Prebiotic proanthocyanidins inhibit bile reflux-induced esophageal adenocarcinoma through reshaping the gut microbiome and esophageal metabolome

The gut and local esophageal microbiome progressively shift from healthy commensal bacteria to inflammation -linked pathogenic bacteria in patients with gastroesophageal reflux disease, Barrett's esophagus, and esophageal adenocarcinoma (EAC). However, mechanisms by which microbial communities and metabolites contribute to reflux-driven EAC remain incompletely understood and challenging to target. Herein, we utilized a rat reflux-induced EAC model to investigate targeting the gut microbiome-esophageal metabolome axis with cranberry proanthocyanidins (C -PAC) to inhibit EAC progression. Sprague-Dawley rats, with or without reflux induction, received water or C -PAC ad libitum (700 mu g/rat/day) for 25 or 40 weeks. C -PAC exerted prebiotic activity abrogating reflux-induced dysbiosis and mitigating bile acid metabolism and transport, culminating in significant inhibition of EAC through TLR/NF-kappa B/TP53 signaling cascades. At the species level, C -PAC mitigated reflux-induced pathogenic bacteria (Streptococcus parasanguinis, Escherichia coli, and Proteus mirabilis). C -PAC specifically reversed reflux-induced bacterial, inflammatory, and immune -implicated proteins and genes, including Ccl4, Cd14, Crp, Cxcl1,Il6,Il1b, Lbp, Lcn2, Myd88, Nfkb1, Tlr2, and Tlr4, aligning with changes in human EAC progression, as confirmed through public databases. C -PAC is a safe, promising dietary constituent that may be utilized alone or potentially as an adjuvant to current therapies to prevent EAC progression through ameliorating reflux-induced dysbiosis, inflammation, and cellular damage.