Gut microbiota-astrocyte axis: new insights into age-related cognitive decline

Abstract

With the rapidly aging human population, age-related cognitive decline and dementia are becoming increasingly prevalent worldwide. Aging is considered the main risk factor for cognitive decline and acts through alterations in the composition of the gut microbiota, microbial metabolites, and the functions of astrocytes. The microbiota-gut-brain axis has been the focus of multiple studies and is closely associated with cognitive function. This article provides a comprehensive review of the specific changes that occur in the composition of the gut microbiota and microbial metabolites in older individuals and discusses how the aging of astrocytes and reactive astrocytosis are closely related to age-related cognitive decline and neurodegenerative diseases. This article also summarizes the gut microbiota components that affect astrocyte function, mainly through the vagus nerve, immune responses, circadian rhythms, and microbial metabolites. Finally, this article summarizes the mechanism by which the gut microbiota-astrocyte axis plays a role in Alzheimer's and Parkinson's diseases. Our findings have revealed the critical role of the microbiota-astrocyte axis in age-related cognitive decline, aiding in a deeper understanding of potential gut microbiome-based adjuvant therapy strategies for this condition.

Figure 1

Communication pathways between the gut and brain. The brain–gut axis is a two-way exchange pathway between the gut and brain. The microbiota of the intestine can have a considerable influence on host brain functions and behaviors via multiple pathways, including neuronal, neuroimmune, and neuroendocrine pathways. Created with BioRender.com. BBB: Blood–brain barrier; ECCs: entero-chromaffin cells; EECs: entero-endocrine cells.

Figure 2

Alterations in A1-like reactive astrocytes and astrocyte senescence in the aging brain in age-related cognitive decline. In the aging brain, two subtypes of astrocytes are associated with cognitive impairment, A1-like reactive astrocytes and astrosenescent astrocytes. A1-like reactive astrocytes can cause neuronal death and pathological protein accumulation by releasing complement components, toxic factors, and a series of inflammation mediators such as cytokines, and increasing APOE expression. Astrocyte senescence upregulates the expression of proinflammatory cytokines p16, SA-β-gal, and SASP, decreases mitochondrial mass, and alters the mitochondrial dynamics of cortical neurons, resulting in neuronal death and pathological protein accumulation. The decrease in AQP4 channels in astroglial end-feet contributes to diminished clearance abilities and pathological protein Aβ accumulation. Created with BioRender.com. APOE: Apolipoprotein E; AQP4: aquaporin 4; Aβ: amyloid-beta; FFAs: free fatty acids; IL-6: interleukin 6; SASP: senescence-associated secretory phenotype; SA-β-gal: senescence-associated beta-galactosidase; TGF-β: transforming growth factor β; TNF-α: tumor necrosis factor alpha; VLCPCs: very-long-chain fatty acid acyl chains.

Figure 3

Potential influence of gut microbial metabolites on astrocyte phenotype. SCFAs, produced in the colon, can cross the apical membrane of colonocytes through MCT1 and SMCT1 to generate energy for colonocytes by entering the citric acid cycle. Unconsumed SCFAs in colonocytes can be transported through MCT5 and MCT4 in the basolateral membrane to enter the portal blood. Then, SCFAs can cross the BBB to be transported into astrocytes through MCT1 and MCT4. SCFAs rescue glutamate-delivery deficits in astrocyte-neuron coupling by increasing GS in astrocytes. SCFAs are also involved in regulating neuroinflammation in the CNS by decreasing astrocyte activation. IFN-I in the CNS acts in combination with metabolites derived from dietary tryptophan, such as indole, I3S, IPA, and IAID, released by the gut flora to activate AhR signaling in astrocytes and suppress CNS inflammation. The tryptophan metabolite I3S can also activate microglial AHR. AHR-controlled microglial VEGF-B and TGF-α activate Flt-1 and Erb-B1 in astrocytes to modulate CNS inflammation. QUIN has been reported to exert cytotoxic effects on astrocytes and induce astrocytic activation. KYNA can exert neuroprotective effects by inhibiting astrocyte activation. TUDCA significantly decreases the activation of glial cells and ameliorates memory deficits. DCA increases the permeability of the BBB by disrupting tight junctions. TMA is transported through the portal vein to the liver, where it is oxidized to TMAO via FMO. TMAO can activate astrocytes and promote astrocyte senescence and thereby contribute to neuroinflammation. In addition, physiologically relevant concentrations of TMAO can improve BBB integrity by increasing levels of the tight junction regulator annexin A1. Created with BioRender.com. AHR: Aryl hydrocarbon receptor; AQP4: aquaporin 4; BBB: blood–brain barrier; CNS: central nervous system; DCA: deoxycholic acid; EECs: entero-endocrine cells; Erb-B1: epidermal growth factor receptor, EGFR; FFA: free fatty acids; Flt-1: vascular endothelial growth factor receptor 1; FMO: flavin-containing monooxygenase; Gln: glutamine; Glu: glutamate; GS: glutamine synthetase; I3S: indoxyl-3-sulfate; IA: indole-3-acrylic acid; IAA: indole-3-acetic acid; IAID: indole-3-aldehyde; IAId: indole-3-aldehyde; IFN-I: type I interferon; ILA: indole-3-lactic acid; IPA: indole propionic acid; KYNA: kynurenic acid; LCA: lithocholic acid; MCT: monocarboxylate transporter; QUIN: quinolinic acid; SASP: senescence-associated secretory phenotype; SA-β-gal: senescence-associated beta-galactosidase; SCFA: short-chain fatty acid; SMCT: sodium-dependent monocarboxylate transporter; TMA: trimethylamine; TMAO: trimethylamine N-oxide; TUDCA: tauroursodeoxycholic acid; VEGF: vascular endothelial growth factor; VLCPC: very-long-chain fatty acid acyl chains.

Figure 4

Timeline showing the roles of gut microbiota–astrocyte axis described in the literature. Data were from the followed studies (Track, 1980; Hopkins et al., 2001; Caracciolo et al., 2014; Leung and Thuret, 2015; Shultz et al., 2015; Rothhammer et al., 2016; Zhang et al., 2019; Margineanu et al., 2020; Brunt et al., 2021; Sanmarco et al., 2021; Xie et al., 2022; Sun et al., 2023). CircHIPK2: Circular RNA homeodomain-interacting protein kinase-2; LAMP1: lysosomal-associated membrane protein 1; SCFAs: short-chain fatty acids; TMAO: trimethylamine N-oxide; TRAIL: tumor necrotic factor-related apoptosis inducing ligand.