Age-related shifts in gut microbiota contribute to cognitive decline in aged rats

Abstract

Cognitive function declines during the aging process, meanwhile, gut microbiota of the elderly changed significantly. Although previous studies have reported the effect of gut microbiota on learning and memory, all the reports were based on various artificial interventions to change the gut microbiota without involvement of aging biological characteristics. Here, we investigated the effect of aged gut microbiota on cognitive function by using fecal microbiota transplantation (FMT) from aged to young rats. Results showed that FMT impaired cognitive behavior in young recipient rats; decreased the regional homogeneity in medial prefrontal cortex and hippocampus; changed synaptic structures and decreased dendritic spines; reduced expression of brain-derived neurotrophic factor (BDNF), N-methyl-D-aspartate receptor NR1 subunit, and synaptophysin; increased expression of advanced glycation end products (AGEs) and receptor for AGEs (RAGE). All these behavioral, brain structural and functional alterations induced by FMT reflected cognitive decline. In addition, FMT increased levels of pro-inflammatory cytokines and oxidative stress in young rats, indicating that inflammation and oxidative stress may underlie gut-related cognitive decline in aging. This study provides direct evidence for the contribution of gut microbiota to the cognitive decline during normal aging and suggests that restoring microbiota homeostasis in the elderly may improve cognitive function.

Roles of Gut Microbiota in the Regulation of Hippocampal Plasticity, Inflammation, and Hippocampus-Dependent Behaviors

“…At the phylum level, FMT decreased the relative abundance of Bacteroidetes , while increasing the relative abundance of Actinobacteria . At the genus level, FMT rats showed lower levels of Prevotella , Bacteroides , Parabacteroides , and higher levels of Sutterella ( Li et al, 2020 ).…”

“…These results strongly demonstrated that gut microbiota disturbance could induce hippocampal inflammation and memory impairment. Moreover, it has been reported that when FMT is conducted, young recipient rats show impairment in cognitive behavior but an increase in expression of proinflammatory AGEs and their receptor, accompanied by changes in gut microbiota composition ( Li et al, 2020 ). Specifically, Lactobacillus plantarum decreased the expression of hippocampal TLR4 ( Mohammed et al, 2020 ).…”

Gut Microbiome and Cellular Senescence in the Context of Aging and Disease: An Emerging Frontier

“…Similarly, fecal transplant gavages from old mice (but not young mice) to germ free mice showed decreased fecal SCFAs production, and recipient animals demonstrated depressive-like behavior, impaired short-term memory, and spatial memory suggesting that aged microbiome alone is sufficient to decrease SCFAs in the host and to produce cognitive decline (Lee et al, 2020). Similarly, fecal microbiota transplantation from old to young rats impaired cognitive behavior, decreased regional homogeneity, changed synaptic structures, increased glycation-end products and enhanced oxidative and inflammatory stress in recipient young animals (Li et al, 2020b). A single-center clinical trial recommended fecal microbiota transplantation as a home therapy which could clinically benefit recovery in elderly patients with Clostridium infection (Jørgensen et al, 2020).…”

Lower human defensin 5 in elderly people compared to middle-aged is associated with differences in the intestinal microbiota composition: the DOSANCO Health Study

“…Because the intestinal microbiota composition changes along with aging [22,23], relationships between the intestinal microbiota and immunosenescence along with aging have been suggested [24]. In addition, studies using germ-free animal models showed that altered intestinal microbiota along with aging induces increased intestinal permeability, systemic inflammation, and decreased cognitive function [25,26]. Thus, it has been considered that compositional changes in the intestinal microbiota associates with the increase of disease risk along with aging.…”