Lingonberry anthocyanins mitigate high-fat diet-induced intestinal injury in D. melanogaster via regulating a gut microbiota-insulin/IGF-1 signaling-intestinal stem cells axis

• ARLE improves HFD-induced intestinal health in D. melanogaster. • ARLE extends lifespan and enhances locomotor activity. • ARLE reduces lipid content and intestinal antioxidant capacity. • ARLE balances intestinal stem cells via insulin/IGF-1 signaling. • Gut microbiota alterations mediate ARLE's health benefits. Lingonberry anthocyanin, a natural water-soluble polyphenolic pigment, possesses various biological functions, including antioxidant, anti-aging, anti-cancer, hypoglycemic, and hypolipidemic properties. The focus of this study was on the effects of anthocyanin-rich lingonberry extract (ARLE) on high-fat diet (HFD)-induced intestinal health of female D. melanogaster , and the potential mechanism of action was elucidated by examining the gut microbiota profiles and their regulated signaling pathway. The results showed that ARLE could mitigate HFD-induced adverse effects on the lifespan, locomotor activity, lipid content, and intestinal antioxidant capacity. Gene knockout combined with immunostaining demonstrated that ARLE balanced intestinal stem cells (ISCs) proliferation and differentiation via regulating insulin/IGF-1 signaling (IIS). Moreover, 16S rRNA sequencing revealed that ARLE reduced the abundance of Wolbachia and Brevibacterium, while levels of Gilliamella, Faecalibacterium, Leuconostoc , and Lactobacillus were increased . Importantly, experiments in germ-free D. melanogaster further demonstrated beneficial effects induced by ARLE associated with gut microbiota acting on the IIS signalling pathway to regulate intestinal homeostasis. Taken together, ARLE alleviates the intestinal damage induced by HFD in D. melanogaster by controlling the gut microbiota-ISCs axis through IIS signaling, thereby contributing to improved intestinal health.