Gut microbiota-derived 9-OxoODE impaired hepatic energy metabolism and feed conversion ratio via RAB7A-mediated mitochondrial dysfunction

Enhancing the feed conversion ratio (FCR) is pivotal for achieving cost-effective and sustainable animal production. This study elucidated the interplay between gut microbiota-derived metabolites, particularly 9-Oxo-10,12-octadecadienoic acid (9-OxoODE) and their regulation of hepatic mitochondrial function, which impacts FCR in avian models. 9-OxoODE, a metabolite in ducks with low FCR, disrupted mitochondrial ultrastructure and fusion processes in vivo in pseudo-germ-free duck and mouse models. This disruption impaired oxidative phosphorylation and energy metabolism through Ras-related protein Rab-7a (RAB7A)-mediated mitochondrial fusion, activated by PGC-1α/MFN1 signaling in in vitro cultures of duck primary hepatocytes. However, a curcumin and resveratrol combination effectively inhibited 9-lipoxygenase activity and production of 9-OxoODE in an in vitro gut microbiome model, and it enhanced mitochondrial fusion and FCR in an in vivo duck model. The gut gut-liver-mitochondria axis could be a novel strategy to improve both feed efficiency and productivity in economically important animals.提高饲料转化率（Feed Conversion Ratio, FCR）对于实现经济高效且可持续的动物生产至关重要。本研究阐明了肠道菌群衍生代谢物——尤其是9-氧代-10,12-十八碳二烯酸（9-OxoODE）——与肝脏线粒体功能调控之间的相互作用，该作用会影响禽类模型中的FCR。9-OxoODE是低FCR鸭体内的一种代谢物，在假无菌鸭和小鼠模型的体内实验中，该物质会破坏线粒体超微结构与融合过程。在鸭原代肝细胞的体外培养实验中，这种破坏通过Ras相关蛋白Rab-7a（RAB7A）介导的线粒体融合过程损伤了氧化磷酸化与能量代谢，而该融合过程由PGC-1α/MFN1信号通路激活。然而，姜黄素与白藜芦醇的联合制剂在体外肠道菌群模型中可有效抑制9-脂氧合酶活性与9-OxoODE的生成，并在体内鸭模型中增强线粒体融合与FCR。肠-肝-线粒体轴或许可作为提升经济动物饲料利用率与生产性能的全新策略。