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

• Published in: bioRxiv
• Main Authors: Kirkup, Benjamin M, Mckee, Alastain M, Madgwick, Matthew, Price, Christopher A, Dreger, Sally A, Makin, Kate A, Caim, Shabhonam, Gwen Le Gall, Pavely, Jack, Leclaire, Charlotte, Dalby, Matthew, Alcon-Giner, Cristina, Andrusaite, Anna, Martina Di Modica, Triulzi, Tiziana, Tagliabue, Elda, Milling, Simon Wf, Weilbaecher, Katherine N, Korcsmaros, Tamas Douglas, Hall, Lindsay J, Robinson, Stephen Douglas
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 08.03.2020
• Subjects: Animal models; Antibiotics; Breast cancer; Cell activation; Degranulation; Homeostasis; Immune response; Intestinal microflora; Mast cells; Melanoma; Metabolic pathways; Microbiota; Stroma; Tumors
• DOI: 10.1101/2020.03.07.982108

The 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.