How Our Gut Bugs Influence our Memory

By Dr. Austin Perlmutter

What does current research tell us about the connections between the gut microbiome and our memory?

Ancient Greek texts describe two opposing rivers running through the underworld.   Their names were Lethe and Mnemosyne. To drink from Lethe caused one to forget. Drinking from Mnemosyne allowed one to remember everything. Millennia later, we’re still fascinated by the same topic. What can we do to improve our memory? Modern science has implicated a wide variety of pathways involved in the memory process. And as research on the subject of the human microbiome expands, we’re increasingly seeing that our resident microbes may be playing a bigger role in this subject than we could have guessed.

Memory is by definition a cognitive process. This means that most of the existing research on the topic relates to our brain health and function. Extreme examples of neurological damage make it clear that our brains are needed to create, store, and recall memories. But while the brain may house the actual machinery, we now understand that influences outside the central nervous system play a major part in every part of the memory process.

As it relates to memory, the idea that what happens in our bodies affects our brains may be best described in Alzheimer’s, the prototypical disease of memory malfunction. Our risk for developing Alzheimer’s has now been strongly linked to our blood sugar levels, our weight, our blood pressure, and even our sleep habits. To further this case, we also know that our immune and endocrine systems influence our brain function and our risk for developing memory issues. And as it turns out, all of these seemingly disparate influences on our brain health interconnect with the microbiome.

In recent years we’ve seen an explosion in scientific publications discussing the microbiome—the collection of all the microbes that live on or in our bodies. Using a variety of investigative techniques, researchers have shown that these bugs, especially those that live in our intestines (the gut microbiome) play a variety of roles in our health. One area of investigation that has drawn a lot of attention is the gut-brain axis.

The idea is simple: our gut (which includes our cells as well as trillions of microbes) is in constant bidirectional communication with our brains. Though it’s easier to conceptualize our brains sending signals to our gut, it’s far more interesting to know that our gut bugs, and more specifically our gut bacteria, are transferring messages up to our brains. Data provided to our central nervous system from the microbiome are thought to influence our neurotransmitters, regulate our neurons, and even shape the structure of the brain itself.

It’s striking to realize that the bacteria in our gut are influencing our brain structure and function. It means that part of what makes us who we are is determined by the microbiome. When more specifically considering how our bugs influence our memory, something else becomes apparent. Our microbiome may play a key role in many of the best-described pathways involved in memory.

It has been recently demonstrated that memory, and more specifically forgetting, may be controlled by the actions of microglia. Animal research over the last decade has shown that microglia prune away weak connections between neurons. This enhances the signal-to-noise ratio for the remaining connections. As stated in a 2020 paper in The New England Journal of Medicine, this breakthrough may open the door to immunity-based memory therapies.

Microglia have also been implicated in other memory-related processes. For example, we know that an area of the brain called the hippocampus is critical for memory consolidation. People with damage to the hippocampus have major issues forming new memories, and damage to the hippocampus is one of the hallmark features of Alzheimer’s disease. Notably, the hippocampus is one of the few regions of the brain thought to grow new neurons across the lifespan. But activated microglia seem to disable this process through the release of inflammatory molecules.

If microglia are in fact key stewards of our memory, we need ask how to preserve their healthy function. To this end, it’s very important to recognize that microglial dysfunction is thought to be a common factor in a variety of brain diseases ranging from depression to Alzheimer’s. This interesting fact seems in part a reflection of a property of microglia: they appear to act as translators of immune messages from the body into the brain. In pathologic conditions like depression and Alzheimer’s disease, microglia create problems in part by sensing and amplifying inflammatory signals from the rest of the body. Moving upstream, if microglia are pathologically activated by systemic inflammation, we have to ask what regulates systemic inflammation. Here again, the gut and the microbiome take center stage.

It’s been established that up to 70% of our immune system resides in and around our gut. These immune cells are in close proximity with the gut microbiome and engage in a continuous exchange of data with these bugs. Indeed, the healthy function of the gut immune system is dependent on the gut microbiome. In addition to directly supporting balanced gut immunity, these gut microbes also take partial responsibility for maintaining the integrity of the gut lining. It is increasingly recognized that a permeable gut barrier (sometimes called leaky gut) may trigger systemic inflammation. So, to help prevent the type of widespread inflammatory immune dysfunction that can reach the brain, activate microglia, and compromise our memory, a healthy microbiome appears essential.  

Another area of active microbiome research concerns short chain fatty acids (SCFAs). Gut bacteria create SCFAs when they break down fiber in our food. These molecules are thought to have a variety of positive effects on our bodies. Locally, SCFAs act as fuel for gut cells and regulate gut hormone release. Systemically, they appear to regulate immunity and energy use. Newer research suggests that SCFAs also reach the brain, where they may have several effects on the processes involved in memory. Notable among these are the influences that SCFAs have on neurons, their connections. and the molecules that transfer signals between neurons.

When considering the substrate of memory, neurons are obviously principal characters. Damage to, or destruction of neurons can cause significant memory impairments. To this end, it’s notable that SCFAs appear to influence levels of chemicals that protect neurons and promote new neuron growth. These chemicals are called neurotrophic factors, and include such molecules as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF).

In addition to the general importance of our neurons in our memories, researchers have also highlighted the significance of our synapses—the connections between our neurons. Synapses are where signals from one neuron jump to another. The strength of a synapse is thought to be directly related to the strength of a memory. Remarkably, the same neurotrophic factors increased by SCFAs also regulate the strength of our synapses. 

Finally, SCFAs seem to influence our neurotransmitters—the chemical messengers that carry information from one neuron to another. Acting through these molecules, SCFAs may affect memory by altering the way that data in the brain are processed and stored. To this end, it’s also worth knowing that the microbiome directly synthesizes many neurotransmitters on its own. It is thought that several of these neurotransmitters may reach and influence our brains. Of course, neurotransmitters are only one set of the numerous chemical signals that affect the function of our neurons.

Over the last 50 years, scientists have gained tremendous insight into the effects of stress on the brain. Chronic elevations in stress hormones like cortisol appear to preferentially affect specific areas within the central nervous system. And of these, the hippocampus is particularly vulnerable. Sustained exposure to stress is associated with atrophy of the hippocampus—a literal shrinking in its size.

Chronic, sustained life stress has been linked to a higher risk for developing dementia. And it’s now understood that the microbiome helps regulate this stress response.

Of all the chemicals associated with stress, cortisol gets the most press. Measurements of this hormone are commonly used as a surrogate for a person’s level of stress. However, more important than this general lab value for cortisol is how it’s used by the body, and how much of it is in its active form. This is why it’s fascinating to note that our microbes possess multiple enzymes that alter the availability of cortisol. Elevated inflammation appears to also drive overactivation of the stress axis, and as noted previously, the gut and its microbiome are major gatekeepers of systemic inflammation. In animal research, early life exposure to part of a bacterial cell alters the animal’s stress response in adulthood. Treating people with certain strains of probiotics (microbes that benefit our health) has been linked to a decreased stress response. Animals raised in the absence of a microbiome have been shown to display increased activation of elements of the stress response. 

It’s worth noting one last mechanism linking our memory and our microbiome. This involves our metabolism and the brain’s fuel. In studying Alzheimer’s disease pathology, researchers have noticed several salient facts. First, it was noted that people with type 2 diabetes were much more likely to develop this form of dementia. Type 2 diabetes is commonly characterized by an inability to process and remove glucose from the bloodstream, leading to elevated blood sugar. But we now know that elevated glucose is preceded by insulin resistance, a condition where our cells are less sensitive to the effects of the hormone insulin.

Insulin resistance itself has been associated with inflammation, which relates to worsened memory by all the mechanisms described previously. More directly, our neurons are dependent on insulin signaling. At the most basic level, our neurons need insulin for energy. To be clear, insulin isn’t the fuel itself. When insulin binds to receptors on brain cells, it facilitates uptake of glucose, which neurons can then use for energy. In insulin resistance, even though there may be lots of glucose nearby, the neurons seem unable to access it. The inability of neurons to adequately capture and utilize glucose for fuel is now considered a potential contributor to dementia, and may in fact occur long before objective declines in memory. Additionally, insulin appears to influence multiple other brain pathways involved in memory. For example, it seems to play a role in maintaining the strength of the connections between neurons.

Insulin as well as insulin resistance have been increasingly linked to the health of the microbiome. Again, inflammation may provide a cornerstone for this connection, as it’s thought that inflammatory molecules from our gut bugs may directly increase insulin resistance. Bacteria in the gut microbiome can also synthesize vitamins like B12 and folate, both of which are important to insulin sensitivity. In one trial, providing these vitamins to people with pre-existing health issues improved insulin resistance.

Another connection between the microbiome and insulin comes in the form of SCFAs. In one study in people with type 2 diabetes, higher levels of SCFAs predicted less insulin resistance. In another study, mice fed a high-fat diet developed insulin resistance, while those eating the same diet but supplemented with SCFAs did not. Finally, insulin resistance was reversed when mice fed a high-fat diet were given a probiotic.

Overall, the research connecting the microbiome with memory is still in its early stages. In truth, our understanding of the individual topics of memory and the microbiome both have a long way to go. But it is clear that even now, there are several important molecular pathways that link these two seemingly disparate concepts. And, given that conditions like Alzheimer’s are affecting so many, with no cure in sight, it seems to make sense to employ low-risk interventions that may optimize our memory by way of a healthier microbiome. This means taking steps to protect and enhance the wellbeing of our gut bugs through lifestyle choices and considering targeted supplementation.

First, it’s been recognized that certain chemicals appear to throw off the balance of our microbes. This may lead to negative consequences on our health. Some data have implicated over-the-counter drugs like proton pump inhibitors (PPIs) and nonsteroidal anti-inflammatory drugs (NSAIDS). However, the clearest example of this idea involves antimicrobials, medications explicitly designed to effect changes in our microbes. There are several types of antimicrobials, including antibiotics (which target bacteria) and antifungals (which target fungi).

In this conversation, the general concern for antimicrobial drugs is that they can damage the microbiome, which may contribute to a variety of disease states. By altering the microbiome, antimicrobials, especially antibiotics, may negatively impact immunity in humans. In animals, antibiotics are linked to a decrease in SCFA production. Antibiotic use in infants has been associated with decreased diversity in the microbiome, and similar effects are seen in adults. Reduced microbial diversity is thought to play a role in conditions like Alzheimer’s disease, potentially by permitting inflammation from gut bacteria to reach the bloodstream and enter the brain.

With this said, some antibiotics may in fact have a positive “eubiotic” impact on gut bugs. In a 2004 study, patients with Alzheimer’s disease were treated with a combination of two antibiotics, rifampin and doxycycline. Compared to those given a placebo, patients given the antibiotics demonstrated better cognitive function at 6 months. Much recent research has also focused on the beneficial effects of an antifungal called rapamycin (or Sirolimus). In animal studies, rapamycin has been associated with number of benefits to memory.

On the other end of the spectrum, a growing body of research has studied the effects of probiotics on our cognitive health. Probiotics are naturally found in high concentrations in fermented foods like kefir, yogurt, kimchi, sauerkraut, and some cheeses. Generally speaking, it’s thought that consuming a range of probiotics in our diet may confer health benefits. Perhaps of more interest, however, are the potential benefits of taking probiotics in supplement form. In February of 2020, a meta-analysis published in the journal Aging examined the existing research on probiotics and cognition and Alzheimer’s disease. It concluded that consuming probiotics was associated with a significant lowering of an inflammatory marker called CRP. It also found an overall improvement in cognition in those taking probiotics.

Another area of active of conversation around microbiome-centric interventions concerns prebiotics. Prebiotics are most easily understood as food for our microbes. In a more scientific sense, these are components of our diet that reach the gut microbiome undigested, providing fuel for out gut bugs and benefiting our health. Generally speaking, prebiotics are indigestible fibers, but not all fiber can be called a prebiotic. Foods like garlic, onion, leeks, and dandelion greens are particularly high in prebiotic fibers. In obese mice, plant-based prebiotics appear to increase BDNF in the brain as well as increase SCFA production. At this stage, prebiotic research on humans and cognitive benefits is more scarce and less convincing.

While less specific in nature, the final theme in microbiome intervention may be the most relevant for the average person. The idea is rather simple: eating a diverse, generally healthy diet rich in plants supports a diverse, healthy microbiome. This has been substantiated in the scientific research. For example, a 2019 study showed that a higher quality diet predicts increased diversity of the microbiome. When researchers narrowed in on the key variables, they found that frequency of whole grain and vegetable consumption most strongly predicted microbial diversity.

In sum, current scientific literature provides several mechanistic links between the microbiome and memory function. These include the microbiome’s effects on our immune system, our hormones, our neurotransmitters, our neurons, and our body’s energy systems. Though research is still in its early stages, efforts to maintain a healthy microbiome may present a viable tool in helping preserve optimal memory function. To this end, careful consideration of the effects of antimicrobials and supplementing with probiotics may provide targeted interventions to protect and enhance microbial health. For those seeking to take the most basic and cost-effective steps in this direction, eating a wide range of plant-based foods, with an emphasis on those containing prebiotics and probiotics, is likely a good place to start.