title: Apoptosis, Dysbiosis and Expression of Inflammatory Cytokines are Sequential Events in the Development of 5-Fluorouracil-Induced Intestinal Mucositis in Mice.
abstract: The chemotherapeutic agent 5-fluorouracil (5-FU) causes intestinal mucositis with severe diarrhoea, but the pathogenesis is not fully understood. In this study, we investigated the pathogenic effects of 5-FU in mice, focusing on apoptosis, enterobacteria and inflammatory cytokines. Repeated administration of 5-FU caused severe intestinal mucositis on day 6, accompanied by diarrhoea and body-weight loss. TNF-α expression increased 1 day after exposure to the drug, and spiked a second time on day 4, at which point myeloperoxidase activity and IL-1β expression also increased. Apoptotic cells were observed in intestinal crypts only on day 1. 5-FU also induced dysbiosis, notably decreasing the abundance of intestinal Firmicutes while increasing the abundance of Bacteroidetes and Verrucomicrobia. Twice-daily co-administration of oral antibiotics significantly reduced the severity of intestinal mucositis and dysbiosis, and blocked the increase in myeloperoxidase activity and cytokine expression on day 6, without affecting apoptosis and TNF-α up-regulation on day 1. In cultured colonic epithelial cells, exposure to 5-FU also up-regulated TNF-α expression. Collectively, the data suggest that crypt apoptosis, dysbiosis and expression of inflammatory cytokines are sequential events in the development of intestinal mucositis after exposure to 5-FU. In particular, 5-FU appears to directly induce apoptosis via TNF-α and to suppress intestinal cell proliferation, thereby resulting in degradation of the epithelial barrier, as well as in secondary inflammation mediated by inflammatory cytokines.
authors.affiliation: Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan.
authors.forename: Nahla
authors.initials: N
authors.lastname: Hamouda
authors.affiliation: Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan.|Second Department of Internal Medicine, Osaka Medical College, Takatsuki, Osaka, Japan.
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Sano
authors.affiliation: R&D Center, Biofermin Pharmaceutical Co., Ltd., Kobe, Hyogo, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Oikawa
authors.affiliation: R&D Center, Biofermin Pharmaceutical Co., Ltd., Kobe, Hyogo, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Ozaki
authors.affiliation: R&D Center, Biofermin Pharmaceutical Co., Ltd., Kobe, Hyogo, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Shimakawa
authors.affiliation: Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan.
authors.forename: Kikuko
authors.initials: K
authors.lastname: Amagase
authors.affiliation: Second Department of Internal Medicine, Osaka Medical College, Takatsuki, Osaka, Japan.
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Higuchi
authors.affiliation: Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kato
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D003967:Diarrhea / Q000209:etiology / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control; D004359:Drug Therapy, Combination; D064806:Dysbiosis / Q000209:etiology* / Q000276:immunology / Q000382:microbiology; D005472:Fluorouracil / Q000009:adverse effects*; D000069196:Gastrointestinal Microbiome / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000254:growth & development / Q000276:immunology; D007410:Intestinal Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007700:Kinetics; D008297:Male; D008810:Mice, Inbred C57BL; D052016:Mucositis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D015431:Weight Loss
chemical_list: D000900:Anti-Bacterial Agents; D000964:Antimetabolites, Antineoplastic; D016207:Cytokines; D005472:Fluorouracil