Microbial-derived metabolites as a risk factor of age-related cognitive decline and dementia

Abstract

A consequence of our progressively ageing global population is the increasing prevalence of worldwide age-related cognitive decline and dementia. In the absence of effective therapeutic interventions, identifying risk factors associated with cognitive decline becomes increasingly vital. Novel perspectives suggest that a dynamic bidirectional communication system between the gut, its microbiome, and the central nervous system, commonly referred to as the microbiota-gut-brain axis, may be a contributing factor for cognitive health and disease. However, the exact mechanisms remain undefined. Microbial-derived metabolites produced in the gut can cross the intestinal epithelial barrier, enter systemic circulation and trigger physiological responses both directly and indirectly affecting the central nervous system and its functions. Dysregulation of this system (i.e., dysbiosis) can modulate cytotoxic metabolite production, promote neuroinflammation and negatively impact cognition. In this review, we explore critical connections between microbial-derived metabolites (secondary bile acids, trimethylamine-N-oxide (TMAO), tryptophan derivatives and others) and their influence upon cognitive function and neurodegenerative disorders, with a particular interest in their less-explored role as risk factors of cognitive decline.

Mapping trends and hotspot regarding gastrointestinal microbiome and neuroscience: A bibliometric analysis of global research (2002–2022)

“…In addition, numerous experts in microbiology and neuroscience from Ireland, China, the United States, and other countries have studied the characteristics of the gastrointestinal microbiota in health and neuroscience disease states, the connection between pathological function and neuroscience disease, and other topics. These professionals, who serve as a foundation for the creation and publication of papers in this area, include Cryan JF, Dinan TG, Clarke G, Stanton C, O’Mahony SM, Bastiaanssen TFS, Yang C, Xie P, Bailey MT, Green SJ, Keshavarzian A, and Forsyth CB ( Clarke et al, 2013 ; Dinan et al, 2014 ; Mayer et al, 2014 ; Stilling et al, 2015 ; Tarr et al, 2015 ; Dodiya et al, 2020 ; Joers et al, 2020 ; Li et al, 2020 ; van de Wouw et al, 2020 ; Frausto et al, 2021 ; Zheng et al, 2021 ; Connell et al, 2022 ; Teng et al, 2022 ). It is worth noting that the citations of articles published in the United States rank first, followed by Ireland and China.…”

Faecal microbiota transplantation from Alzheimer’s participants induces impairments in neurogenesis and cognitive behaviours in rats

“…Importantly, we found that an impairment in pattern separation, which is reported in AD (Ally et al, 2013; Parizkova et al, 2020) and is associated with indicators of Alzheimer’s pathology such as increased cortical beta-amyloid burden (Webb et al, 2020), medial temporal lobe tau (Leal et al, 2019), cerebrospinal fluid levels of phosphorylated tau (Berron et al, 2019), and apolipoprotein E genotype (Sinha et al, 2018), was transferred via the gut microbiota to manifest as a behavioural impairment in rats. While alterations in the gut microbiome have been associated with hippocampal-dependent cognition during ageing (Connell et al, 2022), there is no published evidence to date of the contribution of gut microbiota to this AHN-reliant behaviour. We found that AD-FMT also induced an impairment in long-term spatial memory, which is also associated with AHN levels (Drapeau et al, 2003), and supports a recent intra-species report using a transfer of faecal sample from the 5xFAD mouse model of AD into a WT recipient (Kim et al, 2021).…”

Adolescent kratom exposure affects cognitive behaviours and brain metabolite profiles in Sprague-Dawley rats

“…The tryptophan metabolism is balanced by two distinct enzymes: tryptophan hydroxylase and indoleamine 2, 3-dioxygenase (IDO), which act in the serotonin and kynurenine pathways, respectively ( Jayamohanan et al, 2019 ; Connell et al, 2022 ). A shift in tryptophan metabolism to the kynurenine pathway reduces the availability of tryptophan in the serotonin pathway and subsequently affects the serotonin level which can be confirmed by detecting its final metabolite, 5-hydroxyindoleacetic acid (5-HIAA, Connell et al, 2022 ; Jayamohanan et al, 2019 ). In the present study, 5-HIAA was upregulated in animals treated with morphine and mitragynine but downregulated in animals treated with LKD.…”