Researchers developed a modified version of the probiotic gut bacteria E. coli Nissle 1917 to generate a molecule that through normal metabolism, becomes a hunger-suppressing lipid – and found that mice that drank water laced with the engineered bacteria ate less, had lower body fat and staved off diabetes, even when fed a high-fat diet.
Led by Sean Davies and colleagues at Vanderbilt University team modified the bacteria to produce N-acyl-phosphatidylethanolamines (NAPEs), which are produced in the small intestine after a meal and are quickly converted into potent appetite-suppressing lipids known as N-acyl-ethanolamines (NAEs).
“We genetically modified the intestinal bacteria E. coli Nissle 1917 to secrete NAPEs by expressing NAPE acyltransferase (pNAPE-EcN),” explained the team. “We found that administration of pNAPE-EcN bacteria to mice in their drinking water markedly inhibited body weight and body fat gain of mice fed a high-fat diet compared to mice administered control bacteria or vehicle only.”
“Our studies provide proof-of-concept that incorporating bacteria engineered to secrete NAPE into the gut microbiota can be an effective long-term strategy for inhibiting development of obesity and provide insight into the mechanisms of action of these therapeutic bacteria,” added Davies and his colleagues, who will describe their approach in a presentation at the 249th National Meeting & Exposition of the American Chemical Society (ACS).
Davies and his team noted that research in recent years has demonstrated that the population of microbes living in the gut may be a key factor in determining the risk for obesity and related diseases - suggesting that strategically altering the gut microbiome may have beneficial impacts on human health.
In the current study, mice that are pre-disposed to obesity and fatty liver disease were fed the engineered bacteria in water and compared to those fed just water or a non-engineered control bacteria in water.
Compared to mice that received plain water or water containing control bacteria, the mice drinking the NAPE-making bacteria gained 15% less weight over the eight weeks of treatment, said the team. In addition, their livers and glucose metabolism were better than in the control mice.
Indeed, mice that received the engineered bacteria remained lighter and leaner than control mice for up to 12 weeks after testing ended, they noted.
NAPEs or NAEs for human trials?
In a further experiment, Davies and his team found that mice which lacked the enzyme to produce NAEs from NAPEs were not helped by the NAPE-making bacteria; but this could be overcome by giving the mice NAE-making bacteria instead.
"This suggests that it might be best to use NAE-making bacteria in eventual clinical trials," said Davies, noting that it may be possible that some people don't make very much of the enzyme that converts NAPEs to NAEs. "We think that this would work very well in humans."
According to the team, the main obstacle to starting human trials is the potential risk that a person could transmit these special bacteria to another by faecal exposure.
"We don't want individuals to be unintentionally treated without their knowledge," Davies added. "Especially because you could imagine that there might be some individuals, say the very young or old or those with specific diseases, who could be harmed by being exposed to an appetite-suppressing bacteria.”
“We are working on genetically modifying the bacteria to significantly reduce its ability to be transmitted,” he confirmed.
Source: presented at a meeting of the American Chemical Society
“Incorporation of Therapeutic Bacteria into the Gut Microbiome for Treatment of Obesity”
Authors: S. Davies et al