Metformin Alters Microbiota, Improving Insulin Sensitivity

Given the strength of the findings, people who take metformin for their diabetes appear to have an enriched gut microflora that fosters a more efficient response to glucose metabolism.

Written by Kathleen Doheny

With Juan S. Escobar, PhD, and  Caroline Apovian, MD

The use of metformin in people with diabetes appears to favorably alter their gut microbiome, resulting in an improved glucose metabolism. The primary effect of metformin occurs is to stimulate levels of certain microbiota that enrich the bacterial milieu,1according to a team of researchers from Nutrition, Health and Wellness Research Center in Medellin, Columbia and the Johns Hopkins Bloomberg School of Public Health in Baltimore, MD.

"In particular, my colleagues and I found mucin-degrading Akkermansia muciniphila and several butyrate-producing bacteria positively associated with metformin use," said study researcher Juan S. Escobar, PhD, of the Vidarium Research Center in Medellin, Colombia. The findings confirm findings from another recent study.2

"Although we are not the first to demonstrate alterations in the gut microbial community associated with intake of this medication, our study is unique in matching cases and control on sex, age and body mass index, which makes our findings robust," Dr. Escobar said. Even so, he added, he cannot claim a causal relationship yet, as the study was based on observational data.

However, the findings may prove to have clinical relevance, he said, both for preventing disease and helping clinicians tailor treatments not only for those with type 2 diabetes but for other diseases associated with gut microbiota.

"Alterations in the gut microbiota have been shown to be central in many chronic diseases," he said, ''including obesity, cardiovascular disease, and diabetes, among others. In the case of type 2 diabetes (T2D), it was demonstrated a few years ago that patients had an altered gut microbiome relative to non-diabetic people.3 What is new with our study is that yes, patients with T2D have an altered microbiota, but most alterations are due to metformin treatment rather than the disease itself."

Observational Study Bolsters Metformin Benefits

In a community-based, observational study, 28 men and women with type 2 diabetes, were evaluated; half of the participants were taking metformin and half were not.They were compared to individuals without a diagnosis of diabetes. The groups were matched by sex, age, and body mass index (BMI).

All participants gave the researchers fecal samples. The researchers performed gene sequencing to assess the composition of the gut microbiome.

Those taking metformin, in comparison to those without diabetes, had a higher abundance of Akkermansia muciniphila, a microbiota known for degrading mucin, and several microbiotas known to stimulate the production of short chain fatty acids (such as Butyrivibrio).

When the researchers pooled the mucin-degrading microbiomes and those producing short-chain fatty acids, they found A. muciniphila and Butyrivibrio were more abundant, [3.4 and 4.4 times, respectively] in those with type 2 diabetes taking metformin than in those with type 2 diabetes, not on metformin.1

The differences were statistically significant for A muciniphila [P=0.003], but not for Butyrivibrio [p=0.08].

The higher abundance of both types of bacteria in those taking metformin suggested that the benefits of metformin may have developed in response to a improve integrity of the intestinal mucosal barrier, said the researchers. When the mucin layer lining the gut is maintained, the translocation of proinflammatory lipopolysaccharides is reduced, thus controlling fat storage, adipose tissue metabolism, and glucose homeostasis, according to the experts.

Future studies will be needed to see if the bacterial shifts continue to mediate metformin's glycemic and anti-inflammatory properties, Dr. Escobar told EndocrineWeb.

In another new study in which the microbiome of individuals with type 1 diabetes (T1D) was evaluated,4 a distinct gut microflora was found. Gastrointestinal tissue was extracted by endoscopy and analyzed. The gut lining of patients with T1D showed greater signs of inflammation, then individuals with celiac disease or a healthy gut.3 The significance of this finding pertains to the growing evidence of the anti-inflammatory nature of metformin, the immune dysregulation in the gut of those with diabetes and a distinct gut bacteria, the authors concluded.

Metformin Credited With Improving Insulin Sensitivity

The findings may change some current thinking about how metformin works, says Caroline Apovian, MD, professor of medicine and pediatrics at Boston University School of Medicine and director of nutrition and weight management, Boston Medical Center. She reviewed the findings for Endocrine Web.

"Current thinking is that the metformin works because it improves insulin sensitivity in the liver," she explained. However, these findings, as well as results from recent studies, suggest that the gut may have an active role in glucose metabolism. Dr. Escobar and his team are ''linking the use of metformin with a beneficial change in the gut microbiota."

The strength of the new research, Dr. Apovian said, is that the researchers matched the cases by age, gender, and body mass index then compared those taking versus not receiving metformin, and also looked at healthy controls.

Clinically, she said, ''it could mean that metformin not only helps people with diabetes but could help people with prediabetes and maybe even people without diabetes because you are improving the gut microbiome."

For instance, there has been researching finding that metformin may help treat and prevent breast cancer,5 and it may have an anticancer mechanism for other cancers, including prostate, colorectal and endometrial, according to the National Cancer Institute. 6

Metformin, Gut Microbiome Hold Promise for Disease Prevention

More research is needed, both Dr. Apovian and Dr. Escobar agree. Physicians aren’t to the point where they are testing patient's stools routinely to assess individual gut bacteria, said Dr. Apovian. However, the study findings do suggest that metformin should be used more broadly than just for people with diabetes, she said.

Dr. Escobar’s lab aims to examine how to restore balance in the gut microbiota to prevent disease onset. However, he also championed the prospect of its use for those who already have a disease.

"For those already sick, our results can inform novel ways in which therapies could potentially be used to treat an assortment of gut microbiota-associated diseases, including type 2 diabetes."

Future research must also determine if the observed associations are causal, Dr. Escobar said, and of course, that would necessitate a randomized controlled trial.

Sources

1. de la Cuesta-Zuluaga J, Mueller NT, Corrales-Agudelo V, et al. Metformin Is Associated With Higher Relative Abundance of Mucin-Degrading Akkermansia muciniphila and Several Short-Chain Fatty Acid–Producing Microbiota in the Gut. Diabetes Care. 2017;40(1):54-62.

 http://care.diabetesjournals.org/content/early/2016/10/19/dc16-1324

2. Forslund K, Hildebrand F, Nielen T. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature. 2015;528:262-266.

3. Larsen N, Vogensen FK, van den Berg FWJ, et al. Gut microbiota in human adults with type 2 diabetes differs from non-diabetic adults. PLoS One 2010;5:e9085.

4. Pellegrini S, Sordi V, Mario Bolla A, et al. Duodenal Mucosa of Patients with Type 1 Diabetes Shows Distinctive Inflammatory Profile and Microbiota. Published online ahead of print. Accessed January 19, 2017. Available at https://academic.oup.com/jcem/article-lookup/doi/10.1210/jc.2016-3222.

 5. University of Pennsylvania School of Medicine. Diabetes drug metformin holds promise for cancer treatment and prevention: Results show survival benefit for some breast cancer patients and potential treatment option for patients with endometrial hyperplasia. Science Daily. June 2016.  

 https://www.sciencedaily.com/releases/2016/06/160604051019.htm

6. National Cancer Institute. Metformin: Can a diabetes drug help prevent cancer? Accessed on January 14, 2017. Available at: https://www.cancer.gov/about-cancer/causes-prevention/research/metformin.

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