Alteration of Gut Microbiota and Inflammatory Cytokine/Chemokine Profiles in 5-Fluorouracil Induced Intestinal Mucositis.

Abstract

Disturbed homeostasis of gut microbiota has been suggested to be closely associated with 5-fluorouracil (5-Fu) induced mucositis. However, current knowledge of the overall profiles of 5-Fu-disturbed gut microbiota is limited, and so far there is no direct convincing evidence proving the causality between 5-Fu-disturbed microbiota and colonic mucositis. In mice, in agreement with previous reports, 5-Fu resulted in severe colonic mucositis indicated by weight loss, diarrhea, bloody stool, shortened colon, and infiltration of inflammatory cells. It significantly changed the profiles of inflammatory cytokines/chemokines in serum and colon. Adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and VE-Cadherin were increased. While tight junction protein occludin was reduced, however, zonula occludens-1 (ZO-1) and junctional adhesion molecule-A (JAM-A) were increased in colonic tissues of 5-Fu treated mice. Meanwhile, inflammation related signaling pathways including NF-κB and mitogen activated protein kinase (MAPKs) in the colon were activated. Further study disclosed that 5-Fu diminished bacterial community richness and diversity, leading to the relative lower abundance of Firmicutes and decreased Firmicutes/Bacteroidetes (F/B) ratio in feces and cecum contents. 5-Fu also reduced the proportion of Proteobacteria, Tenericutes, Cyanobacteria, and Candidate division TM7, but increased that of Verrucomicrobia and Actinobacteria in feces and/or cecum contents. The fecal transplant from healthy mice prevented body weight loss and colon shortening of 5-Fu treated mice. In addition, the fecal transplant from 5-Fu treated mice reduced body weight and colon length of vancomycin-pretreated mice. Taken together, our study demonstrated that gut microbiota was actively involved in the pathological process of 5-Fu induced intestinal mucositis, suggesting potential attenuation of 5-Fu induced intestinal mucositis by manipulating gut microbiota homeostasis.

• Authors: Hong-Li Li, Lan Lu, Xiao-Shuang Wang, Li-Yue Qin, Ping Wang, Shui-Ping Qiu, Hui Wu, Fei Huang, Bei-Bei Zhang, Hai-Lian Shi, Xiao-Jun Wu
• Journal: Frontiers in cellular and infection microbiology (Front Cell Infect Microbiol) Vol. 7 Pg. 455 ( 2017) ISSN: 2235-2988 [Electronic] Switzerland
• PMID: 29124041 (Publication Type: Journal Article)

Chemical References

• Antigens, CD
• Cadherins
• Cell Adhesion Molecules
• Chemokines
• Cytokines
• F11r protein, mouse
• NF-kappa B
• RNA, Ribosomal, 16S
• Receptors, Cell Surface
• Vascular Cell Adhesion Molecule-1
• Zonula Occludens-1 Protein
• cadherin 5
• Intercellular Adhesion Molecule-1
• Mitogen-Activated Protein Kinases
• Fluorouracil

Topics

• Animals
• Antigens, CD (metabolism)
• Bacteria (classification, drug effects, genetics, metabolism)
• Body Weight (drug effects)
• Cadherins (metabolism)
• Cell Adhesion Molecules (metabolism)
• Chemokines (metabolism)
• Colon (metabolism, pathology)
• Cytokines (metabolism)
• Fecal Microbiota Transplantation
• Feces (microbiology)
• Fluorouracil (adverse effects)
• Gastrointestinal Microbiome (drug effects)
• Immunohistochemistry
• Inflammation (complications, pathology)
• Intercellular Adhesion Molecule-1 (metabolism)
• Intestinal Mucosa (metabolism, pathology)
• Intestines (pathology)
• Male
• Mice
• Mice, Inbred BALB C
• Mitogen-Activated Protein Kinases (metabolism)
• Mucositis (chemically induced, metabolism, microbiology, pathology)
• NF-kappa B (metabolism)
• RNA, Ribosomal, 16S (genetics)
• Receptors, Cell Surface (metabolism)
• Vascular Cell Adhesion Molecule-1 (metabolism)
• Zonula Occludens-1 Protein (metabolism)