Infant Microbiome May Influence Type 1 Diabetes Development

Liam Davenport

April 20, 2017

Environmental factors that affect the health of the intestinal microbiome, such as the widespread use of antibiotics, may underlie some of the marked differences in the prevalence of type 1 diabetes seen between neighboring populations, say Finnish researchers.

Finnish children have a much higher rate of type 1 diabetes than Russian children in the next-door region of Karelia, and a series of studies by a PhD student and colleagues indicate that this variance could be due, at least in part, to differences in the gut microbiome.

Tommi Vatanen, the PhD student from the department of computer science, Aalto University, Helsinki, Finland, and others looked at microbiome changes just before the onset of type 1 diabetes, and they also investigated the impact of antibiotic treatment on the microbiome.

Their findings have been disseminated in four previously published papers involving almost 300 infants in Finland, Estonia, and Russian Karelia, alongside data on more than 1000 Dutch adults. Now the work has been combined for the first time and published online by Aalto University on March 24 for Vatanen's doctoral thesis.

"The composition of the microflora in children's intestines was extremely different in Russian and Finnish infants," Mr Vatanen explains in an Aalto University press release.

"Finnish subjects began to develop autoantibodies to type 1 diabetes, meaning the disease's early symptoms. Russian children did not develop the antibodies at all."

For Vatanen, the findings underline the importance of the microbiome in the first years of immune-system development. He said: "In a way, intestinal microbes teach the body's immune system. If something goes wrong this early on, autoimmune diseases may become more common."

Striking Differences From Early in Life Between Finland, Estonia, and Karelia

Speaking to Medscape Medical News, Mr Vatanen said that, from very early on when they started looking at the three populations in Finland, Estonia, and Russian Karelia, they saw "a striking difference there, so then the goal was basically to find some meaningful details in those differences."

They began the project 4 years ago, at the beginning of his PhD studies. "Back then, very little was known about the infant microbiota," he explained. "This whole field has developed so quickly that we basically set out the first study to describe the dynamic nature of the developing microbiome."

The inspiration came from previous work showing that, despite sharing a geographical region and a similar genetic background, there is a steep gradient of autoimmune diseases and allergies between Finland and Russian Karelia, with, for example, the incidence of type 1 diabetes being five- to sixfold higher and the incidence of allergic diseases two- to sixfold higher in Finland.

Furthermore, the incidence of both type 1 diabetes and allergies has been increasing rapidly in Estonia, from levels similar to those in Russian Karelia up to those seen in Finland, in tandem with the modernization of lifestyles there in recent years.

To investigate further, the team conducted the DIABIMMUNE study, in which 678 infants and their families from Finland, Estonia, and Russian Karelia were recruited, with all infants followed until 3 years of age.

Collecting stool samples monthly, alongside blood samples at 3, 6, 12, 18, 24, and 36 months of age, the team initially compared the gut microbiomes in 222 infants from all three countries. They found that Bacteroides species were much less abundant in Russian children but dominated in their Finnish and Estonian counterparts. Then they showed that, in mice, Bacteroides species may be "immune silencing," interfering with normal immunological development.

Next, the team investigated 33 infants genetically predisposed to type 1 diabetes and found specific alterations in the gut microbiome that precede type 1 diabetes onset and distinguish type 1 diabetes progressors from nonprogressors.

They then conducted a study, published in Science Translational Medicine, comparing the microbiomes of infants who had never received antibiotic treatment with those who had received more than nine such treatments during the first years of life.

The microbiota of antibiotic-treated children was less diverse in terms of both bacterial species and strains, with some species often dominated by single strains.

And antibiotic-resistance genes carried on microbial chromosomes showed a peak in abundance after antibiotic treatment followed by a sharp decline, although some of these genes persisted longer after antibiotic therapy ended.

In a fourth investigation, published in Science, the researchers carried out detailed sequencing of the gut microbiomes through fecal sampling of 1135 participants from the LifeLines prospective population cohort of 165,000 Dutch adults. They also gave the participants questionnaires and found that gut microbiota composition correlated with a range of factors including diet, use of medication, red blood cell counts, fecal chromogranin A, and stool consistency. The data gave some hints for possible biomarkers of normal gut communities.

Could Use of Probiotics Prevent Type 1 Diabetes in Newborns?

Mr Vatanen was careful to point out that, from their findings, it is not possible to say that it is the increased use of antibiotics, per se, that is causing the marked differences in the incidence of type 1 diabetes between the populations they studied.

Type 1 diabetes onset is "fairly complicated, and there are multiple factors affecting it," although "gut microbiota is probably one of them," he noted.

It is going to take a lot more work and "some time" to delve further into the connection and establish whether there is any causal relationship, he emphasized, noting he and his colleagues have already set out their next project in this area.

"One really concrete plan we have next is to look for something that may be protective, so going a little bit to the other direction," he explained.

"There are some recent findings that suggest that probiotics, especially in very early life, say, the first 4 weeks, may be protective against type 1 diabetes."

These include a data set from The Environmental Determinants of Diabetes in the Young (TEDDY) project, an ongoing international study in over 7000 children. In one report published in JAMA Pediatrics in 2015, as reported by Medscape Medical News, infants who were at genetic risk of developing type 1 diabetes and who were given probiotics before 3 months of age had a 33% reduction in the risk of pancreatic beta-cell islet autoimmunity.

Mr Vatanen and colleagues are now in the process of recruiting families for a probiotic trial, where some infants will be given probiotics but others will be included as controls, in a double-blind manner.

"Then we will hopefully learn something a little bit more specific about this probiotic protective effect," he concluded.

This work was generously supported and funded by former Helsinki Doctoral Program in Computer Science (Hecse), the Juvenile Diabetes Research Foundation (JDRF), and Academy of Finland's Center of Excellence in Molecular Systems Immunology and Physiology Research (SyMMyS). No relevant financial relationships were declared.

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Vatanen T. Metagenomic Analyses of the Human Gut Microbiome Reveal Connections to the Immune System [dissertation]. Helsinki: Aalto University, 2016. Abstract

 

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