Oxaliplatin-induced changes in microbiota, TLR4+ cells and enhanced HMGB1 expression in the murine colon

• Published in: PloS one 2018-06, Vol.13 (6), p.e0198359
• Main Authors: Stojanovska, Vanesa, McQuade, Rachel M, Fraser, Sarah, Prakash, Monica, Gondalia, Shakuntla, Stavely, Rhian, Palombo, Enzo, Apostolopoulos, Vasso, Sakkal, Samy, Nurgali, Kulmira
• Format: Article
• Language: English
• Subjects: Animals; Antigens; Apoptosis; Bacteria - classification; Bacteria - drug effects; Bacteria - genetics; Biology and Life Sciences; Cancer; Cancer therapies; Cell death; Chemokines; Chemotherapy; Colon; Colon - drug effects; Colon - metabolism; Colon - microbiology; Colorectal cancer; Complications and side effects; Cytokines; Cytotoxicity; Damage patterns; Dendritic cells; DNA, Bacterial - genetics; DNA, Ribosomal - genetics; Drug dosages; Gastrointestinal Microbiome - drug effects; Gene expression; Gene Expression Regulation - drug effects; High-Throughput Nucleotide Sequencing; HMGB1 protein; HMGB1 Protein - metabolism; Immune system; Immunogenicity; Immunosuppression; Inflammation; Lamina propria; Leukocyte Common Antigens - metabolism; Ligands; Lymph nodes; Lymphocytes; Macrophages; Male; Medicine and Health Sciences; Mice; Microbiota; Microbiota (Symbiotic organisms); Mitochondrial DNA; Mobility; Molecular chains; Motility; Oxaliplatin; Oxaliplatin - adverse effects; Peyer's Patches - drug effects; Peyer's Patches - metabolism; Peyer's Patches - microbiology; Phylogeny; Platinum; Proteins; Pseudopodia; Receptors; Reduction; RNA, Ribosomal, 16S - genetics; Rodents; Sequence Analysis, DNA; T cell receptors; TLR4 protein; Toll-Like Receptor 4 - metabolism; Toll-like receptors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0198359

Oxaliplatin is a platinum-based chemotherapeutic used for cancer treatment. Its use associates with peripheral neuropathies and chronic gastrointestinal side-effects. Oxaliplatin induces immunogenic cell death by provoking the presentation of damage associated molecular patterns. The damage associated molecular patterns high-mobility group box 1 (HMGB1) protein exerts pro-inflammatory cytokine-like activity and binds to toll-like receptors (namely TLR4). Gastrointestinal microbiota may influence chemotherapeutic efficacy and contribute to local and systemic inflammation. We studied effects of oxaliplatin treatment on 1) TLR4 and high-mobility group box 1 expression within the colon; 2) gastrointestinal microbiota composition; 3) inflammation within the colon; 4) changes in Peyer's patches and mesenteric lymph nodes immune populations in mice. TLR4+ cells displayed pseudopodia-like extensions characteristic of antigen sampling co-localised with high-mobility group box 1 -overexpressing cells in the colonic lamina propria from oxaliplatin-treated animals. Oxaliplatin treatment caused significant reduction in Parabacteroides and Prevotella1, but increase in Prevotella2 and Odoribacter bacteria at the genus level. Downregulation of pro-inflammatory cytokines and chemokines in colon samples, a reduction in macrophages and dendritic cells in mesenteric lymph nodes were found after oxaliplatin treatment. In conclusion, oxaliplatin treatment caused morphological changes in TLR4+ cells, increase in gram-negative microbiota and enhanced HMGB1 expression associated with immunosuppression in the colon.