Objective Probiotic Lactococcus lactis is known to confer health benefits to humans. Here, we aimed to investigate the role of L. lactis in colorectal cancer (CRC). Design L. lactis abundance was evaluated in patients with CRC (n=489) and healthy individuals (n=536). L. lactis was isolated from healthy human stools with verification by whole genome sequencing. The effect of L. lactis on CRC tumourigenesis was assessed in transgenic Apc Min/+ mice and carcinogen-induced CRC mice. Faecal microbiota was profiled by metagenomic sequencing. Candidate proteins were characterised by nano liquid chromatography-mass spectrometry. Biological function of L. lactis conditioned medium ( HkyuLL 10 -CM) and functional protein was studied in human CRC cells, patient-derived organoids and xenograft mice. Results Faecal L. lactis was depleted in patients with CRC. A new L. lactis strain was isolated from human stools and nomenclated as HkyuLL 10. HkyuLL 10 supplementation suppressed CRC tumourigenesis in Apc Min/+ mice, and this tumour-suppressing effect was confirmed in mice with carcinogen-induced CRC. Microbiota profiling revealed probiotic enrichment including Lactobacillus johnsonii in HkyuLL 10 -treated mice. HkyuLL 10 -CM significantly abrogated the growth of human CRC cells and patient-derived organoids. Such protective effect was attributed to HkyuLL 10 -secreted proteins, and we identified that α-mannosidase was the functional protein. The antitumourigenic effect of α-mannosidase was demonstrated in human CRC cells and organoids, and its supplementation significantly reduced tumour growth in xenograft mice. Conclusion HkyuLL 10 suppresses CRC tumourigenesis in mice through restoring gut microbiota and secreting functional protein α-mannosidase. HkyuLL 10 administration may serve as a prophylactic measure against CRC. All data relevant to the study are included in the article or uploaded as supplementary information.

中文翻译：

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乳酸乳球菌 HkyuLL 10 通过其产生的 α-甘露糖苷酶抑制结直肠肿瘤发生并恢复肠道微生物群

目的 已知益生菌乳酸球菌可为人类带来健康益处。在这里，我们的目的是研究乳酸乳球菌在结直肠癌（CRC）中的作用。设计 在 CRC 患者 (n=489) 和健康个体 (n=536) 中评估乳酸乳球菌丰度。乳酸乳球菌是从健康人粪便中分离出来的，并通过全基因组测序进行验证。在转基因 Apc Min/+ 小鼠和致癌物诱导的 CRC 小鼠中评估了乳酸乳球菌对 CRC 肿瘤发生的影响。通过宏基因组测序对粪便微生物群进行了分析。通过纳米液相色谱-质谱法对候选蛋白质进​​行了表征。在人 CRC 细胞、患者来源的类器官和异种移植小鼠中研究了乳酸乳球菌条件培养基 (HkyuLL 10 -CM) 和功能蛋白的生物学功能。结果 CRC 患者粪便中的乳酸乳球菌已被耗尽。从人类粪便中分离出一种新的乳酸乳球菌菌株，并将其命名为 HkyuLL 10。补充 HKyuLL 10 可以抑制 Apc Min/+ 小鼠中的 CRC 肿瘤发生，并且这种肿瘤抑制作用在患有致癌物诱导的 CRC 的小鼠中得到证实。微生物群分析显示，HkyuLL 10 处理的小鼠体内益生菌富集，包括约氏乳杆菌。 HkyuLL 10 -CM 显着抑制人类 CRC 细胞和患者来源的类器官的生长。这种保护作用归因于 HkyuLL 10 分泌蛋白，我们确定 α-甘露糖苷酶是该功能蛋白。 α-甘露糖苷酶的抗肿瘤作用在人类结直肠癌细胞和类器官中得到证实，其补充可显着减少异种移植小鼠的肿瘤生长。结论 HkyuLL 10 通过恢复肠道菌群和分泌功能蛋白 α-甘露糖苷酶来抑制小鼠 CRC 肿瘤的发生。 HKyuLL 10 给药可作为 CRC 的预防措施。与研究相关的所有数据都包含在文章中或作为补充信息上传。