Hospital Universitari de Tarragona Joan XXIII, Institut d'Investigació Sanitària Pere Virgili, Tarragona, Spain.
CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)-Instituto de Salud Carlos III (ISCIII), 28029, Madrid, Spain.
Microbiome. 2022 Aug 25;10(1):135. doi: 10.1186/s40168-022-01306-y.
Succinate is produced by both human cells and by gut bacteria and couples metabolism to inflammation as an extracellular signaling transducer. Circulating succinate is elevated in patients with obesity and type 2 diabetes and is linked to numerous complications, yet no studies have specifically addressed the contribution of gut microbiota to systemic succinate or explored the consequences of reducing intestinal succinate levels in this setting.
Using germ-free and microbiota-depleted mouse models, we show that the gut microbiota is a significant source of circulating succinate, which is elevated in obesity. We also show in vivo that therapeutic treatments with selected bacteria diminish the levels of circulating succinate in obese mice. Specifically, we demonstrate that Odoribacter laneus is a promising probiotic based on its ability to deplete succinate and improve glucose tolerance and the inflammatory profile in two independent models of obesity (db/db mice and diet-induced obese mice). Mechanistically, this is partly mediated by the succinate receptor 1. Supporting these preclinical findings, we demonstrate an inverse correlation between plasma and fecal levels of succinate in a cohort of patients with severe obesity. We also show that plasma succinate, which is associated with several components of metabolic syndrome including waist circumference, triglycerides, and uric acid, among others, is a primary determinant of insulin sensitivity evaluated by the euglycemic-hyperinsulinemic clamp.
Overall, our work uncovers O. laneus as a promising next-generation probiotic to deplete succinate and improve glucose tolerance and obesity-related inflammation. Video Abstract.
琥珀酸由人体细胞和肠道细菌产生，作为一种细胞外信号转导物将代谢与炎症联系起来。肥胖症和 2 型糖尿病患者的循环琥珀酸水平升高，与许多并发症有关，但尚无研究专门探讨肠道微生物群对系统性琥珀酸的贡献，或探讨在这种情况下降低肠道琥珀酸水平的后果。
使用无菌和微生物耗尽的小鼠模型，我们表明肠道微生物群是循环琥珀酸的重要来源，而肥胖症患者的循环琥珀酸水平升高。我们还在体内表明，用选定的细菌进行治疗可以降低肥胖小鼠的循环琥珀酸水平。具体来说，我们证明 Odoribacter laneus 是一种有前途的益生菌，因为它能够消耗琥珀酸并改善两种独立肥胖模型（db/db 小鼠和饮食诱导肥胖小鼠）中的葡萄糖耐量和炎症特征。在机制上，这部分是通过琥珀酸受体 1 介导的。支持这些临床前发现，我们在一组严重肥胖症患者中证明了血浆和粪便中琥珀酸盐水平之间存在反比关系。我们还表明，与代谢综合征的几个成分（包括腰围、甘油三酯和尿酸等）相关的血浆琥珀酸是通过正葡萄糖高胰岛素钳夹评估的胰岛素敏感性的主要决定因素。
总的来说，我们的工作揭示了 O. laneus 作为一种有前途的下一代益生菌，可以消耗琥珀酸并改善葡萄糖耐量和肥胖相关炎症。视频摘要。
