Role of the intestine in the development of type 1 diabetes

Type 1 diabetes (T1D) is an autoimmune disease with destruction of the pancreatic beta-cells resulting in
insulin deficiency and hyperglycemia. Despite the existing insulin treatment regiments, T1D can cause severe
late complications, which results in reduced life expectancy for individuals with T1D. Also, the T1D incidence
is rising world-wide, thus preventive measures in at-risk individuals are needed. Research in this area is
complicated as the exact etiopathogenesis of T1D is still not fully understood. T1D has a complex etiology,
where both genetic and environmental factors are important. The intestinal barrier in T1D is defective, since
increased intestinal permeability, microbiota alterations as well as an intestinal inflammatory state is found
in T1D patients. The barrier-forming mucus layer has not been thoroughly examined in T1D but
phosphatidylcholines (PC) seem to have a protective hydrophobic function in the mucus layer. A gluten-free
diet in utero in Non-Obese Diabetic (NOD) mice has been found to improve the jejunal villus-to-crypt (V:C)
ratio and reduce the diabetes incidence. These results provide basis for initiating this PhD study.
This PhD thesis contains two separate manuscripts: a review (Chapter 1) and a mouse study (Chapter 2).
In the review, we thoroughly examined the literature related to T1D and intestinal permeability. The major
output of the review were extensive tables creating an overview of studies examining T1D-related intestinal
permeability experiments in the categories: in vivo permeability, ex vivo permeability, zonulin, molecular
permeability and blood markers. The tables show that the intestinal permeability is increased in T1D in both
human and animal studies. However, the choice of methodology is important and the results can be difficult
to interpret. In intervention studies using animal models of T1D, diabetes-alleviation and decreased
permeability were positively related and vice versa.
The mouse study thoroughly examined several factors of the intestinal barrier function comparing NOD to
C57BL/6 mice in three pre-diabetic ages. In jejunum, an age-dependent activation of innate pattern
recognition receptors was found in isolated epithelial cells. These receptors were chosen from enriched T1Drelated
functional annotation terms derived from transcriptomics data. These were, however, not
accompanied by alterations in intestinal permeability nor signs of enteropathy or reduced mucus production.
Signs of decreased short-chain fatty acid (SCFA) production in cecal microbiota were found. This discovery
was based on specific bacteria differences driving an altering β-diversity. Furthermore, several PC species
were reduced in the colonic mucus layer, which to some degree also was observed in plasma together with
signs of β-oxidation. Lastly, through a T1D genome-wide association study (GWAS), no apparent genetic
predisposition to increased intestinal permeability was found in genes from three relevant Kyoto
Encyclopedia of Genes and Genomes (KEGG) maps.
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In conclusion, the PhD thesis sheds light on the importance of the intestine in the development of T1D. The
review showed that the intestinal permeability is increased in human and animal T1D, the GWAS suggested
no genetic predisposition to increased intestinal permeability in human T1D and the key findings in the
animal study were an age-dependent activation of innate pattern recognition receptors and reduced PC
species levels in the colonic mucus layer.