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Abstract：
BACKGROUND: Bladder cancer is a common malignancy with high recurrence rate. Early diagnosis and recurrence surveillance are pivotal to patients\' outcomes, which require novel minimal-invasive diagnostic tools. The urinary microbiome is associated with bladder cancer and can be used as biomarkers, but the underlying mechanism is to be fully illustrated and diagnostic performance to be improved.
METHODS: A total of 23 treatment-naïve bladder cancer patients and 9 non-cancerous subjects were enrolled into the Before group and Control group. After surgery, 10 patients from the Before group were further assigned into After group. Void mid-stream urine samples were collected and sent for 16S rDNA sequencing, targeted metabolomic profiling, and flow cytometry. Next, correlations were analyzed between microbiota, metabolites, and cytokines. Finally, receiver operating characteristic (ROC) curves of the urinary biomarkers were plotted and compared.
RESULTS: Comparing to the Control group, levels of IL-6 (p < 0.01), IL-8 (p < 0.05), and IL-10 (p < 0.05) were remarkably elevated in the Before group. The α diversity of urine microbiome was also significantly higher, with the feature microbiota positively correlated to the level of IL-6 (r = 0.58, p < 0.01). Significant differences in metabolic composition were also observed between the Before and Control groups, with fatty acids and fatty acylcarnitines enriched in the Before group. After tumor resection, cytokine levels and the overall microbiome structure in the After group remained similar to that of the Before group, but fatty acylcarnitines were significantly reduced (p < 0.05). Pathway enrichment analysis revealed beta-oxidation of fatty acids was significantly involved (p < 0.001). ROC curves showed that the biomarker panel of Actinomycetaceae + arachidonic acid + IL-6 had superior diagnostic performance, with sensitivity of 0.94 and specificity of 1.00.
CONCLUSIONS: Microbiome dysbiosis, proinflammatory environment and altered fatty acids metabolism are involved in the pathogenesis of bladder cancer, which may throw light on novel noninvasive diagnostic tool development.
METHODS: A total of 23 treatment-naïve bladder cancer patients and 9 non-cancerous subjects were enrolled into the Before group and Control group. After surgery, 10 patients from the Before group were further assigned into After group. Void mid-stream urine samples were collected and sent for 16S rDNA sequencing, targeted metabolomic profiling, and flow cytometry. Next, correlations were analyzed between microbiota, metabolites, and cytokines. Finally, receiver operating characteristic (ROC) curves of the urinary biomarkers were plotted and compared.
RESULTS: Comparing to the Control group, levels of IL-6 (p < 0.01), IL-8 (p < 0.05), and IL-10 (p < 0.05) were remarkably elevated in the Before group. The α diversity of urine microbiome was also significantly higher, with the feature microbiota positively correlated to the level of IL-6 (r = 0.58, p < 0.01). Significant differences in metabolic composition were also observed between the Before and Control groups, with fatty acids and fatty acylcarnitines enriched in the Before group. After tumor resection, cytokine levels and the overall microbiome structure in the After group remained similar to that of the Before group, but fatty acylcarnitines were significantly reduced (p < 0.05). Pathway enrichment analysis revealed beta-oxidation of fatty acids was significantly involved (p < 0.001). ROC curves showed that the biomarker panel of Actinomycetaceae + arachidonic acid + IL-6 had superior diagnostic performance, with sensitivity of 0.94 and specificity of 1.00.
CONCLUSIONS: Microbiome dysbiosis, proinflammatory environment and altered fatty acids metabolism are involved in the pathogenesis of bladder cancer, which may throw light on novel noninvasive diagnostic tool development.
摘要：
背景：膀胱癌是一种常见的恶性肿瘤，复发率高。早期诊断和复发监测对患者预后至关重要，这需要新颖的微创诊断工具。尿微生物组与膀胱癌相关，可用作生物标志物，但潜在的机制是充分说明和诊断性能有待提高。
方法：共有23名未经治疗的膀胱癌患者和9名非癌性受试者被纳入前治疗组和对照组。手术后,将来自Before组的10名患者进一步分配到After组。收集空的中流尿液样本并送去进行16SrDNA测序，靶向代谢组学分析，和流式细胞术。接下来,分析了微生物群之间的相关性，代谢物，和细胞因子。最后,绘制并比较了尿液生物标志物的受试者工作特征（ROC）曲线。
结果：与对照组相比，IL-6水平（p<0.01），IL-8（p<0.05），IL-10在治疗前显著升高(p<0.05)。尿微生物组的α多样性也显著增高,该特征菌群与IL-6水平呈正相关(r=0.58,p<0.01)。在之前和对照组之间也观察到代谢组成的显着差异。前一组富含脂肪酸和脂肪酰基肉碱。肿瘤切除后，后组的细胞因子水平和整体微生物组结构与前组相似，但脂肪酰肉碱显著减少(p<0.05)。通路富集分析显示显著涉及脂肪酸的β-氧化(p<0.001)。ROC曲线显示放线菌科+花生四烯酸+IL-6的生物标志物组具有优越的诊断效能,敏感性为0.94，特异性为1.00。
结论：微生物菌群失调，促炎环境和脂肪酸代谢改变与膀胱癌的发病机制有关,这可能会给新型无创诊断工具的开发带来启示。
方法：共有23名未经治疗的膀胱癌患者和9名非癌性受试者被纳入前治疗组和对照组。手术后,将来自Before组的10名患者进一步分配到After组。收集空的中流尿液样本并送去进行16SrDNA测序，靶向代谢组学分析，和流式细胞术。接下来,分析了微生物群之间的相关性，代谢物，和细胞因子。最后,绘制并比较了尿液生物标志物的受试者工作特征（ROC）曲线。
结果：与对照组相比，IL-6水平（p<0.01），IL-8（p<0.05），IL-10在治疗前显著升高(p<0.05)。尿微生物组的α多样性也显著增高,该特征菌群与IL-6水平呈正相关(r=0.58,p<0.01)。在之前和对照组之间也观察到代谢组成的显着差异。前一组富含脂肪酸和脂肪酰基肉碱。肿瘤切除后，后组的细胞因子水平和整体微生物组结构与前组相似，但脂肪酰肉碱显著减少(p<0.05)。通路富集分析显示显著涉及脂肪酸的β-氧化(p<0.001)。ROC曲线显示放线菌科+花生四烯酸+IL-6的生物标志物组具有优越的诊断效能,敏感性为0.94，特异性为1.00。
结论：微生物菌群失调，促炎环境和脂肪酸代谢改变与膀胱癌的发病机制有关,这可能会给新型无创诊断工具的开发带来启示。
