Gut-Derived Metabolite Trimethylamine N-Oxide Promotes Inflammation and Fibrosis Following Ischemia/Reperfusion through CCR2-Mediated Macrophage Infiltration

Inflammation plays a crucial role in the development of acute kidney injury (AKI) and subsequent chronic kidney disease (CKD) following renal ischemia-reperfusion (IR). It has been demonstrated that metabolites from the gut microbiota can trigger inflammatory responses and modulate renal damage induced by IR. However, the exact driving factors and underlying mechanisms of this process remain unclear. Trimethylamine N-oxide (TMAO), a choline metabolite derived from the gut, has been observed to increase in AKI and CKD patients. Our study reveals that glycyrrhizic acid (GA) exacerbates IR-induced AKI and subsequent CKD through TMAO. To delve into the underlying mechanisms, we employed single-cell sequencing to construct a molecular map of kidney cells. Overall design: To investigate the effect of TMAO on renal injury development after IR, we used conventionally reared C57BL/6J mice. These mice were pre-fed either a control diet with 0.14% choline or a choline-supplemented diet with 1.4% choline for a period of 14 days. Subsequently, the mice received left renal artery clamping for 45 minutes to induce unilateral renal IR injury. Throughout the experiment, the mice remained on their respective diets and were administered glycyrrhizic acid via gastric gavage. They were then sacrificed on postoperative days 3, 14, and 21 (representing AKI, AKI-to-CKD transition, and CKD respectively)