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.

The toxidrome associated with death from the synthetic cathinones includes hyperthermia as part of the sympathomimetic syndrome. Here, we examine the gender differences in the development of tolerance to the hyperthermia mediated by the synthetic cathinone methylone. In addition to temperature changes, expression differences in genes encoding the uncoupling proteins (UCP) 1 & 3, and TGR5 in skeletal muscle (SKM) and brown adipose tissue (BAT) were examined. Male and female rats were treated weekly with methylone (10 mg/kg). The females developed a tolerance to the methylone-induced hyperthermia by week two of drug exposure. By the third week, females displayed a hypothermic response to methylone. Conversely, males continued to display a hyperthermic response up to and including week four. At week four, the males demonstrated a significantly lower hyperthermia and a complete tolerance seen at week five with no significant hyperthermia. Tissue samples collected after treatment on the sixth week indicate that chronic exposure to methylone reduced UCP1 expression in SKM and BAT of the female rats. Only the females displayed increased TGR5 expression in BAT. UCP3 expression increased in both the SKM and BAT of the males and females. The differences between responses in male and female subjects further demonstrate the need for gender studies in the toxicology associated with drugs with abuse potential.

Phenethylamines (e.g., methamphetamine) are a common source of drug toxicity. Phenethylamine-induced hyperthermia (PIH) can activate a cascade of events that may result in rhabdomyolysis, coagulopathy, and even death. Here, we review recent evidence that suggests a potential link between the gut-brain axis and PIH. Within the preoptic area of the hypothalamus, phenethylamines lead to changes in catecholamine levels, that activate the sympathetic nervous system (SNS) and increase the peripheral levels of norepinephrine (NE), resulting in: (1) the loss of heat dissipation through α₁ adrenergic receptor (α₁-AR)-mediated vasoconstriction, (2) heat generation through β-AR activation and subsequent free fatty acid (FFA) activation of uncoupling proteins (UCPs) in brown and white adipose tissue, and (3) alteration of the gut microbiome and its link to the gut-brain axis. Recent studies have shown that phenethylamine derivatives can influence the composition of the gut microbiome and thus its metabolic potential. Phenethylamines increase the relative level of <i>Proteus</i>which has been linked to enhanced NE turnover. Bidirectional fecal microbial transplants (FMT) between PIH-tolerant and PIH-naïve rats demonstrated that the transplantation of gut microbiome can confer phenotypic hyperthermic and tolerant responses to phenethylamines. These phenethylamine-mediated changes in the gut microbiome were also associated with epigenetic changes in the mediators of thermogenesis. Given the significant role that the microbiome has been shown to play in the maintenance of body temperature, we outline current studies demonstrating the effects of phenethylamines on the gut microbiome and how these microbiome changes may mechanistically contribute to alterations in body temperature.

Population explosion, urbanization, changes in lifestyle management, improper food habits and various other factors play focal contributors in the massive prevalence of type 2 diabetes mellitus in the developing countries. Although insulin is the cornerstone in the management of type 1 diabetes; insulin, anti-hyperglycemic and hypoglycemic agents are proved to be effective in type 2 diabetes, although their efficacy decreases with the progress of the disease. Moreover a significant number of side effects, mostly hypoglycemia and weight gain have put a bar in using these drugs confidently. Many novel therapeutic strategies with convincing efficacy and less adverse effects are currently emerging for providing efficient means of treatment of this disorder. This article mainly focuses on newer and unconventional pharmaceutical or biotechnical strategies that may or may not have been implied for the treatment of Type 2 Diabetes mellitus on a widescale basis so far. These strategies are supposed to be efficient in controlling glycemic levels and possess a significant potential to reduce the co-morbidities associated with this disease.

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