Reshaping the Gut Microbiome in An Apc-Mutant Genetic Background: Mechanistic Insights From Integrated Multi-Omics
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AbstractBackground: Complex interrelationships govern the dynamic interactions between gut microbes, the host, and exogenous drivers of disease outcome. A multi-omic approach to cancer prevention by spinach was pursued in the polyposis in rat colon (Pirc) model of colorectal cancer. Results: Spinach fed for 26 weeks (10% w/w, freeze-dried in the diet) exhibited significant antitumor efficacy in the Pirc model and, despite the Apc-mutant genetic background, no changes were detected in b-catenin protein expression. To provide mechanistic leads, we performed 16S rRNA sequencing of the gut microbiome and unbiased transcriptomic analyses of colon polyps and matched normal-looking tissues. For dietary spinach intervention groups, increased microbiome diversity coincided with reversal of taxonomic composition in both wild type and Apc-mutant rats. Metagenomic prediction implicated linoleate and butanoate metabolism, tricarboxylic acid cycle, and pathways in cancer, which was supported by mechanistic leads from metabolomic analyses. Specifically, anticancer outcomes were linked to several spinach-derived linoleate bioactives with known anti-inflammatory and proapoptotic mechanisms, as well as N-aceto-2-hydroxybutanoate changes that were consistent with altered butanoate metabolism stemming from the increased a-diversity of the gut microbiome. On the other hand, L-glutamate and N-acetylneuraminate were reduced markedly in colon tumors from spinach-fed rats, implicating deregulated mitochondrial energetics and altered cell surface glycans involved in oncogenic signaling networks, immune evasion, and other pathways in cancer.Conclusions: Tumor suppression by dietary spinach was observed for the first time in the Apc-mutant Pirc model, and was independent of the mechanistic targeting of b-catenin. Marked reshaping of the gut microbiome in spinach-fed rats occurred along with changes in host transcriptomics and RNA-miRNA networks. Metabolomics provided mechanistic support for linoleate and butanoate metabolism, which are both strongly linked to anticancer outcomes in the colon. Tumor-associated changes in L-glutamate and N-acetylneuraminate warrant further investigation in the context of synthetic lethality and circumventing deregulated signaling networks in colorectal cancer patients.
