Probiotics May Improve Glucose Control

Gut microbiota can exert beneficial effects in diabetic patients by altering oxidative stress biomarkers

With Orville Kolterman MD

Bacteria and probiotics in the intestines

There is a long list of conditions and ailments that probiotics have been touted to help, but not many of the suppositions have been tested in good studies. A review report from earlier this year which studied the impact of probiotics on pregnant women with gestational diabetes found inconclusive evidence, in part because there is little homogeneity in the types of probiotics used in various studies. There is some evidence that probiotics can reduce inflammatory markers such as C-reactive protein (CRP) and interleukin 6 (IL-6). It also found probiotics are associated with better lipid profiles compared to placebo, as well as reduction in markers for insulin resistance and insulin secretion.

Another review article from 2019 on the impact of probiotics on Type 2 diabetes patients determined there was evidence that consuming probiotics improved fasting blood glucose, insulin sensitivity and inflammation markers. Another study found that dental health improved in patients with both diabetes and periodontitis when they took probiotics.

Recent Studies

The results of these recent studies all conclude the same thing, best summed up by yet another review report that investigated the role of the microbiome in the gut on blood sugar control: “It seems that gut microbiota can exert beneficial effects in diabetic patients via altering oxidative stress' biomarkers. The beneficial effect of gut microbiota however was modest…and non-significant on HbA1C. These results need to be confirmed by conducting more reliable studies.”

One study out of India has found that a novel proprietary formula of multiple probiotic strains had a “significant” beneficial effect on A1c in the patients given the study medication versus those who took a placebo. The study medication group also lost more weight than their counterparts.

Another study published this fall in the British Medical Journal works off the premise that patients with Type 2 diabetes are deficient in adequate and adequately heterogeneous gut bacteria. In particular, the authors note that there is a decline in Akkermansia muciniphila and microbes involved in the conversion of dietary fiber to short-chain fatty acids, especially butyrate.

Much of the previous work, summarized in all those review articles, worked with commercially available strains of bacteria. This study used five different strains created specifically for Pendulum Therapeutics of San Francisco, which funded the study. It included A. muciniphila, B. infantis, A. halliiC. beijerincki, and C. butyricum, as well as a dietary fiber and inulin from chicory root. 

The study was conducted at six sites around the United States and included 76 subjects, 23 of whom were assigned to the placebo arm and 26 and 27 in each of the two arms of the study that received the probiotic formula. The difference in the two arms getting the medication was the formulation used. One group contained Clostridium butyricum, Clostridium beijerinckii and Bifidobacterium infantis. The other also included the two additional strains Akkermansia muciniphila and Anaerobutyricum hallii. The study lasted 12 weeks.

The main outcome studied was the area under the curve during a three-hour meal tolerance test at 12 weeks, compared to at the start of the study and CRP levels. Other endpoint measurements included:

  • area under the curve A1c
  • fasting glucose and insulin
  • incremental and total area under the insulin curve during the meal tolerance tests
  • IL-6
  • IL-10
  • tumor necrosis factor alpha
  • transforming growth factor beta

Results

There were not statistically significant differences in inflammatory markers, nor in the area under the curve at the three-hour meal test for either of the medication arms. The results of this most recent study included: 

  • A1c and incremental glucose were slightly improved in the group taking just three strains of probiotics, but not to a statistically significant degree.
  • In the other group, there was a statistically significant decrease in total glucose area under the curve at the three-hour meal, translating to a decrease in the group of 7%.
  • Incremental glucose also declined in that group, by 32.5%, compared to an increase of more than a quarter in the placebo group.
  • A1c declined by 0.6 in that group compared to placebo.
  • There was a small increase in butyrate concentration over 12 weeks relative to baseline for both medication groups.
  • The placebo group increased by 3.2%. 

Discussion and Analysis

One of the study authors, Orville Kolterman MD, found a “dysbiosis” in the pattern of microbes in people with Type 2 diabetes in his earlier work. “Specifically, it is characterized by a number of functionalities that people usually have that were diminished or missing in patients with Type 2 diabetes.” He notes that the missing and diminished functionalities overlap in people with diabetes, prediabetes and those who are obese.

The role of butyrate in particular is intriguing, he says. “It serves a nutrient function for epithelial cells lining the gastrointestinal tract, especially the colon. It works as a signaling molecule.” In animal models, butyrate stimulates GLT1 from cells that line the gut.

Over the last five years or so, Kolterman notes that there is evidence that those with Type 2 diabetes are in a state of inflammation driven in part by leaky gut syndrome that is due to a thinning of the mucus layer in the gut.

In the recent explorations of the role of the microbiome and Type 2 diabetes, researchers have tried full fecal transplants. “That’s more of a shotgun approach. It improved the metabolic state of patients, but it’s overly broad. We wanted a sniper approach: to find the bacteria that are good butyrate producers and can help maintain the mucus layer.”

The authors theorized that if you introduced those beneficial bugs back into patients, they would improve. “The major challenge now is that all of the microorganisms that we are interested in are anaerobic, which means they have to be grown in the absence of oxygen,” he says. “It hasn’t been done large scale, so we had to develop the techniques before trying this in humans.”

While he works for a corporation that manufactures these probiotics, Kolterman says that this is a controlled clinical study that followed FDA guidelines on good study protocols. “It’s double blind, placebo controlled and with a good number of subjects over a good amount of time.”

That they were able to overcome the financial interest concerns at the BMJ and be published should inspire confidence in the results, he adds. “We went through a rigorous peer review, and we answered all the questions they had before they published it,” he says.

While the study officially ended after 12 weeks, Kolterman says that they checked study participants’ stool samples a month after they stopped taking supplements to see if there was any lingering positive impact. “The strains disappeared completely in 80% of the subjects, in the remaining 20%, no one had more than one strain, and the one retained varied.”

It is possible that longer term treatment will provide a longer lasting benefit after patients stop taking probiotics. Kolterman says that the functions of these bacteria were missing or diminished in the study subjects. “It can take 6 weeks for glucose lowering effects to appear, as the strains need time to establish and replicate.” 

He adds that fecal transplants, while effective, only last 6 weeks and have an “ick factor” they have to overcome for patients to buy into them.

The treatment also isn’t covered by insurance presently – payers need more proof before they cover something considered experimental or out of the norm, he says. “But there is an evolving attitude towards treatments like this that could improve outcomes and reduce costs.”

Next up are larger scale studies, with a couple are already in progress, Kolterman says, including one on probiotics and patients with prediabetes. 

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