Intestinal interoceptive dysfunction drives age-associated cognitive decline [cohousing]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE307836 | GEO | 2025/11/22
REPOSITORIES: GEO
Dataset's files
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Project description:Aging is accompanied by declining memory function, necessitating the development of effective countermeasures1. Brain- extrinsic factors influencing cognitive decline, including the intestinal microbiome, have emerged as attractive targets for peripheral interventions2-6, but the underlying mechanisms remain largely unclear. Here, by charting a high-resolution map of microbiome aging and its functional consequences throughout the lifespan of mice, we identify a mechanism whereby age- associated inhibition of gut-brain signalling results in impaired novelty-induced neuronal activation in the hippocampus and loss of memory encoding. Specifically, gut bacteria producing medium-chain fatty acids, such as Parabacteroides goldsteinii, accumulate over the lifespan and drive intestinal myeloid cell inflammation through GPR84 signalling. As a result, the function of afferent gut-innervating vagal neurons is impaired, the interoceptive signal received by the brain is weakened, and hippocampal function declines. We leverage this pathway to define interventions that restore memory in aged mice, such as phage targeting of Parabacteroides, GPR84 inhibition, and restoration of vagal activity. These findings indicate a key role for interoceptive signalling from the gastrointestinal tract in regulating brain aging and suggest that interoceptomimetics that stimulate gut-brain communication may counteract age-associated cognitive decline.
2025-11-22 | GSE307834 | GEO
Project description:Aging is accompanied by declining memory function, necessitating the development of effective countermeasures1. Brain- extrinsic factors influencing cognitive decline, including the intestinal microbiome, have emerged as attractive targets for peripheral interventions2-6, but the underlying mechanisms remain largely unclear. Here, by charting a high-resolution map of microbiome aging and its functional consequences throughout the lifespan of mice, we identify a mechanism whereby age- associated inhibition of gut-brain signalling results in impaired novelty-induced neuronal activation in the hippocampus and loss of memory encoding. Specifically, gut bacteria producing medium-chain fatty acids, such as Parabacteroides goldsteinii, accumulate over the lifespan and drive intestinal myeloid cell inflammation through GPR84 signalling. As a result, the function of afferent gut-innervating vagal neurons is impaired, the interoceptive signal received by the brain is weakened, and hippocampal function declines. We leverage this pathway to define interventions that restore memory in aged mice, such as phage targeting of Parabacteroides, GPR84 inhibition, and restoration of vagal activity. These findings indicate a key role for interoceptive signalling from the gastrointestinal tract in regulating brain aging and suggest that interoceptomimetics that stimulate gut-brain communication may counteract age-associated cognitive decline.
2025-11-22 | GSE307838 | GEO
Project description:Background and Aims Interoceptive impacts on the brain triggered by changes in the intestinal microbial ecosystem influence mood-related behaviors such as anxiety and depression. Although changes in the gut microbiome can be driven by genetic mutations in the host, how alterations in the gut microbiome caused by host genetic variations affect behavioral outcomes is not fully understood. To investigate how host genetic variation affects interoceptive responses, we analyzed the gut microbiota and investigated gut–brain interactions in sirtuin 3 (Sirt3)-knockout (KO) mice. Methods We evaluated the composition of the gut microbiome and behavior in Sirt3-KO and wild-type (WT) mice. To distinguish microbiome-driven effects from genetic influences, we conducted cohousing experiments and compared results with heterozygous littermates. Region-specific changes in gene expression in the brain were identified by transcriptomic profiling of the limbic system. We also analyzed metabolites in the nucleus of the solitary tract (NTS) generated by gut microbiome–vagal signaling. The role of the vagus nerve in the gut-brain axis was further examined through vagotomy, alongside comparative choline analysis in both mood disorder patients and mice. Results Mood-related neurobehavioral changes and alterations in synaptic plasticity-related genes in the amygdala and bed nucleus of the stria terminalis (BNST) of Sirt3-KO mice appeared to be dependent on gut microbiome composition. Elevated plasma choline levels in both mood disorder patients and Sirt3-KO mice, together with reduced neurotransmitter-related metabolites (e.g., -aminobutyric acid [GABA] in the NTS), suggested that externalizing behaviors in Sirt3-KO mice are mediated by vagus nerve-dependent gut–brain axis signaling. Consistent with this, vagotomy abolished these changes, including GABA in the NTS, as well as alterations in synaptic plasticity in the amygdala and BNST. Conclusions Our findings suggest the novel finding that an altered gut microbiome caused by a host genetic change, namely a Sirt3 deficiency, is sensed in the NTS of the brain via the vagus nerve, leading to externalizing behaviors.
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Project description:The mammalian gastrointestinal tract contains a diverse ecosystem of microbial species collectively making up the gut microbiome. Emerging evidence highlights a critical relationship between gut microbiota and neurocognitive development. Consumption of unhealthy yet palatable dietary factors associated with obesity and metabolic dysfunction (e.g., saturated fat, added sugar) produces microbiota dysbiosis and negatively impacts neurocognitive function, particularly when consumed during early life developmental periods. Here we explore whether excessive early life consumption of added sugars negatively impacts neurocognitive development via the gut microbiome. Using a rodent model of habitual sugar-sweetened beverage (SSB) consumption during the adolescent stage of development, we first show that excessive early life sugar intake impairs hippocampal-dependent memory function when tested during adulthood while preserving other neurocognitive domains. Gut microbiome genomic sequencing analyses reveal that early life SSB consumption alters the abundance of various bacterial populations, including elevations in operational taxonomic units within the genus Parabacteroides (P. distasonis and P. johnsonii) whose abundance negatively correlated with memory task performance. Additional results reveal that in vivo Parabacteroides enrichment of cultured P. distasonis and P. johnsonii bacterial species in adolescent rats severely impairs memory function during adulthood. Hippocampus transcriptome analyses identify gene expression alterations in neurotransmitter synaptic signaling, intracellular kinase signaling, metabolic function, neurodegenerative disease, and dopaminergic synaptic signaling-associated pathways as potential mechanisms linking microbiome outcomes with memory impairment. Collectively these results identify microbiota dysbiosis as a mechanism through which early life unhealthy dietary patterns negatively impact neurocognitive outcomes.
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Project description:Aging is associated with declining immunity and inflammation as well as alterations in the gut microbiome with a decrease of beneficial microbes and increase in pathogenic ones. The aim of this study was to investigate aging associated gut microbiome in relation to immunologic and metabolic profile in a non-human primate (NHP) model. 12 old (age>18 years) and 4 young (age 3-6 years) Rhesus macaques were included in this study. Immune cell subsets were characterized in PBMC by flow cytometry and plasma cytokines levels were determined by bead based multiplex cytokine analysis. Stool samples were collected by ileal loop and investigated for microbiome analysis by shotgun metagenomics. Serum, gut microbial lysate and microbe-free fecal extract were subjected to metabolomic analysis by mass-spectrometry. Our results showed that the old animals exhibited higher inflammatory biomarkers in plasma and lower CD4 T cells with altered distribution of naïve and memory T cell maturation subsets. The gut microbiome in old animals had higher abundance of Archaeal and Proteobacterial species and lower Firmicutes than the young. Significant enrichment of metabolites that contribute to inflammatory and cytotoxic pathways was observed in serum and feces of old animals compared to the young. We conclude that aging NHP undergo immunosenescence and age associated alterations in the gut microbiome that has a distinct metabolic profile.
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Project description:Exercise exerts a wide range of beneficial effects for healthy physiology. However, the mechanisms regulating an individual's motivation to engage in physical activity remain incompletely understood. An important factor stimulating the engagement in both competitive and recreational exercise is the motivating pleasure derived from prolonged physical activity, which is triggered by exercise induced neurochemical changes in the brain. Here, we report on the discovery of a gut brain connection in mice that enhances exercise performance by augmenting dopamine signalling during physical activity. We find that microbiome dependent production of endocannabinoid metabolites in the gut stimulates the activity of TRPV1 expressing sensory neurons and thereby elevates dopamine levels in the ventral striatum during exercise. Stimulation of this pathway improves running performance, whereas microbiome depletion, peripheral endocannabinoid receptor inhibition, ablation of spinal afferent neurons or dopamine blockade abrogate exercise capacity. These findings indicate that the rewarding properties of exercise are influenced by gut derived interoceptive circuits and provide a microbiome dependent explanation for interindividual variability in exercise performance. Our study also suggests that interoceptomimetic molecules that stimulate the transmission of gut derived signals to the brain may enhance the motivation for exercise.
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