Abstract
There is growing interest in the crosstalk between the gut microbiome, host metabolomic features, and disease pathogenesis. The current investigation compared long–term (26 week) and acute (3 day) dietary spinach intake in a genetic model of colorectal cancer. Metabolomic analyses in the polyposis in rat colon (Pirc) model and in wild–type animals corroborated key contributions to anticancer outcomes by spinach–derived linoleate bioactives and a butanoate metabolite linked to increased α–diversity of the gut microbiome. Combining linoleate and butanoate metabolites in human colon cancer cells revealed enhanced apoptosis and reduced cell viability, paralleling the apoptosis induction in colon tumors from rats given long–term spinach treatment. Mechanistic studies in cell–based assays and in vivo implicated the linoleate and butanoate metabolites in targeting histone deacetylase (HDAC) activity and the interferon–γ (IFN–γ) signaling axis. Clinical translation of these findings to at–risk patients might provide valuable quality–of–life benefits by delaying surgical interventions and drug therapies with adverse side effects.
Highlights
Complex interrelationships govern the dynamic interactions between gut microbes, host metabolomics, and exogenous drivers of disease outcome [1,2,3,4]
Metabolomics Segregated polyposis in rat colon (Pirc) and WT Rats According to Acute vs. Chronic SPI Intake
Among 17,243 metabolomic features identified in colon tissues at the end of the study, Partial Least Squares Discriminant Analysis (PLSDA) segregated groups according to treatment and genotype (Figure 1B)
Summary
Complex interrelationships govern the dynamic interactions between gut microbes, host metabolomics, and exogenous drivers of disease outcome [1,2,3,4]. We recently reported on a multi–omic investigation of cancer prevention by SPI in the polyposis in rat colon (Pirc) model [6]. The Pirc rat is analogous to Apc–mutant mouse models, such as ApcMin/+ mice, but more precisely mimics the small intestine and colon tumor burden observed in human hereditary Familial Adenomatous Polyposis (FAP) [7]. In the Pirc model, rats fed baby SPI for 26 weeks (10% w/w, freeze–dried in the diet) exhibited significant antitumor efficacy, with greater than 60% reduced tumor multiplicity in the colon and small intestine [6]. When colon tumors were compared with matched normal–looking tissues, anticancer outcomes were linked to SPI–derived linoleate bioactives with known pro–apoptotic/anti–
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