Loss of Diurnal Oscillatory Rhythms in Gut Microbiota Correlates with Changes in Circulating Metabolites in Type 2 Diabetic db/db Mice

Abstract

Our hypothesis is that diabetes leads to loss of diurnal oscillatory rhythms in gut microbiota altering circulating metabolites. We performed an observational study where we compared diurnal changes of the gut microbiota with temporal changes of plasma metabolites. Metadata analysis from bacterial DNA from fecal pellets collected from 10-month old control (db/m) and type 2 diabetic (db/db) mice every 4 h for a 24-h period was used for prediction analysis. Blood plasma was collected at a day and night time points and was used for untargeted global metabolomic analysis. Feeding and activity behaviors were recorded. Our results show that while diabetic mice exhibited feeding and activity behavior similar to control mice, they exhibited a loss of diurnal oscillations in bacteria of the genus Akkermansia, Bifidobacterium, Allobaculum, Oscillospira and a phase shift in the oscillations of g.Prevotella, proteobacteria, and actinobacteria. Analysis of the circulating metabolites showed alterations in the diurnal pattern of metabolic pathways where bacteria have been implicated, such as the histidine, betaine, and methionine/cysteine pathway, mitochondrial function and the urea cycle. Functional analysis of the differential microbes revealed that during the day, when mice are asleep, the microbes of diabetic mice were enriched in processing carbon and pyruvate metabolic pathways instead of xenobiotic degradation as was observed for control mice. Altogether, our study suggests that diabetes led to loss of rhythmic oscillations of many gut microbiota with possible implications for temporal regulation of host metabolic pathways.

Mouse model of metformin-induced diarrhea

“…Because the gastrointestinal microbiome modulator improved gastrointestinal intolerance in human patients treated with metformin, the modification of enterobacterial flora has been proposed to be a cause of the gastrointestinal intolerance 14. In addition, in mice, the genetic background, including obesity and diabetic phenotypes (such as db/db mice), and metformin treatment are known to induce the modification of enterobacterial flora 15–18. Therefore, we examined the differences in enterobacterial flora in metformin-induced diarrhea.…”

Metabolic Defects Caused by High-Fat Diet Modify Disease Risk through Inflammatory and Amyloidogenic Pathways in a Mouse Model of Alzheimer’s Disease

“…Multiple experimental and clinical studies have pointed out that changes in gut microbiome composition contribute to the progression of metabolic and neurodegeneration diseases via altered microbial metabolites, immune activation, and bacterial amyloids [ 54 , 55 , 56 , 57 ]. The role of the gut microbiome in neurodegenerative diseases is beginning to be elucidated.…”

Insulin signal transduction is impaired in the type 2 diabetic retina

“…Work showed that intermittent fasting altered the gut microbiome in the db/db mice, which was associated with less retinal damage [4]. Additional studies also showed that diabetes in the db/db mice led to reduced diurnal oscillatory rhythms, which altered metabolic pathways [5]. Other groups reported increased permeability and inflammatory mediators in the retina of db/db mice, which was reduced by C1q/tumor necrosis factor (TNF) related protein 9 [6].…”