Cancer
Breast cancer reproductive risk factors and gut microbiome in US women: findings from a large epidemiological study Tengteng Wang* Tengteng Wang Curtis Huttenhower Mingyang Song Eric N. Taylor Rulla Tamimi Cheng Peng Eric B. Rimm Walter C. Willett Yang-Yu Liu A. Heather Eliassen
Background: No epidemiological study has systematically examined the association between breast cancer reproductive risk factors and gut microbiome features.
Methods: Participants of this cross-sectional study included 1,982 postmenopausal women from microbiome sub-studies embedded in the Nurses’ Health Study II. Reproductive factors and other covariates were measured by questionnaires. We calculated lifetime ovulatory years (LOY) as the difference between age at menopause and age at menarche, subtracting the duration of oral contraceptive use and one year per pregnancy. We collected stool samples and performed shotgun metagenomics sequencing using the 100nt Illumina HiSeq platform. We applied the bioBakery workflow to process the sequencing data and correct batch effects. We performed the a-diversity (using the Shannon index) and the b-diversity analyses (using the Bray-Curtis dissimilarity). We then performed the PERMANOVA test to investigate microbial composition variation according to eight reproductive factors. Multivariable-adjusted generalized linear regressions were used for per-feature analysis.
Results: Our taxonomic and functional profiling resulted in 1,323 species, 2,844 enzymes, and 605 MetaCyc pathways. We observed that microbial a-diversity was statistically significantly higher for women breastfed children ≥6 months (vs. none/shorter duration); however, no differences were observed by other factors. PERMANOVA revealed that breastfeeding (R2 = 0.34%), current postmenopausal hormone (PMH) use (R2 = 0.28%), LOY (R2 = 0.27%), and age at menopause (R2 = 0.26%) were statistically significantly associated with taxonomic variation characterized by beta diversity (all P-values <0.005). In the per-feature analysis, ~90% of the top species belonged to the phylum Bacillota. For example, longer LOY was associated with the abundance of 25 Bacillota-related species and five enzymes related to common housekeeping.
Conclusion: Our study is the first and largest to date to examine the associations between reproductive factors and the gut microbiome. Reproductive factors may contribute to the structural variation of the gut microbiome communities. Factors such as breastfeeding, PMH use, and LOY were associated with multiple β-glucuronidase and short-chain fatty acid-related species and pathways for common housekeeping.