Abstract
Hyperthermia induced by 3,4-methylenedioxymethamphetamine (MDMA) can be life-threatening. Here, we investigate the role of the gut microbiome and TGR5 bile acid receptors in MDMA-mediated hyperthermia. Fourteen days prior to treatment with MDMA, male Sprague-Dawley rats were provided water or water treated with antibiotics. Animals that had received antibiotics displayed a reduction in gut bacteria and an attenuated hyperthermic response to MDMA. MDMA treated animals showed increased uncoupling protein 1 (UCP1) and TGR5 expression levels in brown adipose tissue and skeletal muscle while increased expression of UCP3 was observed only in skeletal muscle. Antibiotics prior to MDMA administration significantly blunted these increases in gene expression. Furthermore, inhibition of the TGR5 receptor with triamterene or of deiodinase II downstream of the TGR5 receptor with iopanoic acid also resulted in the attenuation of MDMA-induced hyperthermia. MDMA-treatment enriched the relative proportion of a Proteus mirabilis strain in the ceca of animals not pre-treated with antibiotics. These findings suggest a contributing role for the gut microbiota in MDMA-mediated hyperthermia and that MDMA treatment can trigger a rapid remodeling of the composition of the gut microbiome.
Highlights
BAT-mediated thermogenesis is an important component in mammalian thermal homeostasis
Treatment with ABX for 14 days prior to MDMA challenge down-regulated the expression of these genes in both BAT and skeletal muscle compared to H2O MDMA group
The present findings suggest that the microbiome-gut-brain axis may play a contributory role in the hyperthermia mediated by MDMA
Summary
BAT-mediated thermogenesis is an important component in mammalian thermal homeostasis. The intestinal microbiome actively modulates the size and composition of the bile acid pool[18]. Mice undergo dramatic remodeling of their gut microbiota when adapting to cold temperatures with accompanying changes in BAT tissue and browning of white adipose tissue. These tissue changes were transferable with microbiota transplantation into germ-free mice[23]. Because of the role of bile acids in UCP regulation and role of the intestinal microbiome in regulating the size and composition of the bile acid pool[18], we further tested the role of the TGR5 receptor[24] and D225 in MDMA-mediated hyperthermia through their inhibition with triamterene and iopanoic acid respectively. The results of this study support this hypothesis and further suggests that MDMA can in turn trigger a rapid remodeling of the microbiota composition in at least some intestinal compartments
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