Gut microbiota mediates intermittent-fasting alleviation of diabetes-induced cognitive impairment

Zhigang Liu,Luanfeng Wang,Xin Jin,Qianxu Wang,Fei Yin,Jiamin Wang,Shancen Zhao,Junru Pan,Xiaoning Liu,Wentong Zhang,Lei Lan,Bo Ren,Tong Zhao,Enrique Cadenas,Xiao Di Tan ,Lin Shi,Yan Hui,Hongbo Zhang,Weiping Jia ,Chuanqi Chu,Danna Wang,Renjie Shi,Xiaoshuang Dai,Tian Yuan,Xuebo Liu

doi:10.1038/s41467-020-14676-4

Abstract

Cognitive decline is one of the complications of type 2 diabetes (T2D). Intermittent fasting (IF) is a promising dietary intervention for alleviating T2D symptoms, but its protective effect on diabetes-driven cognitive dysfunction remains elusive. Here, we find that a 28-day IF regimen for diabetic mice improves behavioral impairment via a microbiota-metabolites-brain axis: IF enhances mitochondrial biogenesis and energy metabolism gene expression in hippocampus, re-structures the gut microbiota, and improves microbial metabolites that are related to cognitive function. Moreover, strong connections are observed between IF affected genes, microbiota and metabolites, as assessed by integrative modelling. Removing gut microbiota with antibiotics partly abolishes the neuroprotective effects of IF. Administration of 3-indolepropionic acid, serotonin, short chain fatty acids or tauroursodeoxycholic acid shows a similar effect to IF in terms of improving cognitive function. Together, our study purports the microbiota-metabolites-brain axis as a mechanism that can enable therapeutic strategies against metabolism-implicated cognitive pathophysiologies.

Highlights

Cognitive decline is one of the complications of type 2 diabetes (T2D)
Whether Intermittent fasting (IF) could alleviate diabetes-related cognitive deficits and the role played by gut microbiota is still unclear, highlighting an urgent need to investigate the mechanisms underlying how IF improves cognitive function
This study has demonstrated for the first time that a 28-day IF treatment alleviated diabetes-induced cognitive impairment via a microbiota–metabolites–brain axis, benefiting from comprehensive investigations on diabetic mice behavior/synaptic structure, mitochondrial/energy metabolism-related signaling, and an integrated analysis of multi-OMICs

Summary

Introduction

Cognitive decline is one of the complications of type 2 diabetes (T2D). Intermittent fasting (IF) is a promising dietary intervention for alleviating T2D symptoms, but its protective effect on diabetes-driven cognitive dysfunction remains elusive. It is noteworthy that interindividual variation of microbiota composition and microbial metabolites, such as short-chain fatty acids (SCFAs), 3-indolepropionic acid (IPA), secondary bile acids (BAs), and serotonin (5-HT), are critically driven by the genotype, age, and dietary patterns of the host[10,12]. They are strongly linked to whole body metabolism and function and have been shown to have potential neuroprotective effects. Our findings suggest that gut microbiota/metabolites mediate the neuroprotective actions of IF on diabetes, highlighting the potential of modulating the gut microbiota as an effective intervention for metabolism-implicated neurodegenerative diseases

Methods

Results

Conclusion