Boston (FRONTLINE MEDICAL NEWS) – A purified food supplement designed to alter gut bacterial composition improved both metformin tolerance and fasting glucose levels among people with type 2 diabetes, according to results from a small randomized study presented at the annual scientific sessions of the American Diabetes Association.

Research into how diabetes affects and is affected by the gut microbiome is still in its infancy. However, compared with nondiabetics, people with type 2 diabetes have been shown to have microbiomes richer in certain types of bacteria than others, and these altered bacterial profiles may be linked to changes in insulin sensitivity, glucose regulation, and methane production.

Mark L Heiman, Ph.D., of MicroBiome Therapeutics in New Orleans, designed the intervention, a powder comprising three purified food ingredients: inulin from agave, beta-glucan from oatmeal, and polyphenols derived from blueberry skins. These were hypothesized to alter gut microbial composition by stimulating blooms of microbes that can generate short-chain fatty acids, displacing some bacteria-producing lactic acid; increase viscosity in the colon (allowing for sequestering of bile acids); and combat oxidative stress and methane production.

Though first investigated as a monotherapy for use in people with prediabetes, the so-called gut microbiome modulator NM504 was found incidentally to improve metformin tolerance in people with newly diagnosed type 2 diabetes ( Benef. Microbes 2014;5:29-32 ), and researchers hypothesized that metformin likely interacts with microbiota in the colon, resulting in an abundance of lactate-producing bacteria. Lactic acid production in the colon, exacerbated by starch or sugar consumption, is a known contributor to adverse GI side effects in people taking metformin.

Dr. Heiman presented results from a randomized, placebo-controlled, single-center crossover study in 10 people with type 2 diabetes (8 female) with difficulty tolerating metformin due to GI symptoms or who had discontinued previous therapy because of these symptoms ( J. Diabetes Sci. Technol. 2015;9:808-14).

Subjects were randomly assigned metformin (500 mg twice daily in the first week titrated to three times daily in the second week) alongside the experimental product or placebo. They were asked to record their glucose and adverse GI symptoms (including stool consistency, urgency to evacuate, bloating sensation, and flatulence) every day; metformin tolerance was measured by these symptoms using a scoring system previously validated in patients with irritable bowel syndrome.

After 2 weeks of treatment and a washout period of 2 weeks with no treatment, subjects’ initial treatment assignments were reversed for an additional 2 weeks, and outcomes were recorded.

The combination of metformin and NM504 resulted in improved tolerance score of metformin, compared with placebo (6.78 ± 0.65 [mean ± standard error of the mean] vs. 4.45 ± 0.69, P = .0006). Mean fasting glucose levels were significantly lower with the metformin/NM504 combination (121.3 ± 7.8 mg/dL) than with metformin-placebo (151.9 ± 7.8 mg/dL), (P < .02).

It is unclear whether the improved glucose was a result of improved availability of metformin or an independent effect of the intervention. Last year Dr. Heiman presented results from a previous study of 28 adults with prediabetes randomized to NM504 monotherapy or placebo who saw significantly lower blood sugar levels at 120 and 180 minutes after a glucose challenge, compared with patients taking placebo. This was presented at the International Congress of Endocrinology’s annual meeting (ICE-Endo) 2014 meeting in Chicago; Dr. Heiman noted that the results are awaiting review and perhaps publication.

Dr. Heiman commented that the glucose-regulating effect seen in the metformin study “appeared somewhat durable, even after the 2-week washout period” among subjects switching from intervention to placebo; however, further studies would be needed to determine its effect on insulin sensitivity. Fecal microbial composition was not investigated before and after treatment.

Dr. Daniel Hsia of Pennington Biomedical Research Center, in Baton Rouge, La., a study coauthor, said in an interview that although larger trials would be needed to validate the results and better understand the activity of the intervention in the gut, the findings were “promising” for a proof-of-concept study.

“At this point, we’re not going to start using this in every single diabetes patient on metformin, but it’s very encouraging that you could potentially make it more accessible. Metformin is a very good agent with one of the longest histories. It’s cheap, it can be used in combination with a lot of other medications, but a certain percentage of people will have to stop metformin altogether due to side effects.” Metformin is also approved for children with type 2 diabetes as young as 10 years, he pointed out. “The fact that [NM504] is food and you could add this to the regimen makes it very appealing” for use in adolescent patients, he said.

Dr. Heiman, a former obesity researcher at Eli Lilly, said that interventions to manipulate gut microbiota were worthy of deeper investigation. “In the past we were content to say ‘you’ve got bacteria to help you digest food’ – but little was known about what they do, whether they convert sugars to short-chain fatty acids, whether they might send out signals that may, for example, make you crave sugar. The exciting things is learning what all the signals are, and how they communicate with the body,” he said.

MicroBiome Therapeutics, owner of a patent on the investigational product, sponsored the study. Dr Heiman is an employee of MicroBiome Therapeutics, and another coauthor disclosed funding from the company. Dr. Hsia and three other coauthors reported no conflicts of interest.