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.  

The microbiome can protect against metabolic dysregulation brought on by disease

Pathogenic infections can lead to metabolic alterations that result in maladies such as cachexia, or muscle wasting.  Antibiotics can be prescribed to treat a variety of intestinal diseases or inflammatory conditions, but these agents can also disrupt the natural microbiome ecology that could perhaps provide benefits to protecting against metabolic dysregulations.  On top of this, harnessing components of the microbiome with respect disease tolerance is an avenue under continuous exploration.  Within this contextual framework, researchers from The Salk Institute for Biological Studies in La Jolla, CA investigated to see whether components of the microbiome could have a protective effect on metabolic dysregulation brought on by gut trauma and/or infection.   

To initiate the investigation, the researchers used an induced-injury model known as the dextran sulfate sodium (DSS) intestinal injury model to create symptoms associated with inflammatory bowel disease/Crohn’s disease.  DSS was applied to mice in two cohorts procured from two distinct laboratories (Jackson labs [Jax] and UC Berkeley lab [CB]).  This treatment was administered to C57 mice followed by an administration of an antibiotic cocktail of ampicillin, vancomycin, neomycin, and metronidazole (AVNM) to provide remedy for the injury.  The AVNM cocktail had no impact on the severity of DSS in mice procured from Jackson labs, whereas mice procured from UC Berkeley colonies demonstrated significantly less muscle wasting.  This observation led to the hypothesis that microbiota composition differences between both cohorts of mice drove this observation. 

After examining cecal content from AVNM-CB and AVNM-Jax mice, it was determined that the CB mice had a higher composition of E. coli compared to the Jax mice.  Building on the original supposition, the researchers then administered E. coli to Jax mice, and upon DSS administration, they demonstrated significantly less wasting pathology as compared to the vehicle control groups (i.e., DSS treatment without being administered E. coli).  The researchers further investigated whether E. coli had a protective effect in response to infectious microbes in addition to induced-DSS injury, and Jax mice were infected with Salmonella Typhimurium or Burkholderia thailandensis.  There was no significant difference in alterations in host metabolism, caloric uptake, or inflammation between E. coli-administered groups and controls.  However, the E. coli group demonstrated increased signaling in the insulin-like growth factor 1/phosphatidylinositol 3-kinase/AKT pathway in skeletal muscle, a pathway implicated in the prevention of muscle wasting.  This finding effectively provides mechanistic evidence of protecting against muscle wasting. 

Together, these findings provide additional evidence that support the microbiome’s role in tempering inflammatory disease or injury.  Further delineation of molecular pathways associated with these maladies will advance our understanding and treatment of disease.   

Helminths may provide therapeutic benefit to treat brain disorder

We’ve recently talked about a few articles that have studied helminth infection with respect to the microbiome, and how these infections could possibly confer some therapeutic benefits.  Another recent study conducted by researchers at Duke University reinforces these findings.  Autoimmune and inflammatory disorders appear to be more common in developed societies, and many have suggested that the microbiome is a major driver of these changes to our immunity.  These investigators wanted to assess whether or not helminths – which have a lot of influence on the immune system – had any effect in modulating the brain immune system in the context of living conditions and early-life infection, as this has been shown to result in neurodevelopment disorders. 

In this study, male and female rats were infected with a H. diminuta cystercircoid rat tapeworm a few weeks prior to breeding.  The rats were segregated by living conditions, housed in either dirty colonies (or “farm-like” environments), where no water or air filtration was provided) or standard clean pathogen-free laboratory conditions.  The offspring in both environments were delivered helminths, and the males were infected with E. coli early in life. 

Later in adulthood, the immune systems of the progeny animals were challenged by lipopolysaccharide (LPS) inductions in learning tests, and brains were collected shortly after to examine changes in molecular immune responses.  Exaggerated immune responses were observed in rats that were infected with E.coli early in life in the standard clean lab conditions.  Alternatively, the cohort that lived in the farm-like conditions did not experience an increase.  Both groups were infected with helminths.

To narrow down further, the researchers examined the impact of helminths alone in rats housed under clean pathogen-free laboratory conditions.  Indeed, cytokine responses in rats infected with E.coli were reduced in the animals whose mothers were infected with helminths before giving birth.  In addition to immunologic modulation, helminth infections in adult rats where shown to reduce memory deficits that are common following E. coli infection, suggesting helminth infection played a role in modulating developmental disorders due to bacterial infection. 

The helminths also had an effect on the microbiomes of the rodents.  16s rRNA sequencing revealed an average 25% shift in microbiome composition of animals infected with helminths (with a predominant shift of Bacilli to Clostridia).  Rats that were infected with E. coli early in life experienced a microbiome composition shift in adulthood, as more harmful Bacteroidetes species were found in adults.  Interestingly, this observation was not found in those who were E.coli infected but also infected with helminths, suggesting helminths prevented this composition shift. 

Overall, these findings suggest that helminths could provide therapeutic benefit, especially after infection early in life.  It will be interesting to see how this research can translate to human models, especially by narrowing down bacterial infections that could harm or benefit development.  Understanding what drives these developmental complications could have immense health benefits for the public. 

Decreased bladder microbiome diversity associated with urinary tract infections

A catheter

Urinary tract infection is one of the top healthcare-associated infections along with pneumonia and gastrointestinal illness, according to the Centers for Disease Control and Prevention. In nursing homes, UTIs are the most common type of infection and are often caused by catheters. Catheters are used to collect urine in both male and female patients. Older patients tend to need catheters for a longer period of time, putting them at higher risk for infections as it allows for the greater colonization of infectious bacteria. In an article published in the Journal of Infection, researchers in Houston, Texas experimented with a catheter coated in a specific strain of Escherichia coli to see if it would prevent catheter-associated urinary tract infections (CAUTIs) in older patients.

Eight men and two women, with a mean age of 70.9, were enrolled in the study. All but one subject received antibiotics prior to the insertion of the catheter. This antibiotic regime most likely caused a significant disruption to the existing microbial balance in the bladder. Despite the antibiotic use, the subjects’ urine still showed the presence of microorganisms after antibiotic treatment and immediately prior to catheter insertion. The study catheters that each patient received were previously colonized in the lab by E. coli strain HU2117, which is a strain that is missing an essential infection-allowing gene. By using the benign strain without this papG gene, the patients were safe from any harm. The hypothesis was that this E. coli strain would be delivered to the bladder and compete with infectious bacteria, not allowing the pathogens to colonize the bladder.

Urine samples were collected from the subjects on days 0, 1, 3, 7, 14, 21, and 28 after catheter insertion. After that, samples were collected monthly until no E. coli was detected. Three of the subjects suffered from febrile UTI, and two from urosepsis/bacteremia, another form of UTI. In these five subjects E. coli was not the predominant bacteria and was not even detected during infection in some cases. From the results of this study we can conclude that E. coli HU2117 is most-likely not effective enough in preventing other pathogenic bacteria from infecting the bladder.  

The researchers explain that the reason why their experiment had a negative result was that the E. coli did not increase bacterial diversity in the bladder. Diversity in colonization is usually what protects from infection and in this study, decreased diversity led to UTIs. This is a theme we have seen over and over again on the blog. Further informative studies could include those that help us understand the healthy and diverse microbiome of the bladder, and subsequently use that information to decrease UTI occurrence.