Abstract
Chemotherapy induced peripheral neuropathy (CIPN), a toxic side effect of some cancer treatments, negatively impacts patient outcomes and drastically reduces survivor’s quality of life (QOL). Uncovering the mechanisms driving chemotherapy-induced CIPN is urgently needed to facilitate the development of effective treatments, as currently there are none. Observing that C57BL/6 (B6) and 129SvEv (129) mice are respectively sensitive and resistant to Paclitaxel-induced pain, we investigated the involvement of the gut microbiota in this extreme phenotypic response. Reciprocal gut microbiota transfers between B6 and 129 mice as well as antibiotic depletion causally linked gut microbes to Paclitaxel-induced pain sensitivity and resistance. Microglia proliferated in the spinal cords of Paclitaxel treated mice harboring the pain-sensitive B6 microbiota but not the pain-resistant 129 microbiota, which exhibited a notable absence of infiltrating immune cells. Paclitaxel decreased the abundance of Akkermansia muciniphila, which could compromise barrier integrity resulting in systemic exposure to bacterial metabolites and products – that acting via the gut-immune-brain axis – could result in altered brain function. Other bacterial taxa that consistently associated with both bacteria and pain as well as microglia and pain were identified, lending support to our hypothesis that microglia are causally involved in CIPN, and that gut bacteria are drivers of this phenotype.
Highlights
Chemotherapy has significantly increased the survival rate for multiple cancers due to improved detection and treatment
These important results provide a framework for future mechanistic studies to determine how the gut bacteria promote Chemotherapy induced peripheral neuropathy (CIPN) and that knowledge is expected to lead to novel, prebiotic, probiotic or synbiotic therapies for CIPN
B6 mice exhibited mechanical allodynia (Fig. 1A) and heat hyperalgesia (Fig. 1C) at day 3, 10, and 15 after Paclitaxel treatment, and cold allodynia by day 10 (Fig. 1E). The development of this form of CIPN in response to Paclitaxel treatment mirrors what we have previously reported for B6 mice treated with oxaliplatin[28]
Summary
Chemotherapy has significantly increased the survival rate for multiple cancers due to improved detection and treatment. Chemotherapy-Induced Peripheral Neuropathy (CIPN) is the most severe and painful toxicity associated with the commonly used anti-cancer drugs, including taxanes, platinum compounds, and vinca alkaloids. Mounting evidence has linked the gut microbiota to chemotherapy efficacy, and to nervous system toxicities, including development of peripheral neuropathy (PN), psychological and cognitive impairments[18,19,20,21]. We found that the gut bacteria, rather than host genetics or physiology are the primary determinants of Paclitaxel induced pain These important results provide a framework for future mechanistic studies to determine how the gut bacteria promote CIPN and that knowledge is expected to lead to novel, prebiotic, probiotic or synbiotic therapies for CIPN
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