Impact of chemotherapy on the intestinal microbiome and epithelial barrier in PDX models of lung cancer

Introduction In the field of lung cancer treatments, significant progresses have been realized during last decade, such as targeted therapies and immunotherapies. Nevertheless, chemotherapy remains the gold standard for cancer. Pemetrexed is a chemotherapeutic agent commonly used in advanced lung cancer. This drug has a broad-spectrum effect that can induce significant side effects in patients. However, the impact of pemetrexed on gut microbiota and gastrointestinal inflammation in PDX mice remains unknown, although the role of the microbiota in carcinogenesis and modulation of efficacy or toxicity of chemotherapy agents has been demonstrated. The aim of this new study was to explore the impact of pemetrexed on the gut microbiota and the integrity of intestinal epithelial barrier and inflammation markers of PDX models following treatment. Methods Upon establishment of the PDX model, mice were treated with pemetrexed for 2 weeks. Stool specimens were collected at 3 time-points: before, after and one week after treatment. Gut microbiota composition was studied by 16S rRNA gene sequencing. The colon integrity of the epithelial barrier was evaluated by a histological examination, a permeability measurement and a selected cytokines expression. In parallel, body weight was recorded and tissues were sampled for assessment of toxicity and inflammation. Results Pemetrexed induced a significant body weight loss after each treatment cycle reflecting toxicity as known in clinical results. We have found that pemetrexed and tumor induced several modifications on microbiota composition, and the more important perturbation was the significant increase of the relative abundance of Enterobacteriaceae. A significant alteration of epithelial barrier integrity associated with early inflammation and infiltration of leukocytes into mucosal tissues was observed following treatment. Moreover, we have shown that pemetrexed effect on the microbiota was reproducible on several models of lung PDX models of lung carcinoma, and that dysbiosis seem proportional to the effectiveness of chemotherapy. Conclusion This work is a preliminary approach, that confirms the relationship between microbiota and chemotherapy. A better understanding of gut microbiota alterations induced by chemotherapy could help reduce side effects. It is essential to expand our knowledge about the chemotherapy impact on microbiota in order to minimize the side effects, avoid infection complications, and improve therapy efficiency. Citation Format: Cindy Pensec, Dominique Guenot, Loreley Calvet, Caroline Mignard, Olivier Duchamp, Thomas Carton, Sebastien Leuillet, Herve M. Blottiere, Francoise Le Vacon. Impact of chemotherapy on the intestinal microbiome and epithelial barrier in PDX models of lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 662.