The novel synbiotic (Lacticaseibacillus rhamnosus NKU FL1-11 and galacto-oligosaccharides) alleviates HCA IQ-triggered aging by reprogramming gut microbial metabolism to coordinate the enterohepatic β-glucuronidase activity.

2-Amino-3-methylimidazo[4,5-f]quinoline (IQ), a nitrogen-containing heterocyclic amine, mainly enters the human body through thermally processed foods and is recognized as a dietary organic pollutant. Although current toxicological studies have focused on the direct health effects of IQ, its pro-gerontic potential remains unknown. In this study, we evaluated the efficacy of a novel synbiotic composed of Lacticaseibacillus rhamnosus NKU FL1-11 and galacto-oligosaccharides against IQ-triggered aging in zebrafish. Multi-biochemical and behavioral analyses revealed that the synbiotic ameliorated IQ-induced locomotor deficits, reduced systemic SA-β-Gal activity, decreased aging markers (Cleaved Caspase3, p16, p21, and p53), enhanced tissue stemness (PCNA), and mitigated fibrosis (α-SMA) and histopathological damage across gonadal, intestinal, renal, and hepatic tissues. Interestingly, we found the synbiotic bidirectionally modulated β-glucuronidase activity, enhancing it in the intestine while suppressing it in the liver, thereby affecting enterohepatic circulation. Gut microbiota remodeling was central to this protection, marked by increased abundance of Cetobacterium, which was linked to elevated production of α-ketoglutaric acid and other organic acids. Mechanistically, the synbiotic suppressed PI3K-AKT/mTOR overactivation and restored FoxO1 expression, a signaling axis essential for its benefits, as confirmed by inhibition assays. Correlation analysis underscored a critical microbiota-metabolite-enterohepatic circulation-signaling axis in mediating the mitigation of IQ-triggered aging and the risk of aging-related disease. These results elucidate the pro-gerontic effects of IQ and reveal the multi-target anti-aging mechanisms of the synbiotic, supporting its potential as a synbiotic product against aging-related phenotypes and providing valuable theoretical insights into the risk management of IQ. Understanding its mechanisms and long-term effects will require further study.