Frontline Science: Microbiota reconstitution restores intestinal integrity after cisplatin therapy

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

article

Alfredo Perales-Puchalt¹  Jairo Perez-Sanz²  Kyle K Payne¹  Nikolaos Svoronos³  Michael J. Allegrezza³  Ricardo A. Chaurio²  Carmen Anadon²  Joseph Calmette²  Subir Biswas²  Jessica A. Mine²  Tara Lee Costich²  Logan Nickels⁴  Jayamanna Wickramasinghe⁵  Melanie R. Rutkowski⁶  Jose R. Conejo-Garcia² 

[1] Translational Tumor Immunology Program, The Wistar Institute;Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute;Tumor Microenvironment and Metastasis Program, The Wistar Institute;Department of Microbiology, University of Pennsylvania;Center for Systems and Computational Biology, The Wistar Institute;Department of Microbiology, University of Virginia

关键词: immunotherapy;    ovarian cancer;    cisplatin;    microbiome;   

DOI  :  10.1002/JLB.5HI1117-446RR

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Due to their cytotoxic activities, many anticancer drugs cause extensive damage to the intestinal mucosa and have antibiotic activities. Here, we show that cisplatin induces significant changes in the repertoire of intestinal commensal bacteria that exacerbate mucosal damage. Restoration of the microbiota through fecal-pellet gavage drives healing of cisplatin-induced intestinal damage. Bacterial translocation to the blood stream is correspondingly abrogated, resulting in a significant reduction in systemic inflammation, as evidenced by decreased serum IL-6 and reduced mobilization of granulocytes. Mechanistically, reversal of dysbiosis in response to fecal gavage results in the production of protective mucins and mobilization of CD11b+ myeloid cells to the intestinal mucosa, which promotes angiogenesis. Administration of Ruminococcus gnavus, a bacterial strain selectively depleted by cisplatin treatment, could only partially restore the integrity of the intestinal mucosa and reduce systemic inflammation, without measurable increases in the accumulation of mucin proteins. Together, our results indicate that reconstitution of the full repertoire of intestinal bacteria altered by cisplatin treatment accelerates healing of the intestinal epithelium and ameliorates systemic inflammation. Therefore, fecal microbiota transplant could paradoxically prevent life-threatening bacteremia in cancer patients treated with chemotherapy.

【 授权许可】

CC BY