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

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 mice, we examined the impact of long-term IF on diabetic retinopathy (DR). Despite no change in glycated hemoglobin, 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 mice on ad libitum feeding, changes in the microbiome of the 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 on IF but not in 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.

Lysosomes Mediate Benefits of Intermittent Fasting in Cardiometabolic Disease: The Janitor Is the Undercover Boss

“…Interestingly, intermittent fasting regimens have been found to alter the gut microbiome as a mechanism for driving beneficial effects in models of retinopathy in db/db mice, a genetic model of obesity and diabetes (23); as well as for induction of beige fat biogenesis and reversing obesity-induced diabetes (115). In the latter study, the molecular mechanism for the observed beige fat induction was ascribed to generation of bacterial fermentation products, acetate and lactate and the elective upregulation of monocarboxylate transporter 1 expression, which was prevented by microbiota depletion and restored by transfer of microbiota from intermittently fasted mice.…”

TGR5 receptor activation attenuates diabetic retinopathy through suppression of RhoA/ROCK signaling

“…Recently, BAs have been recognized as signaling molecules that can integrate with their receptors, including the nuclear Farnesoid X Receptor (FXR) and Bile Acid G‐Protein‐Coupled Membrane Receptor (TGR5). TGR5 is known to be expressed by multiple organ systems such as the liver, the renal system, brain, heart and the retinas . The roles for TGR5 in regulating metabolic homeostasis have been well documented.…”

Factors that affect the translation of dietary restriction into a longer life

“…The intestinal microbiome of intermittently fasted mice shows an increase in bacterial diversity and an enrichment of Bacteroidaceae, Lactobacillaceae, and Prevotellaceae . These effects on the microbiome are also associated with increases in the number of goblet cells and intestinal mucus production …”