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Inflammatory tendencies and overproduction of IL-17 in the colon of young NOD mice are counteracted with diet change.

Alam C, Valkonen S, Palagani V, Jalava J, Eerola E, Hänninen A - Diabetes (2010)

Bottom Line: Young NOD mice showed a disturbed tolerance to autologous commensal bacteria.Increased numbers of activated CD4 T-cells and (CD11b(+)CD11c(+)) dendritic cells and elevated levels of Th17 cells and IL23 mRNA were moreover observed in colon lamina propria.Disrupted immune tolerance in the distal intestine may influence peritoneal cell pools and B-cell-mediated activation of diabetogenic T-cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Microbiology and Immunology, University of Turku, Turku, Finland.

ABSTRACT

Objective: Dietary factors influence diabetes development in the NOD mouse. Diet affects the composition of microbiota in the distal intestine, which may subsequently influence intestinal immune homeostasis. However, the specific effects of antidiabetogenic diets on gut immunity and the explicit associations between intestinal immune disruption and type 1 diabetes onset remain unclear.

Research design and methods: Gut microbiota of NOD mice fed a conventional diet or ProSobee formula were compared using gas chromatography. Colonic lamina propria immune cells were characterized in terms of activation markers, cytokine mRNA and Th17 and Foxp3(+) T-cell numbers, using real-time PCR and flow cytometry. Activation of diabetogenic CD4 T-cells by purified B-cells was assessed in both groups. Immune tolerance to autologous commensal bacteria was evaluated in vitro using thymidine-incorporation tests.

Results: Young NOD mice showed a disturbed tolerance to autologous commensal bacteria. Increased numbers of activated CD4 T-cells and (CD11b(+)CD11c(+)) dendritic cells and elevated levels of Th17 cells and IL23 mRNA were moreover observed in colon lamina propria. These phenomena were abolished when mice were fed an antidiabetogenic diet. The antidiabetogenic diet also altered the expression levels of costimulatory molecules and the capacity of peritoneal B-cells to induce insulin-specific CD4 T-cell proliferation.

Conclusions: Young NOD mice show signs of subclinical colitis, but the symptoms are alleviated by a diet change to an antidiabetogenic diet. Disrupted immune tolerance in the distal intestine may influence peritoneal cell pools and B-cell-mediated activation of diabetogenic T-cells.

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Colon epithelial layer hyperplasia in young NOD mice. A (Left): Representative images of longitudinal sections of colons from NOD (left) and BALB/c (right) mice at 4.5 (top), 6 (middle), and 10 weeks (bottom), stained with hematoxylin and eosin. The black line represents the thickness of the NOD colon at 4.5 weeks. (Right): Average crypt depth ± SEM for 4.5-, 6-, and 10-week-old BALB/c and NOD mice. n = 4 per group. B: Longitudinal sections of colons from NOD, BALB/c, and PNOD mice at 4.5 weeks of age. The black lines represent the thickness of the NOD colon at this age. The bar graph to the right represents average crypt depths ± SEM for NOD, BALB/c, and PNOD at 4.5 weeks. n = 4 per group. ***P < 0.001 using Student t test (A) or one-way ANOVA and Bonferroni post hoc test (B).
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Figure 2: Colon epithelial layer hyperplasia in young NOD mice. A (Left): Representative images of longitudinal sections of colons from NOD (left) and BALB/c (right) mice at 4.5 (top), 6 (middle), and 10 weeks (bottom), stained with hematoxylin and eosin. The black line represents the thickness of the NOD colon at 4.5 weeks. (Right): Average crypt depth ± SEM for 4.5-, 6-, and 10-week-old BALB/c and NOD mice. n = 4 per group. B: Longitudinal sections of colons from NOD, BALB/c, and PNOD mice at 4.5 weeks of age. The black lines represent the thickness of the NOD colon at this age. The bar graph to the right represents average crypt depths ± SEM for NOD, BALB/c, and PNOD at 4.5 weeks. n = 4 per group. ***P < 0.001 using Student t test (A) or one-way ANOVA and Bonferroni post hoc test (B).

Mentions: A histological analysis of the colon revealed hyperplasia in the epithelial crypts of NOD mice at 4.5 weeks of age. The crypts of NOD colons were thicker than the crypts of BALB/c colons at 4.5 weeks of age. However, the epithelial layer of the NOD colon was thinner at 6 and 9 weeks of age compared with 4.5 weeks. This was in contrast to the development of BALB/c colons, where a gradual age-dependent thickening was observed (Fig. 2A). There were no other signs of frank colitis, such as leukocyte infiltration, goblet cell loss, or crypt abscesses in the NOD colons. When NOD mice were kept on ProSobee diet, hyperplasia was not observed at 4.5 weeks of age, indicating that the occurrence of hyperplasia in newly weaned NOD mice is diet related (Fig. 2B).


Inflammatory tendencies and overproduction of IL-17 in the colon of young NOD mice are counteracted with diet change.

Alam C, Valkonen S, Palagani V, Jalava J, Eerola E, Hänninen A - Diabetes (2010)

Colon epithelial layer hyperplasia in young NOD mice. A (Left): Representative images of longitudinal sections of colons from NOD (left) and BALB/c (right) mice at 4.5 (top), 6 (middle), and 10 weeks (bottom), stained with hematoxylin and eosin. The black line represents the thickness of the NOD colon at 4.5 weeks. (Right): Average crypt depth ± SEM for 4.5-, 6-, and 10-week-old BALB/c and NOD mice. n = 4 per group. B: Longitudinal sections of colons from NOD, BALB/c, and PNOD mice at 4.5 weeks of age. The black lines represent the thickness of the NOD colon at this age. The bar graph to the right represents average crypt depths ± SEM for NOD, BALB/c, and PNOD at 4.5 weeks. n = 4 per group. ***P < 0.001 using Student t test (A) or one-way ANOVA and Bonferroni post hoc test (B).
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Figure 2: Colon epithelial layer hyperplasia in young NOD mice. A (Left): Representative images of longitudinal sections of colons from NOD (left) and BALB/c (right) mice at 4.5 (top), 6 (middle), and 10 weeks (bottom), stained with hematoxylin and eosin. The black line represents the thickness of the NOD colon at 4.5 weeks. (Right): Average crypt depth ± SEM for 4.5-, 6-, and 10-week-old BALB/c and NOD mice. n = 4 per group. B: Longitudinal sections of colons from NOD, BALB/c, and PNOD mice at 4.5 weeks of age. The black lines represent the thickness of the NOD colon at this age. The bar graph to the right represents average crypt depths ± SEM for NOD, BALB/c, and PNOD at 4.5 weeks. n = 4 per group. ***P < 0.001 using Student t test (A) or one-way ANOVA and Bonferroni post hoc test (B).
Mentions: A histological analysis of the colon revealed hyperplasia in the epithelial crypts of NOD mice at 4.5 weeks of age. The crypts of NOD colons were thicker than the crypts of BALB/c colons at 4.5 weeks of age. However, the epithelial layer of the NOD colon was thinner at 6 and 9 weeks of age compared with 4.5 weeks. This was in contrast to the development of BALB/c colons, where a gradual age-dependent thickening was observed (Fig. 2A). There were no other signs of frank colitis, such as leukocyte infiltration, goblet cell loss, or crypt abscesses in the NOD colons. When NOD mice were kept on ProSobee diet, hyperplasia was not observed at 4.5 weeks of age, indicating that the occurrence of hyperplasia in newly weaned NOD mice is diet related (Fig. 2B).

Bottom Line: Young NOD mice showed a disturbed tolerance to autologous commensal bacteria.Increased numbers of activated CD4 T-cells and (CD11b(+)CD11c(+)) dendritic cells and elevated levels of Th17 cells and IL23 mRNA were moreover observed in colon lamina propria.Disrupted immune tolerance in the distal intestine may influence peritoneal cell pools and B-cell-mediated activation of diabetogenic T-cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Microbiology and Immunology, University of Turku, Turku, Finland.

ABSTRACT

Objective: Dietary factors influence diabetes development in the NOD mouse. Diet affects the composition of microbiota in the distal intestine, which may subsequently influence intestinal immune homeostasis. However, the specific effects of antidiabetogenic diets on gut immunity and the explicit associations between intestinal immune disruption and type 1 diabetes onset remain unclear.

Research design and methods: Gut microbiota of NOD mice fed a conventional diet or ProSobee formula were compared using gas chromatography. Colonic lamina propria immune cells were characterized in terms of activation markers, cytokine mRNA and Th17 and Foxp3(+) T-cell numbers, using real-time PCR and flow cytometry. Activation of diabetogenic CD4 T-cells by purified B-cells was assessed in both groups. Immune tolerance to autologous commensal bacteria was evaluated in vitro using thymidine-incorporation tests.

Results: Young NOD mice showed a disturbed tolerance to autologous commensal bacteria. Increased numbers of activated CD4 T-cells and (CD11b(+)CD11c(+)) dendritic cells and elevated levels of Th17 cells and IL23 mRNA were moreover observed in colon lamina propria. These phenomena were abolished when mice were fed an antidiabetogenic diet. The antidiabetogenic diet also altered the expression levels of costimulatory molecules and the capacity of peritoneal B-cells to induce insulin-specific CD4 T-cell proliferation.

Conclusions: Young NOD mice show signs of subclinical colitis, but the symptoms are alleviated by a diet change to an antidiabetogenic diet. Disrupted immune tolerance in the distal intestine may influence peritoneal cell pools and B-cell-mediated activation of diabetogenic T-cells.

Show MeSH
Related in: MedlinePlus