Antibiotics deplete intestinal flora and weaken the immune response

According to a recent study conducted by scientists at Emory University in Atlanta, the administration of broad-spectrum antibiotics in mice with malignant melanoma, an aggressive type of skin cancer, expedited their metastatic bone growth. This was most likely because the medications diminished the mice’s intestinal flora and weakened their immune system.

According to one of the study’s authors, Subhashis Pal, Ph.D., a postdoctoral fellow in endocrinology at the Emory University School of Medicine, the findings highlight the significance of the gut microbiome in overall health and suggest that physicians should carefully consider the gastrointestinal effects when using antibiotic therapies to treat cancer or other diseases.

Any disease or therapy that harms the gut microbiome could have a negative impact on our health.”

Subhashis Pal, Postdoctoral Fellow, Endocrinology, Emory University School of Medicine

Dr. Pal presented the report at the annual meeting of the American Society of Bone and Mineral Research in Austin, Texas, USA.

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.”

Subhashis Pal, Postdoctoral Fellow, Endocrinology, Emory University School of Medicine

Dr. Pal adds, “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.”

Malignant melanoma complications include osteolytic bone metastases. The scientists reasoned that depleting the gut microbiota of mice with antibiotics would disrupt their intestinal immune cells, modify their immunological response, and hasten bone metastases. They gave mice that had received broad-spectrum antibiotic treatment injections of B16F10 melanoma cells into their hearts and bones.

Contrary to control mice who had not gotten the injections, the antibiotic injections in those mice accelerated bone metastasis growth.

The study identified melanoma’s metastatic growth mechanism. Intestinal NK and Th1 cells’ proliferation and migration from the gut to tumor-bearing bones were blocked by melanoma by microbiome elimination, according to a flow cytometric examination of Peyer’s patches and bone marrow cells within tumor lesions.

Antibiotics significantly reduced the migration of NK and Th1 cells from the gut to the tumor site, as measured directly by NK and Th1 cell migration in Kaede mice, a type that expresses a photoconvertible fluorescent protein that enables direct tracking of intestinal lymphocytes.

S1PR5 and S1PR1 receptors play a role in the immunological response of the body when NK cells and Th1 cells exit the gut. Antibiotic effects were duplicated by pharmacologically blocking the cells’ movement through the receptors, which involved S1PR5 with NK cells or S1PR1 with Th1 cells. The blockage enhanced the formation of bone metastases by preventing NK cell and Th1 cell expansion in the bone marrow.

The chemokine ligand CXCL9, which is expressed by bone marrow cells, and CXCR3, which is expressed by NK and Th1 cells, control the influx of circulating NK and Th1 cells to the tumor site. Tumor NK and Th1 cell frequency was lowered and tumor frequency was raised by either global ablation of CXCR3 or antibody neutralization of CXCL9.

This study strongly suggests that antibiotic-induced microbiome alterations may have detrimental clinical effects on a variety of illnesses, including melanoma.

Dr. Pal elaborates, “For example, inflammatory bowel disease, or other gut conditions that create inflammation, can lead to increased Th17 cells, TNF producing cell numbers in the gut, which ultimately has a negative impact on our bone health.”

Similarly, we have seen that in a murine model of surgical menopause, reduced levels of estrogen cause bacterial metabolites to pass more easily through the gut barrier and hyperactivate the immune system. As a result, the number of intestinal and bone marrow cytokine producing T cells rises, largely contributing to the development of bone loss.”

Subhashis Pal, Postdoctoral Fellow, Endocrinology, Emory University School of Medicine

Dr. Pal concludes, “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.”