The Dysbiosis-Urolithin A-Melatonin Axis in Advanced Solid Tumors: A Pilot Observational Study and Proposal of a Composite Biomarker Triad

Urolithin A (UA) is a gut microbiota-derived metabolite of dietary ellagitannins with anti-inflammatory, mitochondrial, and neuroprotective properties. Because systemic UA availability depends on specific microbial consortia, dysbiosis may lead to functional loss of urolithin production. Melatonin, assessed via its major urinary metabolite 6-sulfatoxymelatonin (6-SMT), has been linked to cancer risk modulation in epidemiologic studies. In this three-year pilot observational study in Caucasian adults, we compared Group 1 (n = 231) with aggressive stage IV tumors (colorectal, hepatic, pancreatic, NSCLC, SCLC, TNBC, or glioblastoma), Group 2 (n = 118) with less aggressive advanced tumors (stage IV ER/PR+++ HER2-negative breast cancer, WHO grade 2 astrocytoma, or stage IV carcinoid tumors), and healthy controls (n = 117). UA was quantified by HPLC in plasma and stool; stool microbiota were cultured with attention to Streptococcus thermophilus, Enterococcus faecium, and Bacteroidetes; serum IL-6, TNF-α, IL-8, and IL-10 and 24 h urinary 6-SMT were measured. Group 1 exhibited severe selective dysbiosis with loss of S. thermophilus and E. faecium and critical reduction in Bacteroidetes, accompanied by undetectable UA in plasma and stool, marked elevation of pro-inflammatory cytokines (IL-6, TNF-α, IL-8) with normal IL-10, and profoundly reduced 6-SMT. Group 2 showed an attenuated pattern (reduced but detectable UA, moderate dysbiosis, moderately elevated cytokines, and moderate 6-SMT reduction). We identify a reproducible dysbiosis-UA-melatonin triad associated with tumor aggressiveness and propose it as a candidate composite biomarker framework for prospective validation and mechanistic studies.