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Diabetes. 2018 Sep;67(9):1867-1879. doi: 10.2337/db18-0158. Epub 2018 Apr 30.

Restructuring of the Gut Microbiome by Intermittent Fasting Prevents Retinopathy and Prolongs Survival in db/db Mice.

Author information

1
Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN.
2
Department of Neurosurgery, The University of Texas Health Science Center at Houston, Houston, TX.
3
Department of Surgery, Indiana University School of Medicine, Indianapolis, IN.
4
Department of Ophthalmology and Visual Sciences, University of Alabama, Birmingham, AL.
5
Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX.
6
Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN.
7
Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN.
8
Department of Anesthesia, Indiana University School of Medicine, Indianapolis, IN.
9
Department of Chemistry, Vanderbilt University, Nashville, TN.
10
Second Genome, Inc., San Francisco, CA.
11
Northeastern University, Boston, MA.
12
Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, CA.
13
Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
14
Department of Pharmaceutics, University of Florida, Gainesville, FL.
15
Intercept Pharmaceuticals, New York, NY.
16
Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, DC.
17
Department of Medicine, Indiana University School of Medicine, Indianapolis, IN.
18
Department of Ophthalmology, University of Florida, Gainesville, FL.
19
Department of Physiology, Michigan State University, East Lansing, MI.
20
Department of Ophthalmology and Visual Sciences, University of Alabama, Birmingham, AL mariagrant@uabmc.edu.

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.

PMID:
29712667
PMCID:
PMC6110320
[Available on 2019-09-01]
DOI:
10.2337/db18-0158
[Indexed for MEDLINE]

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