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Disease and treatment

Harnessing bacteria to fight type 2 diabetes

Being overweight is a key risk factor for type 2 diabetes, but they are not the same thing. Many overweight people have a well-functioning metabolism and no signs of type 2 diabetes. Researchers have examined metabolic tissues from obese people and have found clear traces of bacteria. It is too early to say whether too many of the wrong bacteria or too few of the right bacteria in these tissues lead to type 2 diabetes. The researchers think that both are probably causal factors, and they hope to be able to help the body on the right path by promoting the good ones.

Intense research and discussion have focused on the gut microbiota in recent years. These bacterial communities seem to be able to control both our mood and health, and the right composition is essential to good health. Now this discussion takes on an extra dimension after researchers have found clear traces of the bacteria outside the intestines – in adipose tissues, liver and blood plasma.

“We analysed the genetic signatures in five types of biological tissue and found clear traces of bacteria beyond the intestinal barrier, such as in adipose tissues. We do not know for certain how they end up there and whether they are live bacteria or bacterial fragments, but the profiles of people with and without type 2 diabetes clearly differ, so we are sure that they play an important role and therefore hope that we can improve people’s health by influencing their profiles,” explains a main author, Benjamin Anderschou Holbech Jensen, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen.

Chronic metabolic inflammation

The hope underpinning the new research was to discover more about the visceral fat that accumulates around the body’s organs, which is considered one of the most important risk factors for developing type 2 diabetes. The researchers therefore decided to analyse the microbial profile of plasma, liver and three distinct adipose tissues of people with a body mass index (BMI) of about 50.

“Remarkably, even though these people were all severely obese, not all had serious metabolic illness, such as type 2 diabetes. We therefore wanted to determine whether the bacterial composition in this group differs – not in the intestines as previously studied but in adipose tissue and organs,” says Benjamin Anderschou Holbech Jensen.

One theory is that the intestinal bacteria play a significant role in the chronic inflammation among people with metabolic disorders and that this may be caused by the path taken by various bacterial components from the gut to the bloodstream and on to the tissue and organs.

“This is not the first time that researchers have searched for bacteria in adipose tissue, but doubts have been raised about the results of previous studies, because contamination with environmental bacteria or stool samples could not be completely refuted. In the new study, we therefore had to take extra precautions in our genetic analysis, which we based on 16S rRNA analysis in the various fat depots and organs,” explains Benjamin Anderschou Holbech Jensen.

The researchers had to control for the contamination of environmental samples at major steps in the analysis. This enabled them to achieve a gene count that was about 1000-fold higher in tissue samples than in negative controls. They could therefore be very confident that the data were reliable and that they reflected the actual microbial content of the tissues rather than the contamination.

“We found clear differences between tissue depots and in disease status. People with type 2 diabetes had several traces of gram-negative enterobacteria, such as Escherichia coli and Shigella spp. in blood plasma and in mesenteric adipose tissue, and a general increase in opportunistic pathogens and bacteria associated with hospital-acquired infections. Some of these findings support what has been found in intestinal samples in the past, thus suggesting that these bacteria have a potential role as type 2 diabetes develops,” says Benjamin Anderschou Holbech Jensen.

A possible paradigm shift

The new study also provides an analysis of differences in microbial signatures between various organs and tissues. For example, the relative prevalence of bacterial deposits was higher for tissues along the anatomical route from the gut to the liver and relatively lower in the subcutaneous adipose tissue and in the peripheral blood system. Nevertheless, the researchers warn against overinterpreting the results.

“We cannot yet answer whether gut-residing immune cells or dendritic cells carry and pass on living bacteria or just fragments of the bacteria through the blood to the various tissues. However, regardless of the answer, the study provides a new and unique insight into the microbiome of the tissues and a microbial signature among overweight people and with or without diabetes,” explains Benjamin Anderschou Holbech Jensen.

The new study may therefore prove to lead to precisely the paradigm shift in microbiome research that this field needs. The molecular mechanisms for the accumulation of fat around our organs are still not fully known, nor is it fully understood how this affects glucose homeostasis.

“It is widely accepted that the inflammatory state of the fat around the organs and in the liver triggers the development of diabetes, but the cause remains elusive. For us, the new discovery of bacteria or bacterial fragments may be a possible explanation for some of that effect, but it is still too early to conclude whether there is a relationship,” says Benjamin Anderschou Holbech Jensen.

Potential for future treatments

However, previous studies on the effect of the bacterial composition in the intestinal system on metabolism have indicated an apparent relationship but also that this is far from simple. For example, previous studies have indicated that the same bacteria can have opposing effects –depending on whether a person’s diet is low in or high in fibre.

“Right now, our theory is that the difference between the fat depots of metabolically healthy and unhealthy individuals results from either too few of the good bacteria or too many of the bad bacteria – perhaps most likely a mix of the two. If we can clarify this relationship, this will provide good opportunities to treat for metabolic diseases, including type 2 diabetes – by influencing bacterial composition,” explains Benjamin Anderschou Holbech Jensen.

Both the literature and ongoing studies indicate that specific bacteria and/or their fragments can affect the host’s immune system both negatively and positively.

“This effect then cascades onward to the metabolism, so with this increased insight into this field we can contribute to developing interventions that either directly affect the immune system or alternatively change the composition of the commensal gut bacteria to affect our health – both metabolically but also in relation to general intestinal diseases. So this offers an exciting potential for future treatment,” says Benjamin Anderschou Holbech Jensen.

Type 2 diabetes influences bacterial tissue compartmentalisation in human obesity” has been published in Nature Metabolism. In 2017, the Novo Nordisk Foundation awarded a grant to Benjamin Anderschou Holbech Jensen for the project A Novel Oral Combination Therapy Targeting the Gut Microbiome to Alleviate Insulin Resistance and Type 2 Diabetes–linked Aortic Valve Stenosis.

Benjamin Anderschou Holbech Jensen
International Researcher
In the molecular understanding of metabolic diseases a major gap exists between basic genetic and microbiome discoveries and their impact on physiology and the potential for clinical translation. The Hansen Group aims to bridge this gap by bringing together genomics discovery and epidemiology, culminating in a physiological and clinical understanding of genomics in metabolism. To study the role of selected genetic variants in human metabolism, we perform physiology and intervention studies based on recruit-by-genotype principles. We also investigate families and populations with extreme metabolic phenotypes and perform physiology and intervention studies in selected individuals with specific microbiome signatures. Finally, we investigate targeted clinical management of carriers of selected high-impact variations in the human genome.