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Gut microbes and weight regain

How gut microbes contribute to post-dieting weight regain

They found that low levels of these flavonoids in weight cycling prevented this fat-derived energy release, causing the post-dieting mice to accumulate extra fat when they were returned to a high-calorie diet

Researchers at the Weizmann Institute of Science have shown in mice that gut microbiome play an unexpectedly important role in exacerbated post-dieting weight gain, and that this common phenomenon may in the future be prevented or treated by altering the composition or function of the microbiome.

The study was performed by research teams headed by Dr Eran Elinav of the Immunology Department and Professor Eran Segal of the Computer Science and Applied Mathematics Department. The researchers found that after a cycle of gaining and losing weight, all the mice's body systems fully reverted to normal – except the microbiome. For about six months after losing weight, post-obese mice retained an abnormal ‘obese’ microbiome. The research, ‘Persistent microbiome alterations modulate the rate of post-dieting weight regain’, is published in the journal Nature.

"We've shown in obese mice that following successful dieting and weight loss, the microbiome retains a 'memory' of previous obesity," said Elinav. "This persistent microbiome accelerated the regaining of weight when the mice were put back on a high-calorie diet or ate regular food in excessive amounts. 

In a series of experiments, the scientists demonstrated that the makeup of the obese microbiome was a major driver of accelerated post-dieting weight gain. For example, when the researchers depleted the intestinal microbes in mice by giving them broad-spectrum antibiotics, the exaggerated post-diet weight gain was eliminated 

In another experiment, when intestinal microbes from mice with a history of obesity were introduced into germ-free mice (which, by definition, carry no microbiome of their own), their weight gain was accelerated upon feeding with a high-calorie diet, compared to germ-free mice that had received an implant of intestinal microbes from mice with no history of weight gain.

They then developed a machine-learning algorithm, based on hundreds of individualised microbiome parameters, which successfully and accurately predicted the rate of weight regain in each mouse, based on the characteristics of its microbiome after weight gain and successful dieting.

Furthermore, by combining genomic and metabolic approaches, they then identified two molecules driving the impact of the microbiome on regaining weight. These molecules – belonging to the class of organic chemicals called flavonoids that are obtained through eating certain vegetables – are rapidly degraded by the post-dieting microbiome, so that the levels of these molecules in post-dieting mice are significantly lower than those in mice with no history of obesity.

The researchers found that under normal circumstances, these two flavonoids promote energy expenditure during fat metabolism. Low levels of these flavonoids in weight cycling prevented this fat-derived energy release, causing the post-dieting mice to accumulate extra fat when they were returned to a high-calorie diet.

Finally, the researchers used these insights to develop new proof-of-concept treatments for recurrent obesity. First, they implanted formerly obese mice with gut microbes from mice that had never been obese. This fecal microbiome transplantation erased the "memory" of obesity in these mice when they were re-exposed to a high-calorie diet, preventing excessive recurrent obesity.

"By conducting a detailed functional analysis of the microbiome, we've developed potential therapeutic approaches to alleviating its impact on weight regain,” said Segal. "We call this approach 'post-biotic' intervention. In contrast to probiotics, which introduce helpful microbes into the intestines, we are not introducing the microbes themselves but substances affected by the microbiome, which might prove to be more safe and effective."

Next, the scientists used an approach that is likely to be more unobjectionable to humans: they supplemented post-dieting mice with flavonoids added to their drinking water. This brought their flavonoid levels, and thus their energy expenditure, back to normal levels. As a result, even on return to a high-calorie diet, the mice did not experience accelerated weight gain.

"Obesity affects nearly half of the world's adult population, and predisposes people to common life-risking complications such as adult-onset diabetes and heart disease," concluded Elinav. "If the results of our mouse studies are found to be applicable to humans, they may help diagnose and treat recurrent obesity, and this, in turn, may help alleviate the obesity epidemic."

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