Bile acids and the gut microbiome are involved in the hyperthermia mediated by 3,4-methylenedioxymethamphetamine (MDMA).

Hyperthermia from the drug MDMA can be life-threatening. The gut microbiome's production of bile acids appears to play a key role. In rats, MDMA caused a significant rise in body temperature and reduced serum concentrations of three bile acids (cholic acid, chenodeoxycholic acid, and deoxycholic acid) 60 minutes after treatment. Pretreatment with antibiotics depleted bile acids and reversed the hyperthermia to hypothermia. Antibiotic-treated rats also showed distinct gut bacterial communities with reduced diversity and fewer bacterial genes related to bile acid metabolism. The findings suggest that gut bacterial bile acids might be essential for MDMA-induced hyperthermia.

Study at a glance

Abstract

Hyperthermia induced by phenethylamines, such as 3,4-methylenedioxymethamphetamine (MDMA), can lead to life-threatening complications and death. Activation of the sympathetic nervous system and subsequent release of norepinephrine and activation of uncoupling proteins have been demonstrated to be the key mediators of phenethylamine-induced hyperthermia (PIH). Recently, the gut microbiome was shown to also play a contributing role in PIH. Here, the hypothesis that bile acids (BAs) produced by the gut microbiome are essential to PIH was tested. Changes in the serum concentrations of unconjugated primary BAs cholic acid (CA) and chenodeoxycholic acid (CDCA) and secondary BA deoxycholic acid (DCA) were measured following MDMA (20 mg/kg, sc) treatment in antibiotic treated and control rats. MDMA-induced a significant hyperthermic response and reduced the serum concentrations of three BAs 60 min post-treatment. Pretreatment with antibiotics (vancomycin, bacitracin and neomycin) in the drinking water for five days resulted in the depletion of BAs and a hypothermic response to MDMA. Gut bacterial communities in the antibiotic-treated group were distinct from the MDMA or saline treatment groups, with decreased microbiome diversity and alteration in taxa. Metagenomic functions inferred using the bioinformatic tool PICRUSt2 on 16S rRNA gene sequences indicated that bacterial genes associated to BA metabolism are less abundant in the antibiotic-MDMA treated group. Overall, these findings suggest that gut bacterial produced BAs might play an important role in MDMA-induced hyperthermia.