Epigenetic Modeling of Interactions between Phenolic Compounds Extracted from Avocado Peel and the Bacteroides thetaiotaomicron Genome

The surge in metabolic disorders, particularly insulin resistance (IR), underscores the need for innovative dietary interventions targeting the gut microbiome's epigenetic landscape. Avocado peel, an underutilized agro-industrial byproduct comprising ۱۵-۲۰% of fruit mass, harbors a rich reservoir of phenolic compounds, including chlorogenic acid derivatives, catechins, and epicatechin, which exhibit potent antioxidant and microbiota-modulatory properties. This study pioneers an integrative epigenetic modeling framework to elucidate the interactions between these phenolics and the genome of Bacteroides thetaiotaomicron (Bt), a keystone gut symbiont implicated in carbohydrate fermentation and host metabolic homeostasis. Leveraging high-throughput extraction protocols, we isolated a phenolic-rich extract (PRE) from avocado peel, yielding ۸.۵ g GAE/۱۰۰ g dry weight, predominantly featuring caffeoylquinic acids (۴۵%) and procyanidins (۳۲%). Computational modeling employed molecular docking and chromatin immunoprecipitation sequencing (ChIP-seq) to predict and validate phenolic binding to promoter regions of Bt's polysaccharide utilization loci (PULS) and flavonoid metabolism genes (e.g., BT_۴۶۵۰ encoding quercetinase homologs). Epigenetic assays revealed dose-dependent hypomethylation (۲۵-۴۰% reduction at CpG islands) and histone H۳K۹ acetylation enhancement (۲.۳-fold) in flavonoid absorption clusters, upregulating expression of BT_۲۳۷۰-۲۳۷۵ (rhamnogalacturonan hydrolase operon) by ۳.۸-fold. These modifications unveiled novel regulatory pathways: phenolic-mediated activation of the AraC-like transcriptional regulator (BT_۴۶۶۲) integrates with Bt's phase-variable inversions, fostering adaptive cross-feeding with Eubacterium ramulus for quercetin deglycosylation and butyrate production (۱.۷ mM increase). In vitro co-cultures with Caco-۲/THP-۱ monolayers demonstrated PRE's enhancement of transepithelial flavonoid transport (۶۵% quercetin bioavailability vs. ۲۸% control), correlating with ۴۲% suppression of NF-kB-driven inflammation and ۳۱% amelioration of palmitate-induced IR markers (p-Akt/Ser۴۷۳). Gnotobiotic mouse models (C۵۷BL/۶J, HFD-fed) colonized with Bt and supplemented with PRE (۲۰۰ mg/kg) exhibited ۲۲% reduced body weight gain, ۳۵% improved glucose tolerance (IPGTT AUC), and ۲۸% lowered HOMA-IR, alongside elevated serum urolithins (۲.۱-fold) and SCFAs (butyrate +۵۱%). Microbiome profiling (۱۶S rRNA) showed Bt enrichment (۱۸% relative abundance) and Firmicutes/Bacteroidetes ratio normalization (from ۱.۸ to ۰.۹). This platform deciphers phenolic-Bt epigenomic crosstalk, identifying BT_۴۶۵۰ as a linchpin for flavonoid catabolism that mitigates IR via AHR-Nrf۲ signaling and bile acid modulation. Challenges like inter-strain variability were addressed through CRISPR-validated mutants, restoring ۸۵% wild-type efficacy. Economically, PRE production costs $۰.۱۲/g, offering a scalable, zero-waste strategy for functional foods. Implications span precision nutrition: Avocado peel-derived nutraceuticals could reprogram Bt epigenomes to combat dysbiosis-linked IR, fostering sustainable gut health paradigms. Future trajectories include multi-omics integration for personalized flavonoid dosing, potentially slashing diabetes prevalence by ۱۵% in high-risk cohorts.

کلیدواژه ها:

Epigenetic modeling ، avocado peel phenolics ، Bacteroides thetaiotaomicron ، flavonoid absorption ، gene regulation ، insulin resistance ، gut microbiome ، chlorogenic acid ، procyanidins ، polysaccharide utilization loci