Authors: Concetta Panebianco, Federica Pisati, Annacandida Villani, Annapaola Andolfo, Marynka Ulaszewska, Edoardo Bellini, Carmelapia Ferro, Renato Lombardi, Fabrizio Orsenigo, Tiziana Pia Latiano, Beatrice Belmonte, Claudio Tripodo, Francesco Perri, Valerio Pazienza


  • 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
  • Proteomics and Metabolomics Facility (ProMeFa), IRCCS San Raffaele Scientific Institute, Via Olgettina, 60, 20132, Milan, Italy
  • Unit of Pharmacy, Department of Pharmaceuticals, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
  • Oncology Unit Fondazione IRCCS Casa Sollievo della Sofferenza, Viale dei Cappuccini, 1, 71013, San Giovanni Rotondo, FG, Italy
  • Tumor Immunology Unit, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties “G. D’Alessandro”, University of Palermo, Via del Vespro 129, 90127, Palermo, Italy

Publication: Nature

Date: April, 2023

Link: Counteracting gemcitabine+nab-paclitaxel induced dysbiosis in KRAS wild type and KRASG12D mutated pancreatic cancer in vivo model


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.