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. 2021 Oct;178(20):4193-4209.
doi: 10.1111/bph.15609. Epub 2021 Aug 1.

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

Deysi Viviana Tenazoa Wong  1   2 , Renata Brito Falcão Holanda  3 , Aurilene Gomes Cajado  4 , Alessandro Maia Bandeira  4 , Jorge Fernando Bessa Pereira  4 , Joice Oliveira Amorim  2 , Clarice Sampaio Torres  4 , Luana Maria Moura Ferreira  4 , Marina Helena Silva Lopes  1 , Roberta Taiane Germano Oliveira  5 , Anamaria Falcão Pereira  4 , Rosane Oliveira Sant'Ana  2   6 , Larissa Mont'alverne Arruda  6 , Howard Lopes Ribeiro-Júnior  5 , Ronald Feitosa Pinheiro  5 , Paulo Roberto Carvalho Almeida  1 , Robson Francisco Carvalho  7 , Fábio Figueiredo Chaves  6 , Duílio Reis Rocha-Filho  8 , Fernando Queiroz Cunha  9 , Roberto César Pereira Lima-Júnior  4
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Free article

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

Deysi Viviana Tenazoa Wong et al. Br J Pharmacol. 2021 Oct.
Free article

Abstract

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.

Keywords: colorectal cancer; diarrhoea; intestinal mucosa; irinotecan; mucositis; single nucleotide polymorphism; toll-like receptor 4.

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