结直肠癌发生和进展与肠道微生物群和肿瘤免疫微环境相关。我们之前的临床试验表明，盐酸小檗碱（BBR）可能减少结直肠腺瘤（CRA）的复发和癌变。本研究旨在进一步探索BBR在预防结直肠癌（CRC）中的作用机制。我们对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，免疫组化以及酶联免疫吸附测定。BBR给药后，粪便中梭杆菌寡小梭杆菌（V. parvula）的丰度显著下降（P = 0.0016），且在从CRA到CRC的过程中逐渐增加。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产生的肠道免疫通路被激活，这一通路的代表性基因TNFSF13B（编码B淋巴细胞刺激素[BLyS]的肿瘤坏死因子超家族13b），以及编码其受体的基因（白细胞介素10和转化生长因子β），其表达显著上调。动物实验显示，V. parvula促进结直肠癌发生，并增加BLyS水平，而BBR则逆转了这种效应。BBR可能抑制V. parvula，进一步削弱V. parvula引起的B细胞的免疫调节效应，从而阻断结直肠肿瘤的发展。ClinicalTrials.gov编号NCT02226185。Copyright © 2023 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.

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.Copyright © 2023 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.