Editors' ChoiceHost-Microbe Interactions

Chemotherapy, pain, and gut microbiota

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Science Signaling  12 Sep 2017:
Vol. 10, Issue 496, eaap9098
DOI: 10.1126/scisignal.aap9098

Chemotherapy triggers gut microbiota to stimulate pain-associated peripheral inflammation.

Neuropathic pain is a major side effect of chemotherapy, which is not only damaging to quality of life but limits dosing and hence the ultimate efficacy of the treatment in patients. Shen et al. show that the gut microbiota play a role in mechanical pain sensitivity in mice after chemotherapy. Oxaliplatin, a common chemotherapeutic for breast cancer patients, induced mechanical hyperalgesia in specific pathogen–free (SPF) mice but not germ-free (GF) mice, except when the gastric compartments of the GF mice were reconstituted with gut microbiota from the SPF mice. Feeding mice a cocktail of antibiotics before chemotherapy exposure also reduced pain sensitivity. The dorsal root ganglion (peripheral sensory neurons) of antibiotic- and oxaliplatin-treated mice had fewer macrophage marker–positive cells and inflammatory cytokines than did those from control mice. Oxaliplatin stimulated cultured macrophages to secrete inflammatory cytokines only in the presence of lipopolysaccharide (LPS), a cell wall component of Gram-negative bacteria and a ligand of Toll-like receptor 4 (TLR4). Mice lacking TLR4, either in all cells or specifically in hematopoietic cells, had markedly reduced oxaliplatin-dependent mechanical hyperalgesia than did their TLR4-expressing littermates. These findings suggest that chemotherapy stimulates some gut microbiota to secrete factors that cause inflammation and macrophage activation around peripheral neurons, suggesting that sequential treatment with antibiotics and then chemotherapy might be beneficial for patients. However, some gut microbiota (Gram-positive bacteria, for example) critically induce antitumor immune responses that promote chemotherapeutic efficacy. Thus, selective antibiotics or inhibition of pain-mediating signals between the gut microbiota and the immune system, such as TLR4, may limit the effect of the microbiota on pain while enabling its effect on antitumor immunity, thereby improving outcomes and life quality in patients undergoing chemotherapy.

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