Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200001, China.
Department of General Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200001, China.
Chin Med J (Engl). 2023 Nov 20;136(22):2722-2731. doi: 10.1097/CM9.0000000000002752. Epub 2023 Aug 9.
Colorectal carcinogenesis and progression are related to the gut microbiota and the tumor immune microenvironment. Our previous clinical trial demonstrated that berberine (BBR) hydrochloride might reduce the recurrence and canceration of colorectal adenoma (CRA). The present study aimed to further explore the mechanism of BBR in preventing colorectal cancer (CRC).
We performed metagenomics sequencing on fecal specimens obtained from the BBR intervention trial, and the differential bacteria before and after medication were validated using quantitative polymerase chain reaction. We further performed ApcMin/+ animal intervention tests, RNA sequencing, flow cytometry, immunohistochemistry, and enzyme-linked immunosorbent assays.
The abundance of fecal Veillonella parvula ( V . parvula ) decreased significantly after BBR administration ( P = 0.0016) and increased through the development from CRA to CRC. Patients with CRC with a higher V. parvula abundance had worse tumor staging and a higher lymph node metastasis rate. The intestinal immune pathway of Immunoglobulin A production was activated, and the expression of TNFSF13B (Tumor necrosis factor superfamily 13b, encoding B lymphocyte stimulator [BLyS]), the representative gene of this pathway, and the genes encoding its receptors (interleukin-10 and transforming growth factor beta) were significantly upregulated. Animal experiments revealed that V. parvula promoted colorectal carcinogenesis and increased BLyS levels, while BBR reversed this effect.
BBR might inhibit V. parvula and further weaken the immunomodulatory effect of B cells induced by V. parvula , thereby blocking the development of colorectal tumors.
ClinicalTrials.gov, No. NCT02226185.
结直肠癌的发生和发展与肠道微生物群和肿瘤免疫微环境有关。我们之前的临床试验表明盐酸小檗碱（BBR）可能降低结直肠腺瘤（CRA）的复发和癌变风险。本研究旨在进一步探索 BBR 预防结直肠癌（CRC）的机制。
我们对来自 BBR 干预试验的粪便标本进行了宏基因组测序，并使用定量聚合酶链反应验证了用药前后的差异细菌。我们进一步进行了 ApcMin/+动物干预试验、RNA 测序、流式细胞术、免疫组织化学和酶联免疫吸附试验。
BBR 给药后粪便中 Veillonella parvula（V. parvula）的丰度显著降低（P=0.0016），并随着 CRA 向 CRC 的发展而增加。V. parvula 丰度较高的 CRC 患者肿瘤分期较差，淋巴结转移率较高。免疫球蛋白 A 产生的肠道免疫途径被激活，该途径的代表性基因 TNFSF13B（肿瘤坏死因子超家族 13b，编码 B 淋巴细胞刺激因子[BLyS]）及其受体（白细胞介素 10 和转化生长因子β）的基因表达显著上调。动物实验表明，V. parvula 促进结直肠致癌作用并增加 BLyS 水平，而 BBR 逆转了这种作用。
BBR 可能抑制 V. parvula，并进一步减弱 V. parvula 诱导的 B 细胞的免疫调节作用，从而阻断结直肠肿瘤的发展。
ClinicalTrials.gov，编号 NCT02226185。
