Guanxinning Attenuates Diabetic Myocardial Ischemia Reperfusion Injury via Targeting Oral Fusobacterium nucleatum and PTEN Signaling

Yiwen Li¹QIAN XU²Yanfei Liu²Longkun Liu²Wenting Wang²Mengmeng Zhu²Jing Cui²Hongjun Yang²Yue Liu^2*

• ¹Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment of Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing, China
• ²Cardiovascular Diseases Center, Xiyuan Hospital, Beijing, China

Background: The incidence and severity of diabetic myocardial ischemia reperfusion injury (DMIRI) are increasing, highlighting the urgent need for effective prevention and treatment. Previous studies have revealed that specific oral microbiota (Fusobacterium nucleatum)are closely involved in DMIRI, potentially serving as therapeutic targets. Guanxinning (GXN) has shown significant efficacy in treating diabetic cardiomyopathy. However, its mechanisms of action regarding DMIRI and its relationship with specific microbiota remain to be elucidated.Proposal: This study investigates whether GXN alleviates DMIRI by modulating Fusobacterium nucleatum and host interactions.Methods: The effects of GXN on cardiac injury, cardiac protein expression and the abundance of Fusobacterium nucleatum were evaluated in C57BL/6 mice under both conventional and germ-free conditions. GWAS analysis was employed to identify potential mechanisms linking Fusobacterium nucleatum and DMIRI. Fusobacterium nucleatum IgG levels were measured, and LC-MS/MS metabolomics along with Metorigin trace-ability analysis were conducted to validate the proposed mechanisms. Results: GXN treatment significantly reduced myocardial injury in diabetic mice and decreased oral Fusobacterium nucleatum abundance, although its effects on other gut microbiota taxa were variable. Importantly, the cardioprotective efficacy of GXN was markedly attenuated under pseudo-germ-free conditions, suggesting that its benefits are at least partly microbiota-dependent. PI3K signaling pathway as a central mediator of the microbiota interaction in DMIRI. Correspondingly, cardiac tissues from diabetic mice exhibited reduced expression of PTEN, consistent with pathway activation. Notably, Fusobacterium nucleatum exposure elevated plasma levels of specific anti–Fusobacterium nucleatum IgG antibodies and appeared to influence the host PI3K pathway through modulation of phenylalanine metabolism.Conclusion: GXN may alleviate DMIRI by targeting Fusobacterium nucleatum and PTEN related pathways, offering new insights into microbiota-based cardio protection.