Pharma & drug development

A good gut feeling

Scientists from Vanderbilt University have opened new frontiers in obesity research, through bioengineering bacteria to generate a molecule that suppresses hunger in mice. Abi Millar finds out how this research could pave the way for sustained drug delivery through gut microbes. 

Obesity can be an expensive and complicated problem to treat. Although lifestyle changes and medication may work on a short-term basis, rates of weight regain are notoriously high, and in many parts of the world the obesity rate is soaring. Since excess weight is associated with a number of chronic diseases – not least heart disease, certain cancers and type 2 diabetes – the search for a solution is gathering urgency.

While gastric bands, for instance, can help patients lose weight, these require invasive surgery and come with clear disadvantages. As the mechanisms underlying obesity become better understood, researchers in the field are turning their attention to some very different possibilities.

One such researcher is Dr Sean Davies, assistant professor of pharmacology at Vanderbilt University. Along with colleagues, he is exploring the way that probiotics – the so-called ‘friendly’ bacteria found in yogurts – might be used to treat obesity and other chronic diseases.

Recently, he succeeded in programming bacteria to generate a molecule that suppressed hunger in mice. This molecule, NAPE, is normally made by the intestinal tract in response to food intake, where it quickly breaks down into a compound product, NAE. This prompts the person to stop eating and ultimately prevents weight gain.

A growing body of research, however, has shown that this mechanism may be impaired in obese people. Following a meal, it seems that their intestinal tract fails to make enough of either compound, meaning they will still be hungry even if they have already eaten enough food to maintain their weight. Davies’ contention is that, through manipulating the gut microbiome, it may be possible to rectify this issue.

“By having our engineered gut bacteria make a little extra or NAPE or NAE, we expected that it would help turn off the hunger signal and thereby limited overeating,” he says. “To test this, we fed lean mice a high fat diet, which has been previously shown to cause the lean mice to become obese and to develop symptoms of prediabetes. For some groups of the mice, we gave them the bacteria that expressed the NAPE or NAE while the control groups of mice either didn’t get any bacteria, or got bacteria that had not been programmed to make these compounds.”

Promising results

As expected, following eight weeks on the high fat diet, the mice that had received the NAPE- or NAE-expressing bacteria in their drinking water weighed significantly less than the control groups, as well as having lower body fat and reduced rates of insulin resistance. These benefits continued for up to 12 weeks, despite the fact that treatment had stopped and all the mice had continued to eat the high fat diet.

“We showed that these sustained effect were the result of NAPE expressing bacteria colonising the GI tract, so that they were able to continue to deliver NAPE to the mouse and suppress its appetite,” explains Davies. “Eventually however, these bacteria were lost from the GI tract, so the suppression of appetite was lost.”

Because the mechanisms controlling eating behaviour in mice and humans are very similar, Davies’ team think there is strong potential to replicate these results in human trials. Ultimately, there could be implications not just for obesity but for a raft of other health conditions.

“The key for each condition is to identify a compound that the bacteria can make that will be beneficial for the treatment of that illness,” says Davies. “In terms of our NAPE expressing bacteria, we also think that they may be helpful in inflammatory diseases like atherosclerosis or inflammatory bowel disease because NAPE and NAE have anti-inflammatory properties. Bacteria making other therapeutic molecules, say a statin for instance, might be helpful for atherosclerosis as well.”

Microbial miracles

Microbial medicine of this kind could greatly improve the cost and ease of treating chronic conditions. Currently, many patients fail to gain the full benefits of the medications they are taking, either because they forget to renew their prescription, they cannot afford the long-term costs or they simply become lax about taking it every day.

A microbial approach, however, would not require them to be so vigilant. Once the bacteria have colonised their gut, the compound in question would be produced naturally in the body for a reasonable length of time. This treatment would be more akin to receiving a vaccination, followed up with occasional booster shots.

“Even if you did end up needing to take the bacteria several times a week, this approach might still be much more cost-effective because once the appropriate therapeutic bacteria are made, the cost to grow them can be much lower than that required to chemically synthesise the same amount of compound,” points out Davies.

The preliminary results also suggest that, when compounds are delivered by gut bacteria, far less of it the drug is required to generate the same effect, probably because this route of transmission enhances bioavailability. It may also lead to fewer off-target interactions, occasioning reduced side effects.

Controlling colonisation

Before human trials can begin, it will be necessary to address certain challenges. Because these are essentially drug-making bacteria, it is important to ensure the bacteria cannot easily be transmitted to others nearby. To this end, Davies’ team will need to perform follow-up animal studies.

“We also need to demonstrate in animal studies that accidental exposure to our appetite suppressing bacteria wouldn’t have harmful effects on lean, young, very old or immunocompromised animals,” he says. “And we need to demonstrate that if a treated animal begins to have any adverse effects, we can rapidly eliminate the bacteria using antibiotics.”

For the time being, the researchers are endeavouring to fully understand the molecular mechanisms by which NAPE inhibits obesity, as well as engineering the bacteria to reduce the risk of transmission. They are also trying to figure out the best method for achieving long-term colonisation of any therapeutic bacteria, whether these microbes are engineered or derived from a healthy donor.

“Given the role of gut microbiota in various chronic diseases, it would be very helpful to understand the best ways to be able to stably swap beneficial bacteria into the place of disease causing bacteria,” says Davies. “This will also help us achieve our long-term goal of being able to use bioengineered bacteria to treat human obesity.”

This article appears in the July 2015 edition of Pharma Technology Focus

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