Wnt/β-连环蛋白信号传导损伤占结直肠癌 (CRC) 的 85%，包括散发性和家族性腺瘤性息肉病 (FAP)。 PI3K/mTOR 通路和肠道微生物群的改变也会导致结直肠癌的发生。我们研究了这两条途径之间的相互作用以及CRC癌变每个步骤中的微生物群组成。通过RT-qPCR和IHC在健康粪便免疫化学测试阳性的组织中分析了这两条途径的蛋白质和靶基因（FIT，n = 17）， FAP (n = 17) 和 CRC (n = 15) 受试者。通过 NGS 和 Sanger 分析 CRC 相关突变。通过 16 S rRNA 测序分析口腔、粪便和粘膜微生物群。我们发现与 CRC 相比，FAP 病变中 Wnt/β-catenin 和 PI3K/mTOR 通路同时过度激活。 Wnt/β-catenin 分子标记与 FAP 粪便微生物群中的 Clostridium_sensu_stricto_1 呈正相关，与拟杆菌呈负相关。 Alistipes、Lachnospiraceae 和 Ruminococcaceae 在 FAP 粪便和腺瘤中富集，后者还显示出过多的 Lachnoclostridium，其与 cMYC 呈正相关。在 mTOR 突变的 CRC 组织中，p-S6R 与梭杆菌和 Dialister 相关，后者也在粪便生态系统中得到证实。我们的研究揭示了 Wnt/β-catenin 和 PI3K/mTOR 之间的相互作用，其紊乱与特定微生物群相关FAP 和 CRC 患者的特征，并确定新的潜在生物标志物和目标，以改善 CRC 预防、早期腺瘤检测和治疗。© 2024。作者。

Wnt/β-catenin signalling impairment accounts for 85% of colorectal cancers (CRCs), including sporadic and familial adenomatous polyposis (FAP) settings. An altered PI3K/mTOR pathway and gut microbiota also contribute to CRC carcinogenesis. We studied the interplay between the two pathways and the microbiota composition within each step of CRC carcinogenesis.Proteins and target genes of both pathways were analysed by RT-qPCR and IHC in tissues from healthy faecal immunochemical test positive (FIT+, n = 17), FAP (n = 17) and CRC (n = 15) subjects. CRC-related mutations were analysed through NGS and Sanger. Oral, faecal and mucosal microbiota was profiled by 16 S rRNA-sequencing.We found simultaneous hyperactivation of Wnt/β-catenin and PI3K/mTOR pathways in FAP-lesions compared to CRCs. Wnt/β-catenin molecular markers positively correlated with Clostridium_sensu_stricto_1 and negatively with Bacteroides in FAP faecal microbiota. Alistipes, Lachnospiraceae, and Ruminococcaceae were enriched in FAP stools and adenomas, the latter also showing an overabundance of Lachnoclostridium, which positively correlated with cMYC. In impaired-mTOR-mutated CRC tissues, p-S6R correlated with Fusobacterium and Dialister, the latter also confirmed in the faecal-ecosystem.Our study reveals an interplay between Wnt/β-catenin and PI3K/mTOR, whose derangement correlates with specific microbiota signatures in FAP and CRC patients, and identifies new potential biomarkers and targets to improve CRC prevention, early adenoma detection and treatment.© 2024. The Author(s).