Theranostics 2022; 12(8):3794-3817. doi:10.7150/thno.68611 This issue
1. Immunology Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore
2. Department of Physiology, Yong Loo Lin School of Medicine, NUS, Singapore
3. NUS Immunology Program, Life Sciences Institute, NUS, Singapore
4. Saw Swee Hock School of Public Health, NUS, Singapore
5. NUS Environmental Research Institute, NUS, Singapore
6. Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, NUS, Singapore
7. Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore
Background: High emotional or psychophysical stress levels have been correlated with an increased risk and progression of various diseases. How stress impacts the gut microbiota to influence metabolism and subsequent cancer progression is unclear.
Methods: Feces and serum samples from BALB/c ANXA1+/+ and ANXA1-/- mice with or without chronic restraint stress were used for 16S rRNA gene sequencing and GC-MS metabolomics analysis to investigate the effect of stress on microbiome and metabolomics during stress and breast tumorigenesis. Breast tumors samples from stressed and non-stressed mice were used to perform Whole-Genome Bisulfite Sequencing (WGBS) and RNAseq analysis to construct the potential network from candidate hub genes. Finally, machine learning and integrated analysis were used to map the axis from chronic restraint stress to breast cancer development.
Results: We report that chronic stress promotes breast tumor growth via a stress-microbiome-metabolite-epigenetic-oncology (SMMEO) axis. Chronic restraint stress in mice alters the microbiome composition and fatty acids metabolism and induces an epigenetic signature in tumors xenografted after stress. Subsequent machine learning and systemic modeling analyses identified a significant correlation among microbiome composition, metabolites, and differentially methylated regions in stressed tumors. Moreover, silencing Annexin-A1 inhibits the changes in the gut microbiome and fatty acid metabolism after stress as well as basal and stress-induced tumor growth.
Conclusions: These data support a physiological axis linking the microbiome and metabolites to cancer epigenetics and inflammation. The identification of this axis could propel the next phase of experimental discovery in further understanding the underlying molecular mechanism of tumorigenesis caused by physiological stress.
Keywords: 16S rRNA gene sequencing, gut microbiome, metabolic level, epigenetic signature, PICRUSt, differentially methylated regions, machine learning, restraint stress, serum metabolites, feces metabolites, WGBS, breast cancer, tumorigenesis