Antibiotic-induced disturbances of the gut microbiota result in accelerated breast tumor growth

Alastair M McKee, Lindsey J Hall*, Stephen D Robinson

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

13 Citations (Scopus)
39 Downloads (Pure)

Abstract

Highlights

• Microbiota disturbances promote tumor growth in several breast cancer models
• Increased tumor volume positively correlates with stromal mast cell density
• Supplementation with a commensal restores tumor growth to normal

Summary

The gut microbiota’s function in regulating health has seen it linked to disease progression in several cancers. However, there is limited research detailing its influence in breast cancer (BrCa). This study found that antibiotic-induced perturbation of the gut microbiota significantly increases tumor progression in multiple BrCa mouse models. Metagenomics highlights the common loss of several bacterial species following antibiotic administration. One such bacteria, Faecalibaculum rodentium, rescued this increased tumor growth. Single-cell transcriptomics identified an increased number of cells with a stromal signature in tumors, and subsequent histology revealed an increased abundance of mast cells in the tumor stromal regions. We show that administration of a mast cell stabilizer, cromolyn, rescues increased tumor growth in antibiotic treated animals but has no influence on tumors from control cohorts. These findings highlight that BrCa-microbiota interactions are different from other cancers studied to date and suggest new research avenues for therapy development.
Original languageEnglish
Article number103012
Number of pages30
JournaliScience
Volume24
Issue number9
Early online date20 Aug 2021
DOIs
Publication statusPublished - 24 Sep 2021

Bibliographical note

Funding Information:
This work was supported by funding from the UKRI Biotechnology and Biological Sciences Research Council (BBSRC) Norwich Research Park (NRP) Biosciences Doctoral Training Partnership (DTP) to S.D.R./B.M.K. (BB/J014524/1) and L.J.H./C.A.-G. (BB/M011216/1); the UKRI BBSRC NRP DTP as a National Productivity Investment Fund CASE Award in collaboration with BenevolentAI to M.M./T.K. (BB/S50743X/1); a Breast Cancer Now studentship to S.D.R./A.M.M. (2017NovPhD973); a BigC studentship to S.D.R./C.A.P. (18-15R); the Associazione Italiana per la Ricerca sul Cancro to E.T. (IG no 20264); a fellowship to TK in computational biology at the Earlham Institute (Norwich, UK) in partnership with the Quadram Institute Bioscience (Norwich, UK); strategic support from UKRI BBSRC to TK (BB/J004529/1, BB/P016774/1, and BB/CSP17270/1); a Wellcome Trust Investigator award to LJH (100974/C/13/Z); and strategic support from the UKRI BBSRC Institute Strategic Program Gut Microbes and Health BB/R012490/1 and its constituent projects BBS/E/F/000PR10353 and BBS/E/F/000PR10355 to G.L.G. T.K. L.J.H. and S.D.R. S.D.R. and W.J.F. were also supported by Cancer Research UK (grant number C18281/A29019). M.R.R. was supported by Susan G. Komen Career Catalyst award CCR17483602, IRG-17-097-31 (ACS), the University of Virginia Cancer Center, and support from NCI Cancer Center Support grant P30CA44570 as startup funds. T.Y.F. was supported by Farrow Fellowship and by the NCI Cancer Center Support Grant P30 CA44579. Additionally, we thank Norfolk Fundraisers, Mrs Margaret Doggett, and the Colin Wright Fund for their kind support and fundraising over the years. Conceptualization, T.K. L.J.H. and S.D.R.; formal analyses, A.M.M. B.M.K. M.M. W.J.F. C.A.P. S.A.D. R.A. K.A.M. S.C. G.L.G. J.P. C.L. M.D. C.A.-G. A.A. T.-Y.F. M.D.M. T.T. M.R.R. L.J.H. and S.D.R.; investigation, A.M.M. B.M.K. M.M. W.J.F. C.A.P. R.A. K.A.M. S.C. G.L.G. J.P. C.L. M.D. C.A.-G. A.A. T.-Y.F. M.D.M. T.T. E.T. S.W.F.M. K.N.W. M.R.R. T.K. L.J.H. and S.D.R.; resources, S.W.F.M. K.N.W. M.R.R. T.K. L.J.H. and S.D.R.; review and editing, A.M.M. W.J.F. C.A.P. S.A.D. K.A.M. S.C. G.L.G. J.P. C.L. M.D. C.A.-G. A.A. T.-Y.F. M.D.M. T.T. E.T. S.W.F.M. K.N.W. M.R.R. T.K. L.J.H. and S.D.R.; visualization, A.M.M. B.K.M. M.M. W.J.F. C.A.P. R.A. G.L.G. T.-Y.F. T.K. L.J.H. and S.D.R.; supervision, E.T. S.W.F.M. K.N.W. M.R.R. T.K. L.J.H. and S.D.R.; funding acquisition, L.J.H. and S.D.R. All authors declare no conflicts of interest. One or more of the authors of this paper self-identifies as a member of the LGBTQ+ community. One or more of the authors of this paper self-identifies as living with a disability.

Funding Information:
This work was supported by funding from the UKRI Biotechnology and Biological Sciences Research Council ( BBSRC ) Norwich Research Park (NRP) Biosciences Doctoral Training Partnership (DTP) to S.D.R./B.M.K. (BB/J014524/1) and L.J.H./C.A.-G. (BB/M011216/1); the UKRI BBSRC NRP DTP as a National Productivity Investment Fund CASE Award in collaboration with BenevolentAI to M.M./T.K. (BB/S50743X/1); a Breast Cancer Now studentship to S.D.R./A.M.M. (2017NovPhD973); a BigC studentship to S.D.R./ C.A.P . (18-15R); the Associazione Italiana per la Ricerca sul Cancro to E.T . ( IG no 20264); a fellowship to TK in computational biology at the Earlham Institute (Norwich, UK) in partnership with the Quadram Institute Bioscience (Norwich, UK); strategic support from UKRI BBSRC to TK (BB/J004529/1, BB/P016774/1, and BB/CSP17270/1); a Wellcome Trust Investigator award to LJH (100974/C/13/Z); and strategic support from the UKRI BBSRC Institute Strategic Program Gut Microbes and Health BB/R012490/1 and its constituent projects BBS/E/F/000PR10353 and BBS/E/F/000PR10355 to G.L.G., T.K., L.J.H., and S.D.R. S.D.R. and W.J.F. were also supported by Cancer Research UK (grant number C18281/A29019). M.R.R. was supported by Susan G. Komen Career Catalyst award CCR17483602, IRG-17-097-31 ( ACS ), the University of Virginia Cancer Center , and support from NCI Cancer Center Support grant P30CA44570 as startup funds. T.Y.F. was supported by Farrow Fellowship and by the NCI Cancer Center Support Grant P30 CA44579. Additionally, we thank Norfolk Fundraisers, Mrs Margaret Doggett, and the Colin Wright Fund for their kind support and fundraising over the years.

Publisher Copyright:
© 2021 The Author(s)

Structured keywords

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