From the Bathroom to the Brain: How Fecal Microbial Transplants Benefit Social and Cognitive Behavior in Mice

Nestled amongst the intricate folds of the five-foot-long tube in our guts known as the large intestine lives thousands of bacterial species that make up our microbiome. With the average person housing up to 40 trillion bacterial cells alongside about 37 trillion human cells, some researchers playfully remark that we’re only about half-human.  

In recent years, scientists have made massive progress in understanding how these microbes affect aspects of health like digestion and immunity. However, researchers are still uncovering the myriad ways that this ecosystem of gut bacteria impacts brain health, cognition, and behavior.

Now, a recent study from researchers with the Oregon Health & Science University finds for the first time a causal link between gut microbiome alterations and behavioral and cognitive changes in mice. Although it seems like something out of a sci-fi novel, this research shows how our behavior is dictated by these minuscule organisms that we carry in our guts — and how transplanting bacteria from one animal to another can impart behavioral changes along with it.

How the Gut and Brain Communicate

Studies have shown that gut microbes coordinate with the central nervous system via the gut-brain axis. This inter-organ communication system has been shown to affect social behavior associated with age-related cognitive disorders, including anxious, stressed, depressive, or risk-avoiding symptoms. 

Previous research from the same team reported a correlation between the makeup of the gut microbiome and the behavioral and cognitive performance of mice with genotypes — someone’s entire set of genes and their variants —associated with age-related cognitive loss. 

However, no study has yet to uncover if and how the gut microbiome mediates the effect of gene activity on behavior outcomes — which Kundu and colleagues now prove using fecal transplants of gut bacteria. (Yes, fecal transplants are exactly what they sound like.) Despite the ‘ick’ factor, transplanting bacteria from a healthy gut to an unhealthy one can improve microbiome diversity, promote healthy weights, reduce infections, and even change behavior. But it’s been largely unknown how various genotypes play a role in these changes.

Fecal Transplants Foster New Behavior

There are several genotypes related to poor cognitive health with age, including mutations to human amyloid precursor protein (hAPP) and having copies of the gene apolipoprotein E4 (apoE4). Humans (and mice) with these genotypes exhibit elevated levels of neuroinflammation and pathogenic proteins known as amyloid-beta that accumulate in the brain and cause disease. Now, Kundu and colleagues show that fecal microbial transplants influence the behavioral changes that typically arise in mice with these high-risk genotypes.

Rather than transfer healthy bacteria into unhealthy mice to cure them, this study did the opposite — transplanting unhealthy bacteria into healthy mice to determine a cause-and-effect relationship between gut microbes and cognitive-related behavioral changes. Kundu and colleagues took bacteria-rich stool samples from 6-month-old mice with a high genetic risk for developing cognitive disorders and transplanted the stool into mice raised in a germ-free environment with a clean microbial slate. 

After colonizing the new bacteria into the recipient mice’s digestive tracts for a month, the researchers underwent a series of experiments designed to test their behavior, memory, and motor function. They found that the microbial changes induced by fecal transplantation affected several aspects of behavior.

One microbe-altered behavior was novel object recognition. In this test, ​​mice are presented with two similar objects; one of the two objects is then replaced by a new object the next time. As mice tend to spend more time exploring a novel item than a familiar one, this test assesses their recognition memory to see if they remember which item is new. After the fecal transplant, male recipient mice with cognitive disease-promoting genotypes showed significantly impaired novel object recognition compared to transplant recipients from “normal” mice. Essentially, the mice who got the “bad” gut bacteria exhibited greater losses of recognition memory. 

The team also looked at behavioral and cognitive differences between genetically high-risk and normal mice. Male mice with the previously mentioned harmful APP mutations and the APOe4 gene had lower activity levels during an open field test than “normal” mice. More time spent in the center of the open field instead of exploring around indicates higher anxious-related symptoms. 

Modulating the Microbiome

As expected, transplanted microbiomes were significantly influenced by the donor mouse’s genotype, although transplant recipients had slightly lower microbial diversity than their donors. Gut microbiome diversity and composition were also associated with behavioral changes, and the mouse genotypes were found to mediate this relationship. 

As senior author Jacob Raber, Ph.D., professor of behavioral neuroscience in the OHSU School of Medicine, states, "We found that modulating the gut microbiome by fecal implants in germ-free mice induces behavioral and cognitive changes in a [cognitive loss] model… To the best of my knowledge, no one has shown that before."

Go With Your Gut

These results are encouraging for the world of microbiome research, as they show how fecal transplants can alter social and cognitive behavior — a common alteration seen in people with brain- and memory-related disorders. As we can’t change our genomes, but we can change our microbiomes, this study is promising for supporting cognitive health even in the most high-risk individuals — and that peoples’ genetic makeups should be considered when developing new therapies. 

Although it may be a while before we start seeing fecal transplants as a mainstream option (please don’t try this at home!), altering the microbiome in other ways, like bacterial supplements, is already a viable option. Future research will aim to pinpoint the specific bacteria involved in supporting healthy cognition and behavior, which could be bottled up and consumed similar to a probiotic supplement. But, as Dr. Raber is quick to caution, this should be a highly individualized process, stating, "People can buy probiotics over the counter, but we want to make sure the right treatment is being used for each patient, and that it actually benefits them." 

Raber continues, “The gut microbiome is a complex environment. If you change one element, you'll also change other elements, so you want to make sure to select a probiotic that promotes brain health and brain function for each patient, while limiting any negative side effects." 

References: 

Cryan JF, O'Riordan KJ, Cowan CSM, et al. The Microbiota-Gut-Brain Axis. Physiol Rev. 2019;99(4):1877-2013. doi:10.1152/physrev.00018.2018

Kundu P, Stagaman K, Kasschau K, Holden S, Shulzhenko N, Sharpton TJ and Raber J. Fecal Implants From AppNL–G–F and AppNL–G–F/E4 Donor Mice Sufficient to Induce Behavioral Phenotypes in Germ-Free Mice. Front. Behav. Neurosci. 2022;16:791128. doi: 10.3389/fnbeh.2022.791128

Kundu P, Torres ERS, Stagaman K, et al. Integrated analysis of behavioral, epigenetic, and gut microbiome analyses in AppNL-G-F, AppNL-F, and wild-type mice. Sci Rep. 2021;11(1):4678. Published 2021 Feb 25. doi:10.1038/s41598-021-83851-4