Type 2 diabetes drug, metformin, impacts gut bacteria

Patients with type 2 diabetes have what is called insulin resistance, an inability to properly use insulin. The pancreas will make more insulin to keep blood glucose levels normal however, eventually, the pancreas can’t keep up and drugs may need to be taken. The most common drug to treat type 2 diabetes is metformin. A large team of scientists throughout Europe and China published a study in Nature showing that metformin affected gut bacteria in type 2 diabetics.

The researchers analyzed stool samples from 784 individuals with and without type 2 diabetes and looked at the effects that metformin had on gut bacteria. Metformin is usually prescribed in high doses and because it is a chronic disease, patients end up taking the drug often for many years. Based just on stool samples, they were not able to identify which sample was from a diabetic patient or control unless they took metformin. Type 2 diabetics who were on metformin had higher levels of E. coli and lower levels of I. bartletti than the controls or type 2 diabetics not taking metformin.

Studying the bacteria that changed in abundance in the gut suggested to the scientists that butyrate and propionate had elevated production. These two short chain fatty acids are associated with lowering blood glucose levels.

Importantly, this study helps explain some existing studies with conflicting results comparing gut bacteria of people with and without type 2 diabetes. This was most likely due to the fact that there were more individuals taking metformin in one study than another and this was not controlled for.

This study not only informs us on what is happening with gut microbes after taking metformin but also shines a light onto the importance of controlling for all external factors in microbiome studies, including treatments that could have confounding effects.  

Ingesting blueberries and oats may modulate the microbiome and help diabetics

Prebiotics are foods that are consumed in order to modulate the microbiome.  They are normally composed of molecules that are not broken down by our body itself, but rather that remain intact until making it to the large intestine where bacteria can break them down.  Common prebiotics come from plant materials, like long chained complex carbohydrates, as well as polyphenols, like blueberry extract.  In a recent study, scientists from Louisiana State University performed randomized dietary intervention on obese subjects and gave them a mixture of these molecules.  They then monitored the changes in the microbiome that occurred, along with changes in health indicators.  Their results were published in The Journal of Diabetes and its Complications.

The researchers included 30 adults in the study, and split them into two groups: one to receive the microbiome modulating dietary supplement, and the other to receive a placebo.  The dietary supplement included blueberry extract, oat bran cellulose, and inulin (a common oligosaccharide of fructose).  The subjects ingested the supplement daily for four weeks, with samples being collected once before and once at the end of the sudy.

Many positive health consequences were associated with eating the prebiotics.  Those patients had improved glucose tolerance, as well as increases in satiety.  The satiety may have been caused by an increase in fasting PYY concentration, a peptide known to cause hunger suppression, which was higher in those people taking the prebiotic.  In addition, there was an increase in self-reported flatulence from taking the prebiotic, but otherwise no adverse events were recorded.  Interestingly, there were no statistically significant changes in the microbiome that resulted from eating the supplement, however higher levels of short chained fatty acids (SCFAs) were observed in the stools of those patients.  Even though no statistically significant change was measured, it is quite possible that the level of sequencing depth and analysis was robust enough to truly observe changes that may have occurred.

This study is another that shows the benefits of eating prebiotics.  Interestingly, the prebiotic used for this study is the same one used by Microbiome Therapeutics in their metformin formulation.  This prebiotic, when combined with metformin, increases its efficacy for diabetics.  This study shows that possibly the prebiotic alone is responsible for this improvement, although it gets us no closer to explaining how this occurs.  Any of our readers that are taking metformin may want to read the wealth of literature around what Microbiome Therapeutics has done, because just the simple addition of foods to the drug seems to improve the results of taking it.

The oral microbiome of periodontitis patients has distinct profiles dependent on disease severity

A few weeks ago we discussed periodontitis, a bacterial infection of the gums that leads to inflammation and deep pockets to develop in which harmful bacteria can colonize. Periodontitis develops in association with dramatic changes in the makeup of the oral microbiome. Smokers and diabetics are more frequently victims of the disease. The study we discussed previously was one performed by researchers in Istanbul, Turkey in which they tested whether a probiotic lozenge could improve the patients’ condition. In a different, more recently published study concerning periodontitis, researchers in Connecticut and Massachusetts looked not to change the oral microbiome of patients suffering from periodontitis, but to organize and identify the microbial characteristics of the disease.

In the study published in Plos One, seventeen subjects, 8 of whom were diabetic, with Chronic Kidney Disease (CKD) and seventeen subjects without CKD, 3 of whom were diabetic, were studied.  All 34 subjects suffered from periodontitis. Samples were taken from each participant, from the deepest pockets in two different areas of the mouth. DNA was then isolated and sequenced to identify microbial communities in each individual. After much statistical analysis, the researchers found that the microbial communities tended toward two clusters, A and B, with type B communities correlating with more severe periodontitis. Group A subjects had communities with greater health-associated bacteria and cluster B communities were dominated by Porphyromonas gingivalis and Tannerella forsythia. Additionally, the analysis showed that diabetes and CKD are not correlated with a certain periodontitis microbial makeup.

A set-back of this experiment is the low sample size, which makes for less meaningful statistical analysis. Greater sample sizes of each cluster could give stronger claim to the findings of this study. However, this study does begin to clarify the bacterial community characterization of healthy, unhealthy, and severely unhealthy oral microbiomes. In addition, the results from this study could be used to ask further questions about the disease, including questions such as: what environmental factors cause the difference in clusters A and B? Do inflammatory diseases such as CKD and diabetes have anything to do with the severity of inflammatory response of periodontitis? Further analysis may allow us to answer these tough questions.

Episode 5 of The Microbiome Podcast: Diet and its impact on our microbiota and health with Drs. Erica and Justin Sonnenburg

As we read on yesterday's blog post, dietary fibers alter the microbiome. On this week's episode of The Microbiome Podcast we talked in depth with Drs. Erica and Justin Sonnenburg from Stanford University about dietary fibers and their impact on our microbiota and our health.  Erica and Justin wrote a book that was published today called The Good Gut: Taking Control of Your Weight, Your Mood, and Your Long-term Health. You can buy it here on Amazon and it's a highly recommended read for anyone interested in the microbiome. 

Check out the newest episode on iTunes, Stitcher, or listen on our website. 

We will continue answering your questions on the podcast so please call 518-945-8583 with any questions for us or for next week's guest, Dr. Elaine Hsiao.

See below for more detailed show notes from today's episode: 

(1:17) Dr. Rob Knight received a Creative Promise in Biomedical Science Prize from the Vilcek Foundation. Read more.
(3:09) Rob Knight also published a book called Follow Your Gut: The Enormous Impact of Tiny Microbes. Click here to buy it on Amazon. 
(3:33) uBiome recently began a pregnancy microbiome study to better understand how the bacteria in our bodies change during and after pregnancy. Find out more on the uBiome website. 
(4:56) Microbiome Therapeutics performed a clinical study with an investigational drug in type 2 diabetics taking metformin and found that the drug resulted in more tolerability for patients and fewer side effects than metformin without the drug. Read more.  

In the (9:40) conversation with Erica and Justin Sonnenburg (read more about their research), we talked about several topics pertaining to diet and dietary fiber and its impact on our microbiota and health. We also discussed: 

(11:49) Why they decided to write the book.
(16:05) Their personal experiences having children and the importance of nurturing their health and its impact on their lives.
(17:55) Dietary fibers and differences among various types of fibers in our diets.
(26:15) How fast does diet change the microbiota?
(32:05) Bacteroides thetaiotaomicron and why it is Erica and Justin's favorite microbe and a study Justin published in 2005 while he was in Jeff Gordon's lab. Read the paper here.  
(37:35) How microbiome therapies are going to look in the future. 
(41:00) How eating better can make an impact now on our overall health. Read the seminal obesity and microbiome paper Erica mentions from the Gordon laboratory. 

We also answered two other (44:00) listener questions about phage therapy and organic vs. non-organic baby and adult foods. 

Next week we will be talking with Dr. Elaine Hsiao from Cal Tech so please call 518-945-8583 with your questions about autism and the microbiome as well as the microbiome's ability to regulate serotonin levels. 

Schizophrenia and the virome

Schizophrenia PET scan

Schizophrenia is a mental health disorder in which people cannot recognize reality, suffer from hallucinations, and experience social withdrawal.  The causes of schizophrenia are unknown, but it is thought to include genetic, environmental, psychological, and social risk factors.  As we have written about extensively in this blog, the bacteria and viruses in our body have an important connection to our brain and behavior, in what has been termed the ‘gut-brain axis’.  Considering the gut-brain axis, a team of scientists from Johns Hopkins University wondered if the microbiome, and specifically the virome, was somehow related schizophrenia.  They recently published their findings in Schizophrenia Bulletin.

The scientists sampled the throat microbiome from 74 people in the Baltimore, MD area, 41 of whom suffered from schizophrenia and 33 of whom did not.  They discovered that a specific bacteriophage (virus that infects bacteria), Lactobacillus phage phaidh, was linked to schizophrenia, which was found in 17 of the 41 schizophrenia patients, but only 1 of the 33 control individuals.  In addition, 9 of those 17 schizophrenics had a comorbid immune disorder, such as diabetes or Crohn’s disease, whereas only 2 of the remaining schizophrenics without the phage had these diseases.  The scientists also found a loose link between taking the drug valproate and occurrence of the phage.  Interestingly, this drug has been previously shown to affect the microbiome.  Finally, the existence of the phage coincided with higher levels of the bacteria that the phage attacks, Lactobacillus gasseri.  This is an unsurprising result because a phage and its target are usually found together.

The scientists acknowledge that the results of this study do not prove any real association between the microbiome and schizophrenia, but based on the results, they suggest that further research is warranted.  Notably, Lactobacillus gasseri is sometimes included in probiotics to supposedly relieve gastrointestinal issues.  However, if gasseri’s phaidh phage goes along with it, then according to this study, it may cause more harm than good.

The continent you were born on may increase your risk for diabetes

Researchers are finding that imbalances in the gut microbiome can be linked to many diseases, especially autoimmune diseases like type I diabetes. A study called The Environmental Determinants of Diabetes in the Young (TEDDY) was formed to test what environmental factors can trigger type I diabetes in young children that are genetically at-risk for the disease.

In a study published by Diabetes Care, researchers working on the TEDDY study collected fecal samples from infants,at centers located in Finland, Sweden, Germany, Colorado, Washington state, and Georgia/Florida. The samples were collected monthly, and were tested on factors including age, sex, delivery method, early feeding, and later diet.

 The results of the study showed that young type I diabetes at-risk children have specific patterns of microbiome colonization per study site. In other words, there was a significant geographical association with diversity of gut bacteria. Finland, which has the highest incidence of type I diabetes, had  relatively low microbiome diversity and significantly higher abundances of Bacteroides and Veillonella and a lower abundance of traditional infant microbiome bacteria like  Bifidobacterium.  Interestingly, while there were intracontinental similarities between microbiomes, geography did not appear to be a dominant factor.  For example, Swedish microbiomes were more similar to those from Washington state than from Finaland..

 These results are among the first published from the TEDDY study, from which there should be significant discoveries.  For now, it appears the microbiome may play a role in the incidence of diabetes, but as is always the case, until an actual mechanism is proven it is too early to draw further conclusions.