Researchers Find Blocking Gut Metabolite Prevents Cognitive Decline

Scientists find a metabolite secreted by gut bacteria in aged mice that can be blocked to prevent cognitive deficits.

Key Points:

A molecule secreted by gut bacteria in aged mice called IAA (isoamylamine) hinders cognition in young mice.
Inhibiting IAA prevents cognitive deficits in aged mice.
IAA promotes inflammation and cell death by stimulating microglia cells — the brains resident immune cells.

Molecules secreted by the bacteria living in our gut play a crucial role in the progression of disease and could even accelerate the aging process. Still, it is unclear how these small molecules called metabolites can alter our behavior, including our ability to think.

In a new study published in Cell Host and Microbe, Teng and colleagues from the University of Louisville in Kentucky show that the gut bacteria metabolite IAA is associated with age-related cognitive decline in mice. Young mice fed IAA exhibit deficits in learning, memory, and willingness to explore, which are behavioral markers of cognition. On the other hand, by eliminating the bacteria that produce IAA in aged mice, these cognitive features are improved. Furthermore, blocking IAA with a molecule called S100p1-G prevents learning and memory deficits in aged mice.

IAA Hinders Cognition & Promotes Neurodegeneration

To ascertain the deleterious effects of IAA on cognition, Teng and colleagues fed young mice IAA and subjected them to a series of cognitive test. The results showed that IAA induced memory and learning loss, and reduced the willingness of the young mice to explore new paths. On the flip side, aged mice were given a treatment that reduces IAA. This improved learning and memory, and restored the willingness of the aged mice to explore new environments (usually the aged mice stick to familiar paths).

(Teng et al., 2022 | *Cell Host and Microbe*) **Gut Bacteria Metabolite IAA Hinders Cognition.** (B) Schematic of Morris water maze showing mouse insertion points and location of platform. Mice were trained to find the platform in a pool of water, then the platform was removed. A shorter path length to the previous location of the platform indicates improved learning and memory. (C) Untreated young mice (PBS-gray) took a shorter path than young mice given IAA (IAA-magenta) and aged mice given an IAA reducer (Phage^TSD-27-orange) took a shorter path than untreated aged mice (PBS-blue). (D) Quantification of path lengths indicating that IAA hinders cognition.

IAA is a metabolite secreted from a family of gut bacteria that increase in abundance with age (Ruminococcaceae). A molecule called S100p1-G can specifically bind and inhibit IAA. Teng and colleagues hypothesized that S100p1-G could block IAA, resulting in improved cognition in aged mice. Indeed, the Louisville researchers found that treating aged mice with S100p1-G recovered their learning and memory deficits.

Microglia cells play a key role in memory retention by affecting neuron survival. They help keep the brain pristine and healthy, responding to harmful material, sometimes by activating specific genes. One of these genes, known to increase with aging, called S100A8 can become harmful if chronically activated because it promotes inflammation and may contribute to cognitive dysfunction and neurodegeneration. Teng and colleagues demonstrated that IAA is needed to activate S100A8 in microglia cells and cause cell death, suggesting that IAA drives the neurodegneration associated with cognitive decline via microglia cells.

S100p1 Therapy or Probiotics?

Teng and colleagues used S100p1-G to block IAA and improve cognition in aged mice. S100p1-G is a molecule called an oligonucleotide which can be modified to target specific genes or molecules. There have been 13 FDA-approved oligonucleotide therapies, one of which is similar to S100p1-G, as it binds directly to the target molecule (aptamer) and blocks it. This could mean that S100p1-G has the potential of acting as a therapy for cognitive decline in the future. However, since this option is not yet available, probiotics may be the next best choice.

Human and animal studies have shown that gut bacteria can affect cognition, especially in older adults. Therefore, it may be possible to improve cognition or alleviate other age-related conditions like inflammation by changing our gut bacteria composition. This can be achieved by taking probiotics, which are strains of bacteria that can be consumed to alter gut bacteria composition. A recent randomized controlled trial showed that treatment with the probiotics Bifidobacterium bifidum and Bifidobacterium longum for 12 weeks improved cognition in older adults. In a review study, looking at 30 studies, the authors concluded that probiotics can improve cognition. Most of the studies in the review used multiple strains of probiotics, but Lactobacillus plantarum improved cognition as a single strain in several studies. A months supply of probiotic supplements containing these strains can cost anywhere from $20 to $100.