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.
Download full-text PDF |
Source |
---|---|
http://dx.doi.org/10.1111/bcpt.12793 | DOI Listing |
Gut Microbes
December 2025
Department of Biomolecular Health Sciences, Division of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
The intestinal mucosal barrier is a dynamic system that allows nutrient uptake, stimulates healthy microbe-host interactions, and prevents invasion by pathogens. The mucosa consists of epithelial cells connected by cellular junctions that regulate the passage of nutrients covered by a mucus layer that plays an important role in host-microbiome interactions. Mimicking the intestinal mucosa for assays, particularly the generation of a mucus layer, has proven to be challenging.
View Article and Find Full Text PDFTher Adv Drug Saf
December 2024
Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China.
Background: Capecitabine, a prodrug of 5-fluorouracil, is extensively utilized for the treatment of metastatic breast cancer, colorectal cancer, and gastric cancer. Nevertheless, there exist limitations in comprehending adverse reactions (AEs) in clinical practice. In this study, we investigated the distribution of AEs associated with capecitabine and explored potential rare adverse reactions by mining the Food and Drug Administration Adverse Event Reporting System (FAERS).
View Article and Find Full Text PDFCrohn's disease (CD) is a complex inflammatory bowel disease resulting from an interplay of genetic, microbial, and environmental factors. Cell-type-specific contributions to CD etiology and genetic risk are incompletely understood. Here we built a comprehensive atlas of cell-type- resolved chromatin accessibility comprising 557,310 candidate cis-regulatory elements (cCREs) in terminal ileum and ascending colon from patients with active and inactive CD and healthy controls.
View Article and Find Full Text PDFJ Dev Orig Health Dis
December 2024
Department of Physiology, Institute of Biomedical Sciences, Federal University of Uberlândia, Uberlândia, Brazil.
It is known that adverse stimuli, such as altered diets during pregnancy and lactation can result in deleterious effects on the progeny. The aim of this study was to evaluate the possible gastrointestinal repercussions in the offspring of Wistar rats exposed to high-fat diets. Pregnant rats were divided into three groups: normolipidic diet (3.
View Article and Find Full Text PDFEcotoxicol Environ Saf
December 2024
Department of Veterinary Surgery, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China. Electronic address:
Cadmium and microplastics, common pollutants, can accumulate in the body, impacting the intestinal barrier and harming livestock breeding. In order to explore the damage mechanism of cadmium and cadmium combined microplastic on the colon of mice, 60 mice were divided into three groups: The control group (0.2 mL of saline), cadmium group (Cd group, 0.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!