Center for Global Health, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu 211166, PR China; Key Lab of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu 211166, PR China.
Center for Global Health, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu 211166, PR China.
Int Immunopharmacol. 2024 Dec 5;142(Pt A):113054. doi: 10.1016/j.intimp.2024.113054. Epub 2024 Sep 5.
Ulcerative colitis (UC) is becoming a global burden. Previous observational studies have unveiled associations between serum metabolites and UC, but their causal relationship remains unclear.
Serum samples from patients and mice with UC were utilized for untargeted metabolomics to identify UC-associated metabolites. Then, a two-sample mendelian randomization (MR) analysis was employed to estimate their causal relationship. Finally, mice with chronic colitis induced by dextran sodium sulfate (DSS) and macrophages were used to evaluate the protective role of creatine and underlying mechanism.
16 serum metabolites showed associations with UC after adjusting for confounders and multiple testing. Among them, creatine exhibited a robust protective effect against UC (OR=0.39; 95 % CI=0.27-0.56). Significant reduction of creatine was also observed in mice with acute UC induced by DSS. The inverse variance weighted (IVW) MR analysis further confirmed a causal effect of creatine on UC risk (OR IVW=0.45; 95 % CI: 0.27-0.76). Furthermore, creatine supplementation could significantly suppress weight loss, disease activity index, mucosal damage and the infiltration of macrophages in mice with chronic colitis. Remarkably, creatine promoted the polarization of bone marrow-derived macrophage (BMDM) towards M2 phenotype and upregulated the expression of il-10, il-12 and arg-1.
This study revealed a causal relationship between creatine and UC. Creatine supplementation ameliorated chronic colitis by inhibiting the colonic infiltration of macrophages and promoting its polarization towards M2 phenotype. These results offer new insight into the pathogenesis of UC, emphasizing a potential protective role of creatine for UC.
溃疡性结肠炎（UC）正在成为全球性负担。先前的观察性研究揭示了血清代谢物与 UC 之间的关联，但它们的因果关系尚不清楚。
使用 UC 患者和小鼠的血清样本进行非靶向代谢组学分析，以鉴定与 UC 相关的代谢物。然后，采用两样本孟德尔随机化（MR）分析来估计它们的因果关系。最后，使用葡聚糖硫酸钠（DSS）诱导的慢性结肠炎小鼠和巨噬细胞来评估肌酸的保护作用及其潜在机制。
在调整混杂因素和多重检验后，16 种血清代谢物与 UC 相关。其中，肌酸对 UC 具有显著的保护作用（OR=0.39；95%CI=0.27-0.56）。在 DSS 诱导的急性 UC 小鼠中，也观察到肌酸的显著减少。逆方差加权（IVW）MR 分析进一步证实了肌酸对 UC 风险的因果效应（OR IVW=0.45；95%CI：0.27-0.76）。此外，肌酸补充可显著抑制慢性结肠炎小鼠的体重减轻、疾病活动指数、黏膜损伤和巨噬细胞浸润。值得注意的是，肌酸促进骨髓来源的巨噬细胞（BMDM）向 M2 表型极化，并上调 il-10、il-12 和 arg-1 的表达。
本研究揭示了肌酸与 UC 之间的因果关系。肌酸补充通过抑制结肠巨噬细胞浸润并促进其向 M2 表型极化，改善了慢性结肠炎。这些结果为 UC 的发病机制提供了新的见解，强调了肌酸对 UC 的潜在保护作用。
