Changes in Intestinal Microbiota Are Associated with Islet Function in a Mouse Model of Dietary Vitamin A Deficiency

Abstract

Aims. The underlying mechanisms involved in Vitamin A- (VA-) related changes in glucose metabolic disorders remain unclear. Recent evidence suggests that intestinal microbiota is closely linked to the metabolic syndrome. Here, we explored whether and how intestinal microbiota affects glucose homeostasis in VA-deficient diet-fed mice. Methods. Six-week-old male C57BL/6 mice were randomly placed on either a VA-sufficient (VAS) or VA-deficient (VAD) diet for 10 weeks. Subsequently, a subclass of the VAD diet-fed mice was switched to a VA-deficient rescued (VADR) diet for an additional 8 weeks. The glucose metabolic phenotypes of the mice were assessed using glucose tolerance tests and immunohistochemistry staining. Changes in intestinal microbiota were assessed using 16S gene sequencing. The intestinal morphology, intestinal permeability, and inflammatory response activation signaling pathway were assessed using histological staining, western blots, quantitative-PCR, and enzyme-linked immunosorbent assays. Results. VAD diet-fed mice displayed reduction of tissue VA levels, increased area under the curve (AUC) of glucose challenge, reduced glucose-stimulated insulin secretion, and loss of β cell mass. Redundancy analysis showed intestinal microbiota diversity was significantly associated with AUC of glucose challenge and β cell mass. VAD diet-driven changes in intestinal microbiota followed the inflammatory response with increased intestinal permeability and higher mRNA expression of intestinal inflammatory cytokines through nuclear factor-κB signaling pathway activation. Reintroduction of dietary VA to VAD diet-fed mice restored tissue VA levels, endocrine hormone profiles, and inflammatory response, which are similar to those observed following VAS-controlled changes in intestinal microbiota. Conclusions. We found intestinal microbiota effect islet function via controlling intestinal inflammatory phenotype in VAD diet-fed mice. Intestinal microbiota influences could be considered as an additional mechanism for the effect of endocrine function in a VAD diet-driven mouse model.

Role and Mechanism of Vitamin A Metabolism in the Pathophysiology of Parkinson’s Disease

“…Vitamin A deficiency may alter gut microbiota. In mice, vitamin A deficiency reduces bacteria from the Bacteroidetes phylum (to whom B. fragilis belongs to), which altered energy homeostasis of the animal overall, and resulted in glucose and insulin intolerance [181,182]. Young rats from vitamin A deficient mothers also displayed a dysbiosis of colonic mucosal microbiota, in particular with reduced members of the Bacteriodetes phylum [183].…”

Serum Retinal and Retinoic Acid Predict the Development of Type 2 Diabetes Mellitus in Korean Subjects with Impaired Fasting Glucose from the KCPS-II Cohort

“…RA signaling during endocrine specification appears to play a critical role in directing pancreatic endocrine cell fate and function [ 29 , 30 ]. Mice fed a VA-deficient diet for eight weeks had reduced β-cell mass, glucose-stimulated insulin secretion, and tissue VA levels [ 31 ]. Interestingly, VA-deficient rats treated with VA replication or RA recovered glucose-induced insulin secretion in perifused islets [ 32 ].…”

The Pathogenesis of Diabetes

“…In addition to the regulation of communication between organs, many other factors affect glucose homeostasis, such as the proportion of metabolites produced by intestinal flora [ 46 ] and gender [ 47 ]. Numerous studies have shown that intestinal dysbiosis reduces the synthesis of short-chain fatty acids, which, in turn, disturbs the intestinal barrier integrity [ 48 , 49 ], pancreatic β cell proliferation [ 50 ], and insulin biosynthesis [ 51 ]. Intestinal dysbiosis also influences the production of other metabolites, including branched amino acids, trimethylamine, primary bile acids, and secondary bile acids, disrupting glucose homeostasis [ 52 , 53 ].…”