BackgroundColorectal cancers (CRC) are associated with perturbations in cellular amino acids, nucleotides, pentose-phosphate pathway carbohydrates, and glycolytic, gluconeogenic, and tricarboxylic acid intermediates. A non-targeted global metabolome approach was utilized for exploring human CRC, adjacent mucosa, and stool. In this pilot study, we identified metabolite profile differences between CRC and adjacent mucosa from patients undergoing colonic resection. Metabolic pathway analyses further revealed relationships between complex networks of metabolites.MethodsSeventeen CRC patients participated in this pilot study and provided CRC, adjacent mucosa ~10 cm proximal to the tumor, and stool. Metabolomes were analyzed by gas chromatography-mass spectrometry (GC/MS) and ultra-performance liquid chromatography-mass spectrometry (UPLC-MS/MS). All of the library standard identifications were confirmed and further analyzed via MetaboLyncTM for metabolic network interactions.ResultsThere were a total of 728 distinct metabolites identified from colonic tissue and stool matrices. Nineteen metabolites significantly distinguished CRC from adjacent mucosa in our patient-matched cohort. Glucose-6-phosphate and fructose-6-phosphate demonstrated 0.64-fold and 0.75-fold lower expression in CRC compared to mucosa, respectively, whereas isobar: betaine aldehyde, N-methyldiethanolamine, and adenylosuccinate had 2.68-fold and 1.88-fold higher relative abundance in CRC. Eleven of the 19 metabolites had not previously been reported for CRC relevance. Metabolic pathway analysis revealed significant perturbations of short-chain fatty acid metabolism, fructose, mannose, and galactose metabolism, and glycolytic, gluconeogenic, and pyruvate metabolism. In comparison to the 500 stool metabolites identified from human CRC patients, only 215 of those stool metabolites were also detected in tissue. This CRC and stool metabolome investigation identified novel metabolites that may serve as key small molecules in CRC pathogenesis, confirmed the results from previously reported CRC metabolome studies, and showed networks for metabolic pathway aberrations. In addition, we found differences between the CRC and stool metabolomes.ConclusionsStool metabolite profiles were limited for direct associations with CRC and adjacent mucosa, yet metabolic pathways were conserved across both matrices. Larger patient-matched CRC, adjacent non-cancerous colonic mucosa, and stool cohort studies for metabolite profiling are needed to validate these small molecule differences and metabolic pathway aberrations for clinical application to CRC control, treatment, and prevention.Electronic supplementary materialThe online version of this article (doi:10.1186/s40170-016-0151-y) contains supplementary material, which is available to authorized users.

Scope Heat-stabilized rice bran and cooked navy bean powder contain a variety of phytochemicals that are fermented by colonic microbiota and may influence intestinal health. Dietary interventions with these foods should be explored for modulating colorectal cancer risk. Methods and results A randomized-controlled pilot clinical trial investigated the effects of eating heat-stabilized rice bran (30g/day) or cooked navy bean powder (35g/day) on gut microbiota and metabolites (NCT01929122). Twenty-nine overweight/obese volunteers with a prior history of colorectal cancer consumed a study-provided meal and snack daily for 28 days. Volunteers receiving rice bran or bean powder showed increased gut bacterial diversity and altered gut microbial composition at 28 days compared to baseline. Supplementation with rice bran or bean powder increased total dietary fiber intake similarly, yet only rice bran intake led to a decreased Firmicutes:Bacteroidetes ratio and increased short chain fatty acids (propionate and acetate) in stool after 14 days but not at 28 days. Conclusion These findings support modulation of gut microbiota and fermentation by-products by heat-stabilized rice bran and suggest that foods with similar ability to increase dietary fiber intake may not have equal effects on gut microbiota and microbial metabolism.

Heat-stabilized rice bran (SRB) has been shown to regulate blood lipids and glucose, modulate gut mucosal immunity and inhibit colorectal cancer in animal and human studies. However, SRB’s effects on gut microbial composition and metabolism and the resulting implications for health remain largely unknown. A pilot, randomized-controlled trial was developed to investigate the effects of eating 30 g/day SRB on the stool microbiome and metabolome. Seven healthy participants consumed a study meal and snack daily for 28 days. The microbiome and metabolome were characterized using 454 pyrosequencing and gas chromatography-mass spectrometry (GC-MS) at baseline, two and four weeks post-intervention. Increases in eight operational taxonomic units (OTUs), including three from Bifidobacterium and Ruminococcus genera, were observed after two and four weeks of SRB consumption (p < 0.01). Branched chain fatty acids, secondary bile acids and eleven other putative microbial metabolites were significantly elevated in the SRB group after four weeks. The largest metabolite change was a rice bran component, indole-2-carboxylic acid, which showed a mean 12% increase with SRB consumption. These data support the feasibility of dietary SRB intervention in adults and support that SRB consumption can affect gut microbial metabolism. These findings warrant future investigations of larger cohorts evaluating SRB’s effects on intestinal health.

Most breast cancers originate in the epithelial cells lining the breast ducts. Intraductal administration of cancer therapeutics would lead to high drug exposure to ductal cells and eliminate preinvasive neoplasms while limiting systemic exposure. We performed preclinical studies in N-methyl-N’-nitrosourea–treated rats to compare the effects of 5-fluorouracil, carboplatin, nanoparticle albumin-bound paclitaxel, and methotrexate to the previously reported efficacy of pegylated liposomal doxorubicin (PLD) on treatment of early and established mammary tumors. Protection from tumor growth was observed with all five agents, with extensive epithelial destruction present only in PLD-treated rats. Concurrently, we initiated a clinical trial to establish the feasibility, safety, and maximum tolerated dose of intraductal PLD. In each eligible woman awaiting mastectomy, we visualized one ductal system and administered dextrose or PLD using a dose-escalation schema (2 to 10 mg). Intraductal administration was successful in 15 of 17 women with no serious adverse events. Our preclinical studies suggest that several agents are candidates for intraductal therapy. Our clinical trial supports the feasibility of intraductal administration of agents in the outpatient setting. If successful, administration of agents directly into the ductal system may allow for “breast-sparing mastectomy” in select women.