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

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

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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • 6-ethyl-24-norcholane-3,7,23-triol-23 sulfate
  • Bile Acids and Salts
  • Gpbar1 protein, mouse
  • Receptors, G-Protein-Coupled