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

Eleni Beli, Yuanqing Yan, Leni Moldovan, Cristiano P Vieira, Ruli Gao, Yaqian Duan, Ram Prasad, Ashay Bhatwadekar, Fletcher A White, Steven D Townsend, Luisa Chan, Caitlin N Ryan, Daniel Morton, Emil G Moldovan, Fang-I Chu, Gavin Y Oudit, Hartmut Derendorf, Luciano Adorini, Xiaoxin X Wang, Carmella Evans-MolinaRaghavendra G Mirmira, Michael E Boulton, Mervin C Yoder, Qiuhong Li, Moshe Levi, Julia V Busik, Maria B Grant

Research output: Contribution to journalArticle

38 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1867-1879
Number of pages13
JournalDiabetes
Volume67
Issue number9
DOIs
Publication statusPublished - 22 Aug 2018
Externally publishedYes

Bibliographical note

© 2018 by the American Diabetes Association.

Keywords

  • Animals
  • Bacteroidetes/growth & development
  • Bile Acids and Salts/therapeutic use
  • Colon/drug effects
  • Diabetes Mellitus, Type 2/complications
  • Diabetic Retinopathy/complications
  • Dysbiosis/complications
  • Fasting
  • Feces/microbiology
  • Firmicutes/growth & development
  • Ganglia, Sensory/drug effects
  • Gastrointestinal Microbiome/drug effects
  • Goblet Cells/drug effects
  • Intestinal Mucosa/drug effects
  • Leukocytes/drug effects
  • Male
  • Mice, Inbred DBA
  • Mice, Mutant Strains
  • Microvessels/drug effects
  • Receptors, G-Protein-Coupled/agonists
  • Retina/drug effects
  • Retinal Vessels/drug effects
  • Survival Analysis
  • Verrucomicrobia/growth & development

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  • Cite this

    Beli, E., Yan, Y., Moldovan, L., Vieira, C. P., Gao, R., Duan, Y., Prasad, R., Bhatwadekar, A., White, F. A., Townsend, S. D., Chan, L., Ryan, C. N., Morton, D., Moldovan, E. G., Chu, F-I., Oudit, G. Y., Derendorf, H., Adorini, L., Wang, X. X., ... Grant, M. B. (2018). Restructuring of the Gut Microbiome by Intermittent Fasting Prevents Retinopathy and Prolongs Survival in db/db Mice. Diabetes, 67(9), 1867-1879. https://doi.org/10.2337/db18-0158