Several lines of evidence suggest that inflammation plays a pivotal role in the development and progression of colorectal cancer (CRC) and can be unleashed by the loss of innate immunosurveillance. The complement system is a well characterized first line of defense against pathogens and a central component of the immune response. Emerging evidence suggests that complement anaphylatoxin C3a produced upon complement activation and acting via its receptor (C3aR) may play a role in intestinal homeostasis. However, to date, it is unknown whether and how the C3a/C3aR axis can affect CRC. By mining publicly available datasets, we found that CpG island methylation of c3ar1 occurs in CRC patients and is associated with significant downregulation of C3aR. By reverse-translating this finding we were able to shift in APC^Min/+ mice the tumorigenesis from the small intestine to the colon therefore generating a novel mouse model, which more closely mirrors the CRC in humans. Transcriptomic analysis on colorectal polyps from our newly developed genetic mouse model revealed a significant increase in innate and adaptive immune signatures in absence of C3aR. Furthermore, loss of C3aR significantly impacted the fecal and tumor-associated microbiota and supported the blooming of pro-inflammatory bacterial species as confirmed by experiments of fecal microbiota transplantation.

中文翻译：

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C3aR 的缺失在新的自发性结肠癌模型中诱导免疫浸润和炎症微生物群

多项证据表明炎症在结直肠癌 (CRC) 的发展和进展中起着关键作用，并且可以通过先天免疫监视的丧失来释放。补体系统是一种充分表征的针对病原体的第一道防线，也是免疫反应的核心组成部分。新出现的证据表明，补体激活后产生的补体过敏毒素 C3a 并通过其受体 (C3aR) 起作用，可能在肠道稳态中发挥作用。然而，迄今为止，尚不清楚 C3a/C3aR 轴是否以及如何影响 CRC。通过挖掘公开可用的数据集，我们发现c3ar1 的CpG 岛甲基化发生在 CRC 患者中，并且与 C3aR 的显着下调有关。通过反向翻译这一发现，我们能够在 APC 中发生变化^Min/+小鼠的肿瘤发生从小肠到结肠，因此产生了一种新的小鼠模型，它更接近于人类的 CRC。对来自我们新开发的遗传小鼠模型的结直肠息肉的转录组学分析显示，在没有 C3aR 的情况下，先天性和适应性免疫特征显着增加。此外，正如粪便微生物群移植实验所证实的那样，C3aR 的缺失显着影响了粪便和肿瘤相关的微生物群，并支持了促炎细菌物种的大量繁殖。