Carboxyl-containing
metabolites (CCMs) widely exist in living systems
and are the essential components for life. Global characteristics
of CCMs in biological samples are critical for the understanding of
physiological processes and the discovery for the onset of relevant
diseases. However, their determination represents a challenge due
to enormous polarity differences, structural diversity, high structural
similarity, and poor ionization efficiency in mass spectrometry. Herein,
5-(diisopropylamino)amylamine (DIAAA) derivatization coupled with
liquid chromatography–mass spectrometry (LC-MS) was developed
for mapping the CCMs. With this methodology, the sensitivity was significantly
enhanced. More importantly, the hydrophobicity of polar CCMs, amino
acids, TCA cycle intermediates, and short-chain fatty acids and the
hydrophilicity of low-polar CCMs, long-chain fatty acids, and bile
acids were significantly increased, resulting in a remarkable separation
efficiency for which 68 CCMs can be simultaneously determined. Furthermore,
the polarity-tuning effect was confirmed to be induced by the different
impacts of aliphatic chains and nitrogen atom in DIAAA, the latter
existing as a cation in the acidic mobile phase, using different derivatization
reagents. Finally, this derivatization method was utilized to hunt
for the potential biomarkers in colorectal cancer (CRC) patients and
52 CCMs, related with several key metabolic pathways, including amino
acids metabolism, TCA cycle, fatty acid metabolism, pyruvate metabolism,
and gut flora metabolism were identified. This innovative polarity-tuning
derivatization-LC-MS approach was proved to be a valuable tool for
probing global metabolome with high separation efficiency and sensitivity
in various biological samples.
Studies showed that manipulation of gut microbiota (GM) composition through the treatment of prebiotics could be a novel preventive measure against colorectal cancer (CRC) development. In this study, for the first time, we assessed the non-toxic doses of the triterpene saponins (ginsenoside-Rb3 and ginsenoside-Rd) – as prebiotics – that effectively reinstated the dysbiotic-gut microbial composition and intestinal microenvironment in an ApcMin/+ mice model. Rb3 and Rd effectively reduced the size and the number of the polyps that accompanied with the downregulation of oncogenic signaling molecules (iNOS, STAT3/pSTAT3, Src/pSrc). Both the compounds improved the gut epithelium by promoting goblet and Paneth cells population and reinstating the E-cadherin and N-Cadherin expression. Mucosal immunity remodeled with increased in anti-inflammatory cytokines and reduced in pro-inflammatory cytokines in treated mice. All these changes were correlating with the promoted growth of beneficial bacteria such as Bifidobacterium spp., Lactobacillus spp., Bacteroides acidifaciens, and Bacteroides xylanisolvens. Whereas, the abundance of cancer cachexia associated bacteria, such as Dysgonomonas spp. and Helicobacter spp., was profoundly lower in Rb3/Rd-treated mice. In conclusion, ginsenosides Rb3 and Rd exerted anti-cancer effects by holistically reinstating mucosal architecture, improving mucosal immunity, promoting beneficial bacteria, and down-regulating cancer-cachexia associated bacteria.
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