Abrus cantoniensis α-glucan-like polysaccharide alleviates influenza via gut microbial acetate to activate free fatty acid receptor 2/ mitochondrial antiviral signaling protein/interferon-beta pathway

ACP-A1, a novel an α-glucan-like Polysaccharide from Abrus cantoniensis , is structurally resolved for the first time. • ACP-A1 reshapes gut microbiota and triggers the FFAR2/MAVS/IFN-β antiviral circuit. • Microbiota-driven IFN-β signaling underpins ACP-A1 protection against H1N1 influenza. Background The gut microbiota is critical for host defense against influenza. Polysaccharides are known for their microbiota-modulating and immunomodulatory activities; however, the anti-influenza efficacy of homogeneous Abrus cantoniensis polysaccharides (ACP) remains unexplored. Purpose The present study seeks to clarify the protective role of ACP in influenza and explore its underlying molecular mechanisms. Methods Initially, crude polysaccharides were extracted via ethanol precipitation and subsequently purified by gel chromatography. Systematic structural characterization of ACP was then performed using carbohydrate chemistry techniques, including scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR), ultraviolet (UV) spectroscopy, and nuclear magnetic resonance (NMR). The therapeutic efficacy of ACP was assessed by monitoring various indicators such as body weight, survival rate, viral load, and pulmonary pathological changes in mouse models. Furthermore, to elucidate the biological mechanism underlying ACP’s anti-influenza activity via regulation of pulmonary interferon-beta (IFN-β) immune networks by intestinal acetate-producing microbiota, multi-omics analyses integrating metagenomics, metabolomics, gene knockout, immunofluorescence, and Western blot were conducted. Finally, the potential anti-influenza effects of ACP via the gut-lung axis were evaluated based on in vivo and in vitro detection of protein expression of IFN-β, free fatty acid receptor 2 (FFAR2), and mitochondrial antiviral signaling protein (MAVS), as well as antiviral interferon-stimulated genes (ISGs). Results In this study, we purified a novel polysaccharide, ACP-A1, with a backbone of→4)-α-D-Glc p -(1→,→4)-β-D-Gal p -(1→, and →4,6)-α-D-Glc p -(1→ linkages and α-D-Glc p -(1→ branches at O-6. In H1N1-infected mice, oral ACP-A1 alleviated weight loss, increased survival, and reduced lung inflammation and viral load. Metagenomic and targeted metabolomic analyses showed that ACP-A1 enriched Limosilactobacillus reuteri and elevated acetate levels. Fecal microbiota transplantation, FFAR2 inhibition, and MAVS knockout experiments demonstrated that ACP-A1 enhances the FFAR2/MAVS/IFN-β antiviral pathway via microbial-derived acetate. Conclusion Collectively, our findings elucidate that ACP mitigates influenza virus-induced lung dysfunction by promoting the proliferation of acetate-producing gut microbiota, particularly Limosilactobacillus reuteri , and activating the FFAR2/MAVS/IFN-β antiviral axis in pulmonary immune cells. These findings establish ACP-A1 as a natural polysaccharide regulating IFN-β homeostasis, highlighting its potential for influenza prevention. Download: Download high-res image (323KB) Download: Download full-size image