbiome

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A new study in mice suggests that antibiotics can accelerate the growth of melanoma that has spread to bone by disrupting the gut microbiome and weakening the immune response. The results were published in The Journal of Clinical Investigation and presented to the American Society for Bone and Mineral Research (ASBMR) 2022 Annual Meeting.

Our microbiome in health and disease

The gut microbiome is the collection of trillions of microbes, including bacteria, viruses, and fungi that live in our intestines. Bacteria are the most studied members of our gut microbiome, and we each harbor an estimated amount 200 to 1000 species of bacteria in our gut. Research has shown that the composition of our gut microbiome can influence the health of our body during sicknesss such as autoimmune diseases and inflammatory bowel disorders. Additionally, the microbiome has also been implicated in the health of bone tissueincluding the regulation of bone mineral density and skeletal development as well as osteoporosis (weakening of the bones).

Many types of cancer commonly spread (metastasize) to distant sites in the body, including melanoma, an aggressive skin cancer that often spreads to bone. Once metastasized, patients typically have a 5-year survival rate of as little as 30%. Importantly, disturbances and imbalances in the microbiome (called dysbiosis) have been linked to cancer progression, but the role of the microbiome in bone tumor growth is unknown.

In the current study, researchers at Emory University used mouse models to investigate how the microbiome influences immune response and melanoma growth in bone.

Microbiome disruption increases bone tumor growth

Scientists modeled the spread of melanoma in bone by injecting human melanoma cells either into the heart (intracardiac) or directly into the tibia bone of the leg (intratibial) in mice. Their microbiomes were also depleted using a cocktail of broad-spectrum antibiotics, including ampicillin, vancomycin and metronidazole. Testing revealed that antibiotic treatment suppressed >99% of the microbiome and tumor growth was significantly higher in mice given antibiotics compared to untreated controls.

To rule out any accidental “off-target” effects of antibiotics that might be causing the tumor growth, the researchers repeated the experiment with so-called “non-absorbable” antibiotics – drugs that act locally in the intestine and do not are not absorbed in the intestine. body. These also depleted the microbiome and resulted in increased tumor growth, suggesting that this is unlikely due to off-target effects of antibiotics, and is indeed influenced by microbiome depletion.

But what was the mechanism behind this? The team studied two types of immune cells – natural killer (NK) cells and T helper 1 (Th1) cells – which are known to act in the immune response to melanoma, to see what role they had to play in this phenomenon. They showed that the presence of bone tumors increased the number of NK and Th1 cells in the bone marrow. However, depleting the microbiome with antibiotics prevented this increase. Additionally, visualization of NK and Th1 cells using Kaede mice – a special mouse strain that produces a fluorescent signal in these cells – demonstrated that antibiotics decreased the migration of NK and Th1 cells from the intestines to tumors. . Therefore, this suggests that changes in the microbiome caused by antibiotics may alter the immune response to cancer cells in bone.

Taken together, these results indicate that there is a level of gut-bone crosstalk in the immune response. Dr Subhashis Pallead author of the study and a research associate at Emory University School of Medicine, spoke with Technology networks on the results. “Our results showed that antibiotic-induced gut microbiome depletion accelerated melanoma bone metastasis,” Pal explained. “Depletion of the gut microbiome prevented the melanoma-induced expansion of gut NK and Th1 cells and their migration from the gut to tumor-bearing bone.”

Could this apply to other types of cancer?

The results of this study strongly implicate the role of the microbiome in regulating the immune response to bone tumors and suggest that antibiotic use may have negative effects in melanoma patients with bone metastases.

Nonetheless, Pal and his colleagues plan to study how well these findings may translate to human patients as well as other types of cancer. “We are constantly working to better understand gut-bone crosstalk in bone metastases. Currently, we are working with a breast cancer model to determine if the gut microbiome regulates breast cancer bone metastasis. We also plan to work with clinical samples from cancer patients to study the influence of the human microbiome on tumor growth,” Pal explained.

Dr. Subhashis Pal was talking to Sarah Whelan, Science Writer for Technology Networks.

Reference: Pal S, Perrien DS, Yumoto T, et al. The microbiome limits the bone growth of melanoma by promoting the return of intestinal NK and Th1 cells to the bone. J Clin Invest. 2022;132(12). do I: 10.1172/JCI157340

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