1. Candida tropicalis Infection Modulates the Gut Microbiome and Confers Enhanced Susceptibility to Colitis in Mice
- Author
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Luca Di Martino, Carlo De Salvo, Kristine-Ann Buela, Christopher Hager, Mahmoud Ghannoum, Abdullah Osme, Ludovica Buttò, Giorgos Bamias, Theresa T. Pizarro, and Fabio Cominelli
- Subjects
C tropicalis ,A muciniphila ,PBS, phosphate-buffered saline ,RC799-869 ,Th, helper T cell ,CARD9, caspase-associated recruitment domain adaptor 9 ,Mice ,RT, reverse-transcription ,Cldn, claudin ,MLN, mesenteric lymph node ,CD, Crohn’s disease ,Animals ,Humans ,IFN, interferon ,Candida tropicalis ,Lymphocytes ,DSS, dextran sodium sulfate ,RFU, relative fluorescence unit ,CWRU, Case Western Reserve University ,Original Research ,T-bet+, _ ,TNF, tumor necrosis factor ,Hepatology ,IBD, inflammatory bowel disease ,FMT, fecal microbiome transplantation ,RORγT+, __ ,Dextran Sulfate ,Gastroenterology ,ILC, innate lymphoid cell ,Diseases of the digestive system. Gastroenterology ,Colitis ,Immunity, Innate ,B6, C57BL/6 ,CFU, colony forming unit ,Gastrointestinal Microbiome ,IL, interleukin ,Mice, Inbred C57BL ,rRNA, ribosomal RNA ,GF, germ-free ,UC, ulcerative colitis ,IEBD, intestinal epithelial barrier dysfunction ,qPCR, quantitative polymerase chain reaction ,FITC, fluorescein isothiocyanate ,Mycobiome - Abstract
Background & Aims We previously showed that abundance of Candida tropicalis is significantly greater in Crohn’s disease patients compared with first-degree relatives without Crohn’s disease. The aim of this study was to determine the effects and mechanisms of action of C tropicalis infection on intestinal inflammation and injury in mice. Methods C57BL/6 mice were inoculated with C tropicalis, and colitis was induced by administration of dextran sodium sulfate in drinking water. Disease severity and intestinal permeability subsequently were evaluated by endoscopy, histology, quantitative reverse-transcription polymerase chain reaction, as well as 16S ribosomal RNA and NanoString analyses (NanoString Technologies, Seattle, WA). Results Infected mice showed more severe colitis, with alterations in gut mucosal helper T cells (Th)1 and Th17 cytokine expression, and an increased frequency of mesenteric lymph node–derived group 2 innate lymphoid cells compared with uninfected controls. Gut microbiome composition, including changes in the mucin-degrading bacteria, Akkermansia muciniphila and Ruminococcus gnavus, was altered significantly, as was expression of several genes affecting intestinal epithelial homeostasis in isolated colonoids, after C tropicalis infection compared with uninfected controls. In line with these findings, fecal microbiome transplantation of germ-free recipient mice using infected vs uninfected donors showed altered expression of several tight-junction proteins and increased susceptibility to dextran sodium sulfate–induced colitis. Conclusions C tropicalis induces dysbiosis that involves changes in the presence of mucin-degrading bacteria, leading to altered tight junction protein expression with increased intestinal permeability and followed by induction of robust Th1/Th17 responses, which ultimately lead to an accelerated proinflammatory phenotype in experimental colitic mice., Graphical abstract
- Published
- 2021