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Cristiano Pedrozo Vieira, Eleni Beli, Leni Moldovan, Yaqian Duan, Julia V Busik, Maria Grant; Long-term intermittent fasting prevents development of diabetic retinopathy and is associated with an increase in tauroursodeoxycholate (TUDCA) in db/db mice. Invest. Ophthalmol. Vis. Sci. 2018;59(9):5350. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Previously, we showed that in a type 2 diabetes model, the db/db mouse, intermittent fasting (IF) altered the gut microbiota of diabetic and control mice in different ways. As the IF resulted in increased survival and reduced diabetic retinopathy (DR), we sought to understand the mechanism by which altered bile acid metabolism by IF prevented DR.
db/db and db/m mice were maintained either on ad libitum (ad lib) or IF regimen for 8 months. The IF mice regimen was started at 2 months of age, after the development of diabetes, and included feeding for the 24 hours and fasting for the subsequent 24 hrs. Mice were euthanized at 10 months of age for sample collection. Biochemical profiles of the mouse plasma from each cohort was performed. The presence/severity of DR was assessed by enumeration of acellular capillaries and retinal inflammation assessed by enumeration of iba-1+ cells in the IF and ad lib cohorts.
Diabetic ad-lib mice had more acellular capillaries than control ad-lib (20 ± 4 vs 5±1mm-2, p<0.05) and the IF diet reduced the acellular capillaries in the db/db IF mice to 9 ± 2mm-2 (p<0.05). Iba1+ cells within the retina were increased in db/db on the ad lib regimen (40 ± 5) and reduced in the IF-treated db/db mice in feeding (21 ± 7; p<0.05) and fasting (13 ± 4; p<0.008). Significant differences in both primary and secondary bile acids were noted, with disease state and diet-related differences. Ad-lib diabetic mice had increased ratio of cholate/deoxycholate(CA/DCA), indicative of primary/ secondary bile acid conversion due to the microbiota, compared to ad-lib controls (10.19U vs. 0.89U; p<0.05) and IF normalized this ratio to similar levels as the control IF mice. Most interestingly, the conjugated secondary bile acid, TUDCA, shown to have anti-inflammatory effects in the retina, was only increased in the diabetic IF mice and not in the IF control (2.66U vs. 0.68U) indicating a link between certain species of the diabetic IF microbiota to specific secondary bile acid synthesis.
These findings support that IF provides protective effects on the diabetic retina, by reducing inflammatory cell infiltration into the retina and altering bile acid metabolism. IF reduced CA/DCA ratio and increased TUDCA, a bile acid known to provide anti- inflammatory and anti- apoptotic in the retina.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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