Vitamin A Deficiency Exacerbates Gut Microbiota Dysbiosis and Cognitive Deficits in Amyloid Precursor Protein/Presenilin 1 Transgenic Mice

Abstract

Vitamin A deficiency (VAD) plays an essential role in the pathogenesis of Alzheimer’s disease (AD). However, the specific mechanism by which VAD aggravates cognitive impairment is still unknown. At the intersection of microbiology and neuroscience, the gut-brain axis is undoubtedly contributing to the formation and function of neurological systems, but most of the previous studies have ignored the influence of gut microbiota on the cognitive function in VAD. Therefore, we assessed the effect of VAD on AD pathology and the decline of cognitive function in AD model mice and determined the role played by the intestinal microbiota in the process. Twenty 8-week-old male C57BL/6J amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice were randomly assigned to either a vitamin A normal (VAN) or VAD diet for 45 weeks. Our results show that VAD aggravated the behavioral learning and memory deficits, reduced the retinol concentration in the liver and the serum, decreased the transcription of vitamin A (VA)-related receptors and VA-related enzymes in the cortex, increased amyloid-β peptides (Aβ40 and Aβ42) in the brain and gut, upregulate the translation of beta-site APP-cleaving enzyme 1 (BACE1) and phosphorylated Tau in the cortex, and downregulate the expression of brain-derived neurotrophic factor (BDNF) and γ-aminobutyric acid (GABA) receptors in the cortex. In addition, VAD altered the composition and functionality of the fecal microbiota as exemplified by a decreased abundance of Lactobacillus and significantly different α- and β-diversity. Of note, the functional metagenomic prediction (PICRUSt analysis) indicated that GABAergic synapse and retinol metabolism decreased remarkably after VAD intervention, which was in line with the decreased expression of GABA receptors and the decreased liver and serum retinol. In summary, the present study provided valuable facts that VAD exacerbated the morphological, histopathological, molecular biological, microbiological, and behavioral impairment in the APP/PS1 transgenic mice, and the intestinal microbiota may play a key mediator role in this mechanism.

Cerebral Intraparenchymal Hemorrhage Changes Patients’ Gut Bacteria Composition and Function

“…In addition to the immune system that connects the gut and the brain, the vagus nerve provides a direct connection between the central nervous system and the enteric nervous system during gut bacteria-brain interaction, allowing the gut microbiota to send microbial signals from the gastrointestinal tract directly to the brain ( Forsythe et al., 2014 ). Metabolism is a leading mechanism for the gut microbiota to influence brain function as it is involved in numerous aspects of the metabolism process: from producing metabolic precursors for the hormones and neurotransmitter metabolism to directly producing the active metabolites, such as acetate, a short-chain fatty acid that can cross the blood-brain barrier and reduce appetite ( Frost et al., 2014 ; Lyte, 2014 ; Sharon et al., 2014 ; Jameson et al., 2020 ; Chen et al., 2021 ).…”

Research trend of microbiota-gut-brain axis in Alzheimer’s disease based on CiteSpace (2012–2021): A bibliometrics analysis of 608 articles

“…Consistent with conventional nutrition, chemicals in dietary plants influence gut microbiota ( Wang et al, 2022 ), and calorie restriction slows age-related microbiome changes in AD ( Cox et al, 2019 ). Studies also show that vitamin A deficiency exacerbates gut dysbiosis and cognitive deficits ( Chen et al, 2021 ).…”

Nutraceuticals and Physical Activity as Antidepressants: The Central Role of the Gut Microbiota

“…VA and β-carotene levels in patients with Alzheimer’s disease (AD) are significantly lower than those in normal controls, and Vitamin A deficiency (VAD) aggravates cognitive impairment and plays an essential role in the pathogenesis of AD. In order to clarify the role of gut microbiota in VAD cognitive function, Chen et al [ 144 ] analyzed the effect of a VA-deficient diet for 45 days in twenty 8-week-old male C57BL/6J amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice, showing that VAD aggravated the behavioral learning and memory deficits, and decreased the expression of GABA receptors and the liver and serum retinol. VAD increased the morphological, histopathological, molecular biological, microbiological, and behavioral impairment in the APP/PS1 transgenic mice and altered the gut microbiota’s composition and functionality, suggesting that VA has a key mediator role in this mechanism [ 144 ].…”

“…In order to clarify the role of gut microbiota in VAD cognitive function, Chen et al [ 144 ] analyzed the effect of a VA-deficient diet for 45 days in twenty 8-week-old male C57BL/6J amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice, showing that VAD aggravated the behavioral learning and memory deficits, and decreased the expression of GABA receptors and the liver and serum retinol. VAD increased the morphological, histopathological, molecular biological, microbiological, and behavioral impairment in the APP/PS1 transgenic mice and altered the gut microbiota’s composition and functionality, suggesting that VA has a key mediator role in this mechanism [ 144 ]. Furthermore, dietary carotenoids, such as β-carotene and astaxanthin, have been shown to improve immunoglobulin A expression, and the gut immune system maturation, with the consequent promotion of gut health [ 145 ].…”