Antibiotic-induced disturbances of the gut microbiota result in accelerated breast tumour growth via a mast cell-dependent pathway

Abstract

One Sentence Summary:We show that breast cancer progression is accelerated through a unique/novel immune response involving mast cells as a result of an antibiotic induced perturbation of the gut microbiota in a mouse model. AbstractThe diverse community of commensal microbes that comprise the gut microbiota is known to play an integral role in human health, not least through its ability to regulate host immune responses and metabolic pathways. Alterations to the homeostasis of this community, including through the use of broad-spectrum antibiotics, have already been associated with the progression of several cancers, namely melanoma and liver. The aggressive nature of breast cancer (BrCa), largely due to its ability to metastasize early, has ranked the disease with the second highest mortality rate of all cancers globally. Yet the body of research into the complex relationship between the microbiota and BrCa is still limited. This study found that a depletion of the microbiota, through the administration of antibiotics, significantly increased the rate of primary tumour progression in mouse BrCa models. We show that antibiotic-induced microbiota disturbances lead to changes in behaviour of a relatively obscure tumour-immune cell population: mast cells. We observed increases in tumour stroma-associated mast cells in antibiotic treated animals. Moreover, inhibition of mast cell degranulation, via cromolyn, slowed tumour progression in antibiotic treated animals but not in control animals. Thus, it appears that a perturbed microbiota drives stroma-associated mast cell recruitment and activation, which in turn promotes primary tumour growth through an as yet unknown mechanism.

Indoxylsulfate, a Metabolite of the Microbiome, Has Cytostatic Effects in Breast Cancer via Activation of AHR and PXR Receptors and Induction of Oxidative Stress

“…Previously we showed that bacterial tryptophan metabolism is suppressed in early stages of breast cancer, releasing the brake on breast cancer cells [ 16 , 17 , 40 ]. In that sense, IS behaves similar to other cytostatic metabolites [ 16 , 17 , 25 , 32 , 39 , 40 , 41 , 42 , 43 , 45 , 46 ]. Of note, in addition to the loss of cytostatic properties, the breast cancer oncobiome has an increased capacity for reactive estrogens and increase estrogen enterohepatic circulation [ 1 , 93 ].…”

“…Lower biosynthetic capacity is associated with ER cases [ 40 , 51 ] or triple negative cases [ 9 , 12 , 13 ] that have worse clinical outcomes. In addition, the application of antibiotics, which suppress microbial diversity, increases the risk for breast cancer in human and animal studies [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 82 ]. On the other hand, probiotic treatment, which enriches the gut microbiome, decreases the incidence of breast cancer [ 35 , 36 , 37 , 38 ].…”

“…A majority of the reports show decreased diversity in breast cancer patients compared to controls [ 1 , 2 , 3 , 4 , 5 , 8 , 9 , 12 , 13 , 14 , 15 , 18 ]. Antibiotic use can suppress diversity, and in murine experimental models of breast cancer, the combination of Vancomycin, Neomycin, Metronidazole, Amphotericin, and Ampicillin aggravated the disease [ 25 , 26 ]. This observation is supported by suggestive supportive evidence in human population studies [ 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ].…”

“…Currently available data suggest that oncobiosis supports carcinogenesis in breast cancer but has little or no role in initiating oncogenesis. Breast cancer oncobiosis modulates the immune system, including lymphocytes and mast cells [ 16 , 25 , 32 , 39 , 40 , 41 , 42 , 43 ]. Furthermore, oncobiosis supports epithelial-to-mesenchymal transition (EMT) [ 16 , 17 , 40 , 44 ], migration and invasion [ 17 , 40 ], the reduction of oxidative stress [ 40 , 45 ], the proportions of ALDH1+ cancer stem cells [ 17 , 40 ], and widespread metabolic alterations [ 16 , 17 , 40 ] in cancers cells.…”

The role of the microbiome in ovarian cancer: mechanistic insights into oncobiosis and to bacterial metabolite signaling

“…Topical or systemic antibiotic treatment has a strong impact on the composition of the microbiome. Antibiotic treatment impacts the frequency and recurrence of breast cancer (Friedman et al 2006 ; Kirkup et al 2019 , 2020 ; Wirtz et al 2013 ). In the case of pancreatic adenocarcinoma where bacterial colonization of the pancreas is a major driver of carcinogenesis (Kiss et al 2020 ) similar to ovarian cancer, antibiotic treatment was beneficial in animal models (Thomas et al 2018 ).…”