Bacterial diet modulates tamoxifen-induced death via host fatty acid metabolism

Cédric Diot, Aurian P. García-González, Andre F. Vieira, Melissa Walker, Megan Honeywell, Hailey Doyle, Olga Ponomarova, Yomari Rivera, Huimin Na, Hefei Zhang, Michael Lee, Carissa P. Olsen and Albertha J. M. Walhout ()
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Cédric Diot: University of Massachusetts Chan Medical School
Aurian P. García-González: University of Massachusetts Chan Medical School
Andre F. Vieira: Worcester Polytechnic Institute
Melissa Walker: University of Massachusetts Chan Medical School
Megan Honeywell: University of Massachusetts Chan Medical School
Hailey Doyle: University of Massachusetts Chan Medical School
Olga Ponomarova: University of Massachusetts Chan Medical School
Yomari Rivera: University of Massachusetts Chan Medical School
Huimin Na: University of Massachusetts Chan Medical School
Hefei Zhang: University of Massachusetts Chan Medical School
Michael Lee: University of Massachusetts Chan Medical School
Carissa P. Olsen: Worcester Polytechnic Institute
Albertha J. M. Walhout: University of Massachusetts Chan Medical School

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract Tamoxifen is a selective estrogen receptor (ER) modulator that is used to treat ER-positive breast cancer, but that at high doses kills both ER-positive and ER-negative breast cancer cells. We recapitulate this off-target effect in Caenorhabditis elegans, which does not have an ER ortholog. We find that different bacteria dramatically modulate tamoxifen toxicity in C. elegans, with a three-order of magnitude difference between animals fed Escherichia coli, Comamonas aquatica, and Bacillus subtilis. Remarkably, host fatty acid (FA) biosynthesis mitigates tamoxifen toxicity, and different bacteria provide the animal with different FAs, resulting in distinct FA profiles. Surprisingly these bacteria modulate tamoxifen toxicity by different death mechanisms, some of which are modulated by FA supplementation and others by antioxidants. Together, this work reveals a complex interplay between microbiota, FA metabolism and tamoxifen toxicity that may provide a blueprint for similar studies in more complex mammals.

Date: 2022
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DOI: 10.1038/s41467-022-33299-5

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