Type 1 diabetes

Gut microbiome provides clues to T1D pathogenesis

Australian children with islet autoimmunity who progress to types 1 diabetes have been shown to have gut microbiome dysbiosis, increased small intestinal permeability and reduced circulating short-chain fatty acid (SCFA) levels.

Prof Couper

The same changes were not apparent in children with islet autoimmunity who did not progress to type 1 diabetes, according to Professor Jenny Couper whose research presented at #2018 ADA was honoured as an ADA Presidents’ Select Abstract.

The findings suggest there may be a role for interventions such as bespoke probiotics or prebiotics to head off or delay the development of type 1 diabetes.

Professor Couper, head of paediatrics at the University of Adelaide, presented the findings from 18 children with islet autoimmunity, 29 with recent onset diabetes and 41 sibling or unrelated controls.

The children, five to 20 years of age, underwent 16S rRNA sequencing of stool samples, blood tests for intestinal permeability, SCFA, islet autoantibodies, HbA1c and oral glucose tolerance tests, HLA typing and a food frequency questionnaire and were followed for a median of 18 months.

The study found lower observed richness in the microbiome of children with multiple islet autoantibodies and type 1 diabetes compared to sibling and unrelated controls, which did not persist when corrected for age.

“However in the children progressing to type 1 diabetes, compared to non-progressors, there was reduced alpha-diversity or observed richness over time.”

Pair wise comparisons of beta-diversity in the gut microbiome found significant differences between children with type 1 diabetes and controls and those with multiple autoantibodies and controls.

The study found children with type 1 diabetes and multiple autoantibodies had a reduced abundance of anti-inflammatory bacteria such as Butyricimonas paravirosa and Prevotella species compared to controls.

Progressors to type 1 diabetes also had significantly lower abundance of the anti-inflammatory bacteria Oscillibacter valericigenes compared to non-progressors.

Professor Couper said macro and micronutrients or dietary fibre intake did not explain the differences in gut bacteria between the groups.

And while they were able to show a direct relationship between alpha diversity of the microbiome and plasma acetate levels, a SCFA product of the microbiota, plasma acetate could not discriminate between type 1 diabetes, islet autoimmunity or control groups.

“So there is no apparent prospect of this being a biomarker,” she said.

Intestinal permeability using the gold standard lactulose to rhamnose ratio was higher in type 1 diabetes than controls and higher in progressors than non-progressors over time. Lower alpha diversity also predicted higher intestinal permeability across all the groups.

Professor Couper said the findings were the first described gut dysbiosis in Southern Hemisphere children with multiple islet autoantibodies and type 1 diabetes.

“Most of the work in the gut microbiome has been in Finland where there is a very high incidence of type 1 diabetes and comparing with some countries around it but also some work in older children in the US and Europe.”

“We’ve shown some similarities but also some specific differences which you would expect because our gut bacteria are different in different countries. So it is quite important to have Southern Hemisphere or certainly Australian data.”

She said the often-slow progression from multiple islet autoantibodies to types 1 diabetes in older children meant there was quite a lot of time to intervene.

“But it is not just going to be a case of going down the road to get probiotics or prebiotics – it’s going to have to be quite specific and quite bespoke for the type of organisms we are seeing.”

“The type of interventions we’d be thinking about would be prebiotics such as butyrated starches – certainly shown experimentally to be effective to prevent type 1 diabetes – and also to look at a bespoke probiotic as well. Altering the children’s diets looks like it may be disappointing.”

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