A trio of recent studies are uncovering compelling new insights into the role gut bacteria play in the development of type 2 diabetes (T2D). From discovering higher than average bacterial loads in tissue samples from diabetes patients, to a newly discovered bacterial metabolite that could be harnessed for a novel therapeutic treatment, scientists are continually discovering novel ways the microbes inside us can influence our health.

The metastudy

There is good evidence the gut microbiome plays a role in glucose metabolism, insulin sensitivity and overall energy homeostasis. However, scientists have been unable to home in on what specific bacteria can be associated with positive metabolic outcomes in regards to T2D.

A team from Oregon State University recently attempted to systematically analyze a large volume of recent studies investigating links between T2D and the gut microbiome. The subsequent meta-analysis, published in the Lancet journal EBioMedicine, initially describes the current state of T2D microbiome literature as “chaotic”, before summarizing the most reliable and robust research.

The meta-analysis examined 42 human studies looking at associations between gut bacteria and T2D. Despite finding no singular consensus implicating a particular bacteria with the disease, the research did identify several recurring observations.

Bacteroides and Bifidobacterium were the two bacterial genera most frequently identified as potentially protective against T2D. Bifidobacterium in particular was reported in all but one study to be high in healthy subjects and low in T2D patients.

Ruminococcus, Fusobacterium, and Blautia, on the other hand, were more consistently detected in higher levels in T2D patients. The researchers do note there are conflicting results regarding all three of these genera.

The Lactobacillus genus presented the most discordant results according to this meta-analysis. The study hypothesizes the effect of this bacteria may be highly species specific, with some species such as L. acidophilus, L. gasseri and L. salivarius found in high levels in T2D patients, while others such as L. amylovorus, seen in low levels.

Positive effects from Lactobacillus in regards to T2D were seen in 11 studies, however, most of those combined the bacteria with another genera. The most common combination was with Bifidobacterium, leading the researchers to suspect the two microbes may work in some kind of synergistic way to protect against T2D.

The ultimate conclusion of the metastudy is that T2D microbiome research is too heterogeneous, meaning there is most likely no one-size-fits-all solution. Instead, the conclusion suggests we may need to move toward developing, “precision/personalized medicine selecting anti-diabetics and probiotics for a given patient based on the combination of her/his mammalian and microbial genomes.”

It spreads from the gut

A compelling new hypothesis raised in a recently published study is suggesting gut bacteria may indeed be somewhat responsible for the onset of T2D. But, it could be the result of bacteria crossing the intestinal barrier into other tissue in the body. This process is called bacterial translocation.

Location, location location … Beyond knowing the names of bacteria, their location is key to understanding how gut microbes influence host metabolism.

“Location, location location … Beyond knowing the names of bacteria, their location is key to understanding how gut microbes influence host metabolism,” says Fernando Anhe, first author on the new study.

The research, published in the prestigious journal Nature Metabolism, examined tissue from 40 obese subjects. Half of the subjects had normal blood glucose levels, while the other half had T2D. Plasma, liver and three different types of fat tissue were sampled.

The results intriguingly revealed notably different bacterial signatures between the diabetics and non-diabetics. The highest bacterial loads in diabetic subjects were found in liver and omental adipose tissue. Omental tissue is a particular form of fat tissue connecting the transverse colon and the stomach.

“Our findings suggest that in people suffering from severe obesity, bacteria or fragments of bacteria are associated with the development of Type 2 diabetes,” explains lead author André Marette. “We know that the intestinal barrier is more permeable in obese patients. Our hypothesis is that living bacteria and bacterial fragments cross this barrier and set off an inflammatory process that ultimately prevents insulin from doing its job, which is to regulate blood glucose levels by acting on metabolic tissues.”

A closer genetic analysis of the bacteria detected in the tissue samples revealed it most likely came from the intestine. This finding solidifies the hypothesis the microbial load seen in the tissue samples is a result of bacterial translocation.

The bacterial treatment

One of the fundamental ways microbes affect our health is through the production of metabolites. The vast population of bacteria living in our gut produce substantial volumes of metabolites that can influence everything from our immune system to our mental health.

A new collaborative study from researchers at McGill University, Kyoto University and INSERM/University of Paris set out to uncover which gut bacteria metabolites could help those with either type 1 or type 2 diabetes.

Using a process called metabolomic profiling the research team examined blood samples from 148 adults to ascertain biomarkers that could be associated with diabetes. One particular molecule quickly stood out, a metabolite called 4-Cresol.

"We found that 4-Cresol was of real interest,” says first author François Brial. “This product of the metabolism of the intestinal flora appears to be a marker of resistance to diabetes. In particular, concentrations of 4-Cresol in the blood are lower in diabetic patients than in non-diabetic individuals.”

Subsequent animal tests revealed non-toxic, low doses of 4-Cresol increased proliferation of pancreatic beta cells, the cells that secrete insulin, and improved glycemic control while reducing signs of obesity.

4-Cresol is synthesized by a number of bacteria in the gut, as well as being a product of the colonic fermentation of tyrosine and phenylalanine. The molecule is also naturally found in low levels in a number of foods and drinks, including tomatoes, asparagus, dairy products, coffee, and tea.

"While there is currently a lack of therapies to stimulate pancreatic beta cell proliferation and improve beta cell function in order to restore insulin secretion, these results are particularly encouraging,” says Dominique Gauguier, senior author of the new study. “Moreover, they confirm the impact of the intestinal flora on human health, demonstrating the beneficial role of a metabolite produced by intestinal bacteria, and opening up new therapeutic avenues in diabetes, obesity and hepatic steatosis."

So, although at some point in the future 4-Cresol may be directly deployed as a therapeutic treatment for T2D, it is these kinds of metabolic studies that are finally shedding light on exactly how our gut bacteria may be influencing our health.

Gauguier and his research team are more interested, in the short term, in applying the method demonstrated in the diabetes study to other diseases. The goal is to investigate what metabolites can be directly associated with specific diseases, allowing for therapeutic treatments to be deployed, either through direct administration of these molecules, or by modulating the microbiome in targeted fashion to enable the production of these helpful metabolites.

"Our goal is to develop therapeutic approaches that allow fine modulation of the intestinal flora, by promoting the proliferation of 'good' bacteria whose function is well understood and thus the production of bacterial metabolites at therapeutic doses," says Gauguier.

The microbiome metastudy was published in the journal EBioMedicine.

The bacterial translocation study was published in the journal Nature Metabolism.

The 4-Cresol study was published in the journal Cell Reports.

Sources: McMaster University, McGill University