Engineering A Probiotic To Reduce Obesity

Sean Davies PhD Department of Pharmacology Vanderbilt UniversityMedicalResearch.com Interview with:
Sean Davies PhD
Department of Pharmacology
Vanderbilt University

Medical Research: What are the main findings of the study?

Dr. Davies: N-acyl phosphatidylethanolamine (NAPE) is a fat-like molecule normally produced by small intestine of mammals in response to eating high fat foods that helps signal a feeling of fullness to the brain.  This sensation of fullness is what normally helps us decide to stop eating, but in obese people it appears that not enough NAPE is produced so that not enough of that signal gets sent to the brain.  So we wanted to find a way to increase the amount of NAPE made in the intestinal tract, with the hope that this would help protect against obesity. Our approach was to engineer a probiotic bacteria that normally colonizes the gut of humans and other mammals so that it would make NAPE.  Our hope was that when this gut bacteria made the NAPE, it would be absorbed by the intestine and help supplement the NAPE already being made by the intestine so that a more complete sensation of fullness would be send to the brain.

What we found was that our engineered bacteria made a significant amount of NAPE and that when fed to mice, the bacteria would colonize the gut like normal and that the intestinal cells could absorb this NAPE.  Most importantly, we found that mice that received this bacteria ate less of the high fat diet than mice that were not treated or that received bacteria that did not make NAPE. Because the mice ate less of the high fat diet, and also because they burned the fat they had more effectively, the mice receiving the bacteria producing NAPE had only 50% of  the body fat of the control mice.  While the control mice showed the early signs of developing diabetes, the mice that received the NAPE producing bacteria showed almost no signs of developing diabetes. So the presence of these NAPE producing bacteria protected the mice from the harmful effects of the high fat diet.

Another key findings was that because the bacteria live in the GI tract and keep producing the NAPE for many weeks, we didn’t have to keep administering the bacteria to the mice to keep up the protective effect.  Even a month after we stopped giving the bacteria producing NAPE, the mice were still protected from the effects of the high fat diet.  Eventually after about six weeks, the bacteria died out and the mice started eating the same amount of food as the control mice, but even for at least another six weeks after this, they still weighed less than the control mice.


Medical Research: Were any of the findings unexpected?

Dr. Davies: We were pleasantly surprised to find that the bacteria could make enough NAPE to have such a beneficial effect. We were particularly worried that not enough of the NAPE would be absorbed by the intestinal tract to really start the signaling process.  So we were very happy when we started seeing very clear effects.

We were also surprised at how long the effect was able to last after we stop actively giving the bacteria to the mice.  Eventually, we hope to engineer the bacteria so that they can survive and keep producing the NAPE for much longer, but we were still very excited about how well this worked in the initial version of the bacteria.

Medical Research: What should clinicians and patients take away from your report?

Dr. Davies: Someday we may be help to help people who are obese or overweight reach a healthy body weight by incorporating these bacteria in with the other trillions of bacteria that are already in their gut.  Having these bacteria on board should help them fill less hunger, which is one of the biggest challenges of weight loss and maintaining weight loss.  This treatment could be used alone or as an adjuvant to other strategies such as focusing on eating more vegetables and increasing physical activity. We are still a long ways from human trials, but we are hopeful that these will show that this strategy is as effective in humans as it is in mice.

Medical Research: What recommendations do you have for future research as a result of this study?

Dr. Davies: We need to know a lot more about how a person’s gut bacteria affects their health and how we can effectively change them to improve health. Many studies from different labs have shown that these bacteria are important players in health, but often we don’t know exactly how they have the effects that they do.  So continuing investment is needed in this research, with sustained funding to move beyond simply identifying what species are there and how they change under different conditions.

We also have to understand what are the best ways to alter a person’s gut microbiota if we find that this is contributing to their disease.  Simply using antibiotics kills off many of the beneficial bacteria, leading to things like C. difficile infections.  So we need to understand how we can selectively target harmful bacteria and replace them with beneficial ones.  We think that using engineered bacteria may be very helpful in understanding how to incorporate beneficial bacteria into a person’s gut microbiome.

One can imagine using engineered gut bacteria to produce a whole host of endogenous compounds that an individual might be deficient in to some extent. But to do this, we must develop technologies that will allow us to carefully control these bacteria and make sure that other people are notinadvertently getting exposed to these bacteria.

 Citation:

Incorporation of therapeutically modified bacteria into gut microbiota inhibits obesity

Zhongyi Chen1, Lilu Guo1, Yongqin Zhang1, Rosemary L. Walzem2, Julie S. Pendergast3, Richard L. Printz3, Lindsey C. Morris3, Elena Matafonova1, Xavier Stien1, Li Kang4, Denis Coulon5, Owen P. McGuinness4, Kevin D. Niswender3,4,6 and Sean S. Davies1
J. Clin Invest. doi:10.1172/JCI72517.