Obesity in Children Traced to Antipsychotic Drugs’ Impact on Their Gut Microbiome

Obesity in Children Traced to Antipsychotic Drugs’ Impact on Their Gut Microbiome

A new study reveals that gut bacteria and their associated viruses can affect resting metabolic rates — and that drug-induced unhealthy changes in that bacteria can lead to weight gain by lowering resting metabolic rates. The findings, relevant to a better understanding of the biology of metabolic diseases, are in a study titled “Risperidone-induced weight gain is mediated through shifts in the gut microbiome and suppression of energy expenditure,” published in the journal eBiomedicine.

Several recent studies have associated the gut microbiome, the bacterial ecosystem that resides in the human gut, with the modulation of weight gain and metabolic diseases. The microbiome contributes to host metabolism and physiology through several mechanisms, including increased energy harvest from the diet, the modulation of lipid metabolism, altered endocrine function, and inflammatory stability. The gut microbiota is seen to be important in modulating obesity and other metabolic diseases.

An increase in prescriptions of second-generation antipsychotics (SGAs) for children has contributed to the obesity epidemic over the last two decades. SGAs are used to treat several psychiatric illnesses, such as autism, bipolar disorder, and schizophrenia. The most frequently prescribed SGA, risperidone (a benzylamino-piperidine derivative), is a well-recognized cause of significant weight gain, insulin resistance, and metabolic syndrome. Risperidone-induced weight gain is thought to be multifactorial, involving genetic, metabolic, and environmental factors. But recent findings have implicated changes in the gut microbiome as the mechanism by which SGAs contribute to metabolism changes and weight gain.

The researchers uncovered evidence that changes in the gut microbiome of children chronically treated with risperidone are associated with an increase in BMI compared to children not taking antipsychotics.

To test its hypothesis — changes in the gut microbiome were mechanistically associated to weight gain due to risperidone treatment — the research team examined energy balance and weight gain in wild type mice in response to treatment with risperidone alone or in combination with various xenobiotics, transfer of risperidone-altered microbiota, or transfer of the bacteriophage (phage), viruses that infect the microbiome bacteriophage, associated with risperidone-treated microbiota.

Similar to the human studies, the researchers found that risperidone changed the gut microbiota and resulted in mice weight gain of more than 2.5 grams, or approximately 10% of total body mass, over two months compared to controls. They also found the drug significantly altered the bacterial composition of the mouse microbiome. Furthermore, transfer of risperidone-treated fecal material, as well as the phage (viruses) fraction alone, was sufficient to induce similar effects in control mice. The team then showed that altered microbiome caused a reduction in resting metabolic rate that was fully responsible for the excess weight gain.

“Our research leads to the conclusion that it is probably bacteria (in the gut) that are responsible for the calories you burn while you are asleep,” said John Kirby, PhD, professor of microbiology and urology at the University of Iowa Carver College of Medicine and senior author of the study, in the press release.

In a previous study, Kirby and Chadi Calarge, a university pediatric psychiatrist, compared patients taking risperidone for longer periods with patients not taking the drug. They found that weight gain was associated with a significant change in the composition of the patients’ gut microbiome.

“With this study, we now have a mechanism for how a shift in the microbiome contributes to weight gain, and it’s to do with changes to the resting metabolic rate,” added Dr. Kirby.

The team was able to investigate the effect of microbiome change in mice metabolism using new equipment, a total calorimetry machine, created by Dr. Justin Grobe, study co-author. This instrument allowed the precise measurements of energy intake, oxygen consumption and carbon dioxide output, and heat production in a single mouse to determine the total energy change, or “delta G,” of the mouse.

The researchers observed no change in aerobic, i.e., oxygen-dependent, resting metabolic rate for mice fed risperidone compared to control mice, but there was a significant decrease in non-aerobic resting metabolic rate sufficient to account for the mice weight gain. “That is the equivalent of eating one additional cheeseburger every single day,” said Dr. Kirby.

These findings seem to suggest that manipulating resting metabolic rate, particularly by targeting the gut microbiome, may be a new strategy to treat obesity. It also suggests that preventing unhealthy changes to the microbiome would be beneficial for patients undergoing risperidone treatment.

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