Toll-like receptors in the pathogenesis of chemotherapy-induced gastrointestinal toxicity

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Abstract

Purpose of review

Intestinal mucositis represents a common complication and dose-limiting toxicity of cancer chemotherapy. So far chemotherapy-induced intestinal mucositis remains poorly treatable resulting in significant morbidity and reduced quality of life in cancer patients. This review discusses recent insights into the pathophysiology of chemotherapy-induced intestinal mucositis. Novel mechanisms linking gut microbiota, host innate immunity and anticancer drug metabolism are highlighted.

Recent findings

Gut microbiota may affect xenobiotic metabolism by direct and indirect mechanisms, critically modulating gut toxicity of chemotherapy drugs. Composition and metabolic function of the gut microbiome as well as innate immune responses of the intestinal mucosa are severely altered during chemotherapy. Commensal-mediated innate immune signaling via Toll-like receptors (TLRs) ambiguously shapes chemotherapy-induced genotoxic damage in the gastrointestinal tract. TLR2 may accelerate host detoxification by activating the multidrug transporter ATP-binding cassette 1 (ABCB1)/MDR1 P-glycoprotein to efflux harmful drugs, thus controlling the severity of cancer therapy-induced mucosal damage in the gastrointestinal tract. In contrast, selective chemotherapy drugs may drive LPS hyperresponsiveness via TLR4, which exacerbates mucosal injury through aberrant cytokine storms. Broad-spectrum antibiotic treatment does not seem to represent a valid therapeutic option, as drastic reduction in global gut microbiota may enhance risk of gastrointestinal toxicity and reduce efficacy of some chemotherapy drugs, at least in murine models.

Summary

Several variables (environment, metabolism, dysbiosis, infections and/or genetics) influence the outcome of mucosal TLR signaling during cancer treatment. Differences in innate immune responses also reflect chemotherapy drug-specific effects. Future studies must investigate in more detail whether manipulating the delicate balance between gut microbiota and host immune responses by either monotherapy or combinations of different TLR agonists and antagonists may be indeed useful to limit the toxic side-effects of complex chemotherapy regimens, accelerate mucosal tissue regeneration and improve the anticancer treatment response.

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