TLR4 deficiency upregulates TLR9 expression and enhances irinotecan‐related intestinal mucositis and late‐onset diarrhoea

Made available in DSpace on 2022-05-01T07:58:47Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-10-01 Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Fundação Cearense de Apoio ao Desenvolvimento Científico e Tecnológico Background and purpose: Severe diarrhoea, a common gastrointestinal manifestation of anticancer treatment with irinotecan, might involve single nucleotide polymorphisms (SNPs) of toll-like receptors (TLRs), described as critical bacterial sensors in the gut. Here, colorectal cancer patients carrying missense TLR4 A896G (rs4986790) or C1,196T (rs4986791) SNPs and Tlr4 knockout (Tlr4−/−) mice were given irinotecan to investigate the severity of the induced diarrhoea. Experimental approach: Forty-six patients treated with irinotecan-based regimens had diarrhoea severity analysed according to TLR4 genotypes. In the experimental setting, wild-type (WT) or Tlr4−/− mice were given irinotecan (45 or 75 mg·kg−1, i.p.) or saline (3 ml·kg−1). Diarrhoea severity was evaluated by measuring intestinal injury and inflammatory markers expression after animals were killed. Key results: All patients with TLR4 SNPs chemotherapy-treated presented diarrhoea, whereas gastrointestinal toxicity was observed in 50% of the wild homozygous individuals. Mice injected with irinotecan presented systemic bacterial translocation and increased TLR4 immunostaining in the intestine. In line with the clinical findings, Tlr4 gene deficiency enhanced irinotecan-related diarrhoea and TLR9 expression in mice. An increased myeloperoxidase activity and Il-18 expression along with IL-10 decreased production in Tlr4−/− mice also indicated an intensified intestinal damage and inflammatory response. Conclusion and implications: TLR4 deficiency upregulates TLR9 expression and enhances intestinal damage and the severity of late-onset diarrhoea during irinotecan-based treatment. Identifying patients genetically predisposed to chemotherapy-associated diarrhoea is a strategy toward precision medicine. Graduate Program in Pathology Department of Pathology and Forensic Medicine Faculty of Medicine Federal University of Ceará Laboratory of Molecular Biology and Genetics Haroldo Juaçaba Hospital Cancer Institute of Ceará (ICC) Graduate Program in Pharmaceutical Sciences Department of Pharmacy Faculty of Pharmacy Nursing and Dentistry Federal University of Ceará Laboratory of Inflammation and Cancer Pharmacology Drug Research and Development Center (NPDM) Department of Physiology and Pharmacology Federal University of Ceará Cancer Cytogenomic Laboratory Drug Research and Development Center (NPDM) Federal University of Ceará Clinical Oncology Service Haroldo Juaçaba Hospital Cancer Institute of Ceará (ICC) Department of Structural and Functional Biology Institute of Biosciences São Paulo State University (UNESP) Clinical Oncology Service Walter Cantídio University Hospital Federal University of Ceará Department of Pharmacology School of Medicine of Ribeirão Preto University of São Paulo Department of Structural and Functional Biology Institute of Biosciences São Paulo State University (UNESP) CNPq: 310568/2017-0 CNPq: 421202/2018-1 CAPES: CAPES-PROEX 0756/2020 Fundação Cearense de Apoio ao Desenvolvimento Científico e Tecnológico: PR2-0101-00054.01.00/15