A new study suggests that microbiome remodeling is a mechanism behind age-related cognitive decline, with one particular bacterial species identified as the likely culprit. In mice, antibiotics seem to reverse this effect [1].
The gut-brain axis and the microbiome
Memory decline is a common and debilitating feature of aging, but its mechanisms remain poorly understood. The hippocampus, a brain region essential for forming, storing, and retrieving memories, gradually loses its ability to encode new information with age, and this is not fully explained by changes within the brain itself.
In recent years, the gut microbiome has emerged as a surprising factor in brain function. Several studies have shown that the microbiome changes with age and that transferring gut microbes from old animals to young ones could worsen cognition [2]. However, the anatomical and molecular pathways connecting intestinal bacteria to memory processing were largely undefined. In a new study published in Nature, researchers from Stanford University Medical Center offer an intriguing potential explanation.
I’ll give you my bacteria if you give me yours
The authors co-housed young and aged mice for one month. Co-housing in mice leads to microbial transfer, so the young mice acquire an “old-like” microbiome [3]. They then tested cognition using the novel object recognition (NOR) task, which measures short-term memory, and the Barnes maze, a spatial learning and memory test.
The performance of young mice co-housed with old mice was impaired on both tests. Importantly, physical frailty and exploratory behavior were unchanged, meaning that the mice were not just less active; they specifically could not form or retrieve memories as well. The effect was seen in both sexes and across mice from different vendors.
A series of experiments ruled out social effects. For instance, co-housing old and young mice under germ-free conditions did not impair cognition in the latter. Fecal microbiota transplantation (FMT) from aged donors into young germ-free mice recapitulated the cognitive impairment without any co-housing, directly implicating the microbiome. Germ-free mice showed delayed cognitive decline compared to conventionally colonized mice, still performing normally at 18 months.
Ablating the aged microbiome with broad-spectrum antibiotics before or during co-housing prevented the cognitive deficit. Strikingly, even administering antibiotics after the cognitive deficit developed reversed it, both in co-housed young mice and in naturally aged mice. All the results pointed to a microbial influence rather than social stress or aging per se as the cause of the transmissible cognitive decline.
Looking for the species and the mechanism
The researchers then tried to understand which gut bacteria are particularly responsible for this cognitive decline. Parabacteroides goldsteinii emerged as the top-ranked candidate. Its abundance increased with age, it was efficiently transmitted by co-housing and FMT, and germ-free or antibiotic-treated young mice monocolonized with P. goldsteinii developed cognitive impairment.
Features like neurogenesis and spine density were all normal in co-housed young mice; they changed in naturally aged mice but were not transmissible via the microbiome. However, RNA-seq revealed that immediate-early gene (IEG) expression – genes that are rapidly activated when neurons fire, such as Fos – was blunted in co-housed young mice, aged mice, and germ-free recipients of aged microbiota.
FOS staining confirmed reduced neuronal activation in the hippocampus in response to novel object exposure. Colonization with P. goldsteinii alone similarly suppressed hippocampal FOS responses. These results suggest that microbiome specifically impairs the brain’s ability to activate neurons in response to new experiences, rather than causing structural brain damage.
The research stained several brain regions for FOS and zeroed in on the nucleus tractus solitarius (NTS), a structure in the brainstem that serves as the primary receiving station for signals from the vagus nerve – the longest cranial nerve in the body, which innervates most of the visceral organs, including the entire gastrointestinal tract. By ablating and activating various neuronal subtypes, the researchers determined that it’s the vagus nerve that malfunctions and not spinal nerves, some of whom also transmit to the NTS.
Stimulating the vagus nerve restored cognition, confirming the vagal pathway’s importance. The cognitive deficit, however, was not caused by reduced gut hormone production. Something else was suppressing vagal function, so, the researchers searched for a different mechanism.
Medium-chain fatty acids are the key
The liquid that surrounded P. goldsteinii and contained its secreted molecules (its supernatant) was sufficient to impair cognition. Metabolomics helped attribute this effect to the medium-chain fatty acids (MCFAs) that P. goldsteinii produces. Intestinal MCFA levels increased with age in conventionally colonized but not germ-free or antibiotic-treated mice and were transmissible by co-housing.
The authors then screened viruses that infect bacteria (bacteriophages) for their ability to restore memory in aged mice. One phage, φPDS1, which is known to target a different bacterial genus, consistently improved cognition in aged mice. Apparently, the phage works not by killing P. goldsteinii but by altering its gene expression in ways that reduce MCFA production.
GPR84 is a cell-surface receptor known to be activated by MCFAs. GPR84-deficient mice were resistant to cognitive decline, establishing GPR84 as the receptor through which MCFAs exert their effects on cognition. However, single-cell RNA sequencing of intestinal immune cells showed that Gpr84 is expressed exclusively by myeloid cells, such as macrophages, monocytes, and neutrophils, as opposed to microglia, the brain’s resident immune cells, or lymphocytes. This key distinction means that the inflammatory process driving cognitive decline is happening outside the brain.
Finally, the authors showed that the inflammatory cytokines TNF and IL-1β are the downstream effectors of GPR84 signaling that actually impair vagal function. Exogenous TNF or IL-1β was sufficient to impair cognition, and this was reversible by vagal stimulation. Deleting the IL-1β receptor specifically on vagal neurons blocked MCFA’s effect on memory, and forcing those neurons to fire anyway was sufficient to bypass the inflammatory blockade.
“Although memory loss is common with age, it affects people differently and at different ages,” said Christoph Thaiss, Ph.D., assistant professor of pathology. “We wanted to understand why some very old people remain cognitively sharp while other people see significant declines beginning in their 50s or 60s. What we learned is that the timeline of memory decline is not hardwired; it’s actively modulated in the body, and the gastrointestinal tract is a critical regulator of this process.”
“The degree of reversibility of age-related cognitive decline in the animals just by altering gut-brain communication was a surprise,” she added. “This study indicates that we can enhance memory formation and brain activity by changing the composition of the gastrointestinal tract – a kind of remote control for the brain.”
Literature
[1] Cox, T.O., Devason, A.S., de Araujo, A. et al. (2026). Intestinal interoceptive dysfunction drives age-associated cognitive decline. Nature
[2] D’Amato, A., Di Cesare Mannelli, L., Lucarini, E., Man, A. L., Le Gall, G., Branca, J. J., … & Nicoletti, C. (2020). Faecal microbiota transplant from aged donor mice affects spatial learning and memory via modulating hippocampal synaptic plasticity-and neurotransmission-related proteins in young recipients. Microbiome, 8(1), 140.
[3] Ridaura, V. K., Faith, J. J., Rey, F. E., Cheng, J., Duncan, A. E., Kau, A. L., … & Gordon, J. I. (2013). Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science, 341(6150), 1241214.
View the article at lifespan.io
