Panebianco Concetta, Pisati Federica, Villani Annacandida, Andolfo Annapaola, Ulaszewska Marynka, Bellini Edoardo, Ferro Carmelapia, Lombardi Renato, Orsenigo Fabrizio, Latiano Tiziana Pia, Belmonte Beatrice, Tripodo Claudio, Perri Francesco, Pazienza Valerio
Division of Gastroenterology, Fondazione IRCCS Casa Sollievo della Sofferenza, Viale dei Cappuccini, 1, 71013, San Giovanni Rotondo, FG, Italy.
Histopathology Unit, Cogentech S.C.a.R.L, FIRC Institute of Molecular Oncology (IFOM), Via Adamello, 16, 20139, Milan, MI, Italy.
Cell Death Discov. 2023 Apr 5;9(1):116. doi: 10.1038/s41420-023-01397-y.
Pancreatic cancer (PC) has a very low survival rate mainly due to late diagnosis and refractoriness to therapies. The latter also cause adverse effects negatively affecting the patients' quality of life, often requiring dose reduction or discontinuation of scheduled treatments, compromising the chances of cure. We explored the effects of a specific probiotic blend on PC mice xenografted with KRAS wild-type or KRASG12D mutated cell lines alone or together with gemcitabine+nab-paclitaxel treatment to then assess tumor volume and clinical pathological variables. Beside a semi-quantitative histopathological evaluation of murine tumor and large intestine samples, histochemical and immunohistochemical analyses were carried out to evaluate collagen deposition, proliferation index Ki67, immunological microenvironment tumor-associated, DNA damage markers and also mucin production. Blood cellular and biochemical parameters and serum metabolomics were further analyzed. 16S sequencing was performed to analyze the composition of fecal microbiota. Gemcitabine+nab-paclitaxel treatment impaired gut microbial profile in KRAS wild-type and KRASG12D mice. Counteracting gemcitabine+nab-paclitaxel- induced dysbiosis through the administration of probiotics ameliorated chemotherapy side effects and decreased cancer-associated stromatogenesis. Milder intestinal damage and improved blood count were also observed upon probiotics treatment as well as a positive effect on fecal microbiota, yielding an increase in species richness and in short chain fatty acids producing- bacteria. Mice' serum metabolomic profiles revealed significant drops in many amino acids upon probiotics administration in KRAS wild-type mice while in animals transplanted with PANC-1 KRASG12D mutated all treated groups showed a sharp decline in serum levels of bile acids with respect to control mice. These results suggest that counteracting gemcitabine+nab-paclitaxel-induced dysbiosis ameliorates chemotherapy side effects by restoring a favorable microbiota composition. Relieving adverse effects of the chemotherapy through microbiota manipulation could be a desirable strategy in order to improve pancreatic cancer patients' quality of life and to increase the chance of cure.
胰腺癌（PC）的生存率极低，主要原因是诊断较晚且对治疗具有难治性。后者还会产生负面影响患者生活质量的不良反应，常常需要减少剂量或中断既定治疗，从而影响治愈的机会。我们探究了一种特定益生菌混合物对单独移植KRAS野生型或KRASG12D突变细胞系的PC小鼠异种移植瘤的影响，以及与吉西他滨+纳米白蛋白结合型紫杉醇联合治疗后的效果，进而评估肿瘤体积和临床病理变量。除了对小鼠肿瘤和大肠样本进行半定量组织病理学评估外，还进行了组织化学和免疫组织化学分析，以评估胶原蛋白沉积、增殖指数Ki67、肿瘤相关免疫微环境、DNA损伤标志物以及黏液分泌。进一步分析了血细胞和生化参数以及血清代谢组学。进行16S测序以分析粪便微生物群的组成。吉西他滨+纳米白蛋白结合型紫杉醇治疗破坏了KRAS野生型和KRASG12D小鼠的肠道微生物谱。通过施用益生菌抵消吉西他滨+纳米白蛋白结合型紫杉醇诱导的生态失调，可改善化疗副作用并减少癌症相关的基质形成。益生菌治疗还观察到肠道损伤减轻、血细胞计数改善以及对粪便微生物群的积极影响，使物种丰富度和产生短链脂肪酸的细菌增加。KRAS野生型小鼠施用益生菌后，其血清代谢组学谱显示许多氨基酸显著下降，而在移植了PANC-1 KRASG12D突变体的动物中，所有治疗组的血清胆汁酸水平相对于对照小鼠均急剧下降。这些结果表明，抵消吉西他滨+纳米白蛋白结合型紫杉醇诱导的生态失调可通过恢复有利的微生物群组成来改善化疗副作用。通过微生物群调控缓解化疗的不良反应可能是一种理想的策略，以提高胰腺癌患者的生活质量并增加治愈机会。
