1. Restructuring of the Gut Microbiome by Intermittent Fasting Prevents Retinopathy and Prolongs Survival in
- Author
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Fang-I Chu, Julia V. Busik, Qiuhong Li, Gavin Y. Oudit, Yaqian Duan, Steven D. Townsend, Caitlin Ryan, Ashay D. Bhatwadekar, Xiaoxin X. Wang, Ruli Gao, Hartmut Derendorf, Ram Prasad, Fletcher A. White, Raghavendra G. Mirmira, Emil G. Moldovan, Mervin C. Yoder, Moshe Levi, Daniel Morton, Leni Moldovan, Carmella Evans-Molina, Luisa Chan, Luciano Adorini, Michael E. Boulton, Maria B. Grant, Eleni Beli, Yuanqing Yan, and Cristiano P. Vieira
- Subjects
0301 basic medicine ,Male ,Complications ,Endocrinology, Diabetes and Metabolism ,Gut flora ,Receptors, G-Protein-Coupled ,chemistry.chemical_compound ,Mice ,Feces ,0302 clinical medicine ,Intestinal mucosa ,Ganglia, Sensory ,Intermittent fasting ,Leukocytes ,Medicine ,Intestinal Mucosa ,Receptor ,biology ,Microbiota ,Fasting ,G protein-coupled bile acid receptor ,Mice, Inbred DBA ,Goblet Cells ,medicine.medical_specialty ,Colon ,Firmicutes ,Retina ,Bile Acids and Salts ,03 medical and health sciences ,Verrucomicrobia ,Diabetes mellitus ,Internal medicine ,Internal Medicine ,Humans ,Animals ,Diabetic Retinopathy ,business.industry ,Bacteroidetes ,Retinal Vessels ,Retinal ,medicine.disease ,biology.organism_classification ,Survival Analysis ,Mice, Mutant Strains ,Gastrointestinal Microbiome ,030104 developmental biology ,Endocrinology ,chemistry ,Diabetes Mellitus, Type 2 ,Microvessels ,Dysbiosis ,Glycated hemoglobin ,business ,030217 neurology & neurosurgery - Abstract
Intermittent fasting (IF) protects against the development of metabolic diseases and cancer, but whether it can prevent diabetic microvascular complications is not known. In db/db mice, we examined the impact of long-term IF on diabetic retinopathy (DR). Despite no change in glycated hemoglobin, db/db mice on the IF regimen displayed significantly longer survival and a reduction in DR end points, including acellular capillaries and leukocyte infiltration. We hypothesized that IF-mediated changes in the gut microbiota would produce beneficial metabolites and prevent the development of DR. Microbiome analysis revealed increased levels of Firmicutes and decreased Bacteroidetes and Verrucomicrobia. Compared with db/db mice on ad libitum feeding, changes in the microbiome of the db/db mice on IF were associated with increases in gut mucin, goblet cell number, villi length, and reductions in plasma peptidoglycan. Consistent with the known modulatory effects of Firmicutes on bile acid (BA) metabolism, measurement of BAs demonstrated a significant increase of tauroursodeoxycholate (TUDCA), a neuroprotective BA, in db/db on IF but not in db/db on AL feeding. TGR5, the TUDCA receptor, was found in the retinal primary ganglion cells. Expression of TGR5 did not change with IF or diabetes. However, IF reduced retinal TNF-α mRNA, which is a downstream target of TGR5 activation. Pharmacological activation of TGR5 using INT-767 prevented DR in a second diabetic mouse model. These findings support the concept that IF prevents DR by restructuring the microbiota toward species producing TUDCA and subsequent retinal protection by TGR5 activation.
- Published
- 2018