Chemotherapy-induced oral mucositis is associated with detrimental bacterial dysbiosis

Microbiome

Joseph A. Burleson¹  Pujan Joshi²  Dong-Guk Shin²  Linda D. Strausbaugh³  Amanda K. Dupuy³  Patricia I. Diaz⁴  Angela Thompson⁴  Bo-Young Hong⁴  Douglas E. Peterson⁴  Takanori Sobue⁴  Linda Choquette⁴  Evan Fox⁴  Anna Dongari-Bagtzoglou⁴  Peter K. Schauer⁵  Andrew L. Salner⁵  George M. Weinstock⁶ 

[1] Department of Community Medicine and Health Care, UConn Health;Department of Computer Science, University of Connecticut;Department of Molecular and Cell Biology, University of Connecticut;Department of Oral Health and Diagnostic Sciences, School of Dental Medicine, UConn Health;Hartford Healthcare;Jackson Laboratory for Genomic Medicine;

关键词: Microbiome;    Cancer;    Chemotherapy;    Oral mucositis;    Mucosal-microbial crosstalk;   

DOI  :  10.1186/s40168-019-0679-5

来源: DOAJ

【 摘 要 】

Abstract Background Gastrointestinal mucosal injury (mucositis), commonly affecting the oral cavity, is a clinically significant yet incompletely understood complication of cancer chemotherapy. Although antineoplastic cytotoxicity constitutes the primary injury trigger, the interaction of oral microbial commensals with mucosal tissues could modify the response. It is not clear, however, whether chemotherapy and its associated treatments affect oral microbial communities disrupting the homeostatic balance between resident microorganisms and the adjacent mucosa and if such alterations are associated with mucositis. To gain knowledge on the pathophysiology of oral mucositis, 49 subjects receiving 5-fluorouracil (5-FU) or doxorubicin-based chemotherapy were evaluated longitudinally during one cycle, assessing clinical outcomes, bacterial and fungal oral microbiome changes, and epithelial transcriptome responses. As a control for microbiome stability, 30 non-cancer subjects were longitudinally assessed. Through complementary in vitro assays, we also evaluated the antibacterial potential of 5-FU on oral microorganisms and the interaction of commensals with oral epithelial tissues. Results Oral mucositis severity was associated with 5-FU, increased salivary flow, and higher oral granulocyte counts. The oral bacteriome was disrupted during chemotherapy and while antibiotic and acid inhibitor intake contributed to these changes, bacteriome disruptions were also correlated with antineoplastics and independently and strongly associated with oral mucositis severity. Mucositis-associated bacteriome shifts included depletion of common health-associated commensals from the genera Streptococcus, Actinomyces, Gemella, Granulicatella, and Veillonella and enrichment of Gram-negative bacteria such as Fusobacterium nucleatum and Prevotella oris. Shifts could not be explained by a direct antibacterial effect of 5-FU, but rather resembled the inflammation-associated dysbiotic shifts seen in other oral conditions. Epithelial transcriptional responses during chemotherapy included upregulation of genes involved in innate immunity and apoptosis. Using a multilayer epithelial construct, we show mucositis-associated dysbiotic shifts may contribute to aggravate mucosal damage since the mucositis-depleted Streptococcus salivarius was tolerated as a commensal, while the mucositis-enriched F. nucleatum displayed pro-inflammatory and pro-apoptotic capacity. Conclusions Altogether, our work reveals that chemotherapy-induced oral mucositis is associated with bacterial dysbiosis and demonstrates the potential for dysbiotic shifts to aggravate antineoplastic-induced epithelial injury. These findings suggest that control of oral bacterial dysbiosis could represent a novel preventive approach to ameliorate oral mucositis.

【 授权许可】

Unknown