Antibiotics May Increase Melanoma Growth in Bones by Depleting the Microbiome

 A new study in mice suggests that antibiotics may accelerate the growth of melanoma that has spread to the bones by disrupting the gut microbiome and weakening the immune response. The results were published in The Journal of Clinical Investigation and presented at 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 within our intestines. Bacteria are the most well-studied members of our gut microbiome, and we each harbor an estimated 200 to 1000 species of bacteria in our gut. Research has shown that the composition of our gut microbiome can influence our bodies’ health during diseases such as autoimmune conditions and inflammatory bowel disorders. Additionally, the microbiome has also been implicated in the health of bone tissue, including regulating bone mineral density and skeletal development as well as osteoporosis (weakening of the bones).

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

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

Microbiome disruption increases bone tumor growth

The scientists modeled the spread of melanoma into the bones 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 removed > 99% of the microbiome and that tumor growth was significantly higher in the mice that received antibiotics compared to untreated controls.

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

But what was the mechanism causing this? The team investigated two types of immune cells – natural killer (NK) and T helper 1 (Th1) cells – that are known to act in the immune response to melanoma, to see what part they had to play in this phenomenon. They showed the presence of bone tumors increased the number of NK and Th1 cells in the bone marrow. However, depletion of the microbiome with antibiotics prevented this increase. Additionally, visualizing 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 the tumors. Therefore, this suggests that microbiome changes brought about by antibiotics may change the immune response to cancer cells in the bone.

Overall, these results indicate that there is a level of gut–bone crosstalk in the immune response. Dr. Subhashis Pal, lead author of the study and research associate at Emory University School of Medicine, spoke to Technology Networks about the results. “Our findings showed that antibiotic-induced gut microbiome depletion accelerated melanoma bone metastasis,” Pal explained. “Gut microbiome depletion prevented the melanoma‐induced expansion of intestinal NK and Th1 cells and their migration from the gut to tumor‐bearing bones.”

Could this apply to other cancer types?

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

Nevertheless, Pal and colleagues plan to investigate how well these findings may translate to human patients as well as other cancer types. “We are continuously working to better understand the gut–bone crosstalk during bone metastasis. Currently, we are working with a breast cancer model to investigate whether the gut microbiome regulates bone metastasis of breast cancer. We also have a plan to work with clinical samples from cancer patients to study the influence of the human microbiome on tumor growth,” Pal elaborated.

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

Reference: Pal S, Perrien DS, Yumoto T, et al. The microbiome restrains melanoma bone growth by promoting intestinal NK and Th1 cell homing to bone. J Clin Invest. 2022;132(12). doi: 10.1172/JCI157340