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Effects of a germ-free environment on gut immune regulation and diabetes progression in non-obese diabetic (NOD) mice

Alam, C.; Bittoun, E.; Bhagwat, D.; Valkonen, S.; Saari, A.; Jaakkola, U.; Eerola, E.; Huovinen, P.; H�nninen, A.

Authors

E. Bittoun

D. Bhagwat

S. Valkonen

A. Saari

U. Jaakkola

E. Eerola

P. Huovinen

A. H�nninen



Abstract

Aims/hypothesis
Microbial factors influence the development of diabetes in NOD mice. Studies in germ-free animals have revealed important roles of microbiota in the regulation of Th17 and forkhead box P3 (FOXP3)(+) T regulatory (Treg) activation in the intestine. However, the effects of intestinal microbiota in immune regulation and diabetes development in NOD mice are still poorly understood.
Methods
A colony of germ-free NOD mice was established to evaluate the effects of intestinal microbiota on regulatory immunity in the gut, and on the development of insulitis and diabetes in NOD mice.
Results
Diabetes developed in roughly equal numbers in germ-free and specific pathogen-free NOD mice. Insulitis was accentuated in germ-free NOD mice; yet insulin preservation was unaltered. Germ-free NOD mice showed increased levels of Il17 (also known as Il17a) mRNA in the colon, and of Th17 and Th1 cells in the mesenteric and pancreatic lymph nodes, while Foxp3 mRNA and FOXP3(+) Tregs were reduced. In the islet infiltrates, FOXP3(+)CD4(+) T cells were slightly increased in germ-free mice. B cells appeared less activated in the peritoneum and were less abundant in islet infiltrates.
Conclusions/interpretation
These results indicate that lack of intestinal microbiota promotes an imbalance between Th1, Th17 and Treg differentiation in the intestine. This imbalance is associated with accelerated insulitis, but intact recruitment of FOXP3(+) Tregs into islets, suggesting: (1) a microbial dependence of local induction of Treg in the gut and draining lymph nodes; but (2) a potentially compensatory function of naturally occurring Tregs in the islets, which may help control diabetogenic T cells.

Journal Article Type Article
Acceptance Date Feb 1, 2011
Online Publication Date Mar 5, 2011
Publication Date 2011-06
Deposit Date May 26, 2022
Journal Diabetologia
Print ISSN 0012-186X
Publisher Springer
Peer Reviewed Peer Reviewed
Volume 54
Pages 1398-1406
DOI https://doi.org/10.1007/s00125-011-2097-5
Keywords B cells, Germ-free, Gut immunity, Insulitis, NOD mouse, T regulatory cells
Public URL http://researchrepository.napier.ac.uk/Output/2869982