Pyrogallol Modulates Abscopal Tumour and Gut Microbial Responses to Localized Irradiation in an Ehrlich Ascites Carcinoma Model

Abstract

Radiotherapys clinical utility is often limited by radio-resistance, enterotoxicity, and intestinal dysbiosis. This study evaluated pyrogallol--a plant-derived vicinal trihydroxybenzene--as a dual-action radiosensitizer and mucosal protectant in an Ehrlich ascites carcinoma (EAC) BALB/c mouse model subjected to targeted LINAC irradiation (8 Gy). By combining transcriptomic profiling with whole-genome metagenomic sequencing, we interrogated the underlying host-microbiome interactions. Pyrogallol co-treatment significantly augmented radiotherapeutic efficacy, driving marked tumour regression through the upregulation of pro-apoptotic effectors (Bax, Casp3, Casp7) and p53-mediated tumour suppressors (Tp53, p21), alongside Bcl2 repression. Concurrently, pyrogallol blunted oncogenic progression by arresting proliferation (Cdk4, Pcna), inhibiting epithelial-mesenchymal transition (N-cadherin, vimentin), downregulating fibrotic remodelling (Tgf-{beta}, Col1A1, Fibronectin), and attenuating radiation-induced pro-inflammatory cytokine surges (Il-1, Il-6, Il-12). At the gut interface, radiation degraded colonization resistance by depleting homeostatic short-chain fatty acid producers and Clostridium scindens, while fuelling pathobiont blooms (Acinetobacter baumannii, Clostridioides difficile). Pyrogallol reversed this dysbiosis through a distinct ecological shift; despite a reduction in total species richness, the intestinal niche became dominated by the next-generation probiotic Parabacteroides distasonis ([~]94% relative abundance; Berger-Parker index: 0.94). Integrated Spearmans rank correlations demonstrated that host proliferative, EMT, fibrotic, and inflammatory markers aligned positively with pathobiont clusters (Bacteroides caecimuris, B. faecium, A. baumannii). Conversely, tumour regression and anti-inflammatory signatures correlated strongly with pathobiont restriction and P. distasonis enrichment. Overall, pyrogallol emerges as a compelling therapeutic adjuvant that synergistically enhances tumour radiosensitivity while remodelling the gut microbiome into a protective, anti-inflammatory state.