Recent studies have shown that gut microbes can influence human health, behavior and certain neurological disorders such as autism, but just how they communicate with the brain has been unknown.

Results from a new University of Illinois study suggest a pathway of communication between certain gut bacteria and brain metabolites by way of blood cortisol. The researchers said the finding provides a potential mechanism to explain the characteristics of autism.

“Changes in neurometabolites during infancy can have profound effects on brain development, and it is possible that the microbiome — or collection of bacteria, fungi and viruses inhabiting our gut — plays a role in this process,” said Austin Mudd, a doctoral student in the neuroscience program at the University of Illinois. “However, it is unclear which specific gut bacteria are most influential during brain development and what factors, if any, might influence the relationship between the gut and the brain.”

So, what does this have to do with animal agriculture? Like several other recent research projects, Mudd and his colleagues used pigs as a research model.

Specifically, the researchers studied one-month-old piglets, which are remarkably similar to human infants in terms of their gut and brain development. They first identified the relative abundances of bacteria in the feces and ascending colon contents of the piglets and then quantified concentrations of certain compounds in the blood and in the brain.

“Using the piglet as a translatable animal model for human infants provides a unique opportunity for studying aspects of development that are sometimes more difficult or ethically challenging to collect data on in human infants,” Mudd said. “For example, in this study, we wanted to see if we could find bacteria in the feces of piglets that might predict concentrations of compounds in the blood and brain, both of which are more difficult to characterize in infants.”

The researchers took a step-wise approach, first identifying predictive relationships between fecal bacteria and brain metabolites. They found that the bacterial genera Bacteroides and Clostridium predicted higher concentrations of myo-inositol, Butyricimonas positively predicted n-acetylaspartate (NAA) and Bacteroides also predicted higher levels of total creatine in the brain. However, when bacteria in the genus Ruminococcus were more abundant in the feces of the piglets, NAA concentrations in the brain were lower.

“These brain metabolites have been found in altered states in individuals diagnosed with autism spectrum disorder (ASD), yet no previous studies have identified specific links between bacterial genera and these particular metabolites,” Mudd noted.

The next step was to determine if these four bacterial genera could predict compounds in the blood. “Blood biomarkers are something we can actually collect from an infant, so it’s a clinically relevant sample. It would be nice to study an infant’s brain directly, but imaging infants is logistically and ethically difficult. We can, however, obtain feces and blood from infants,” explained Ryan Dilger, associate professor in the University of Illinois department of animal sciences, division of nutritional sciences and neuroscience program.

The researchers found predictive relationships between the fecal microbiota and serotonin and cortisol -- two compounds in the blood known to be influenced by gut microbiota. Specifically, bacteroides were associated with higher serotonin levels, while ruminococcus predicted lower concentrations of both serotonin and cortisol. Clostridium and butyricimonas were not associated strongly with either compound.

Mudd reiterated that the results supported previous findings related to ASD. “Alterations in serum serotonin and cortisol, as well as fecal bacteroides and ruminococcus levels, have been described in ASD individuals,” he said.

Based on their initial analyses, the researchers wanted to know if there was a three-way relationship among ruminococcus, cortisol and NAA. To investigate this further, they used a statistical approach known as mediation analysis and found that serum cortisol mediated the relationship between fecal ruminococcus abundance and brain NAA concentration.

In other words, it appears that ruminococcus communicates with and makes changes to the brain indirectly through cortisol. “This mediation finding is interesting in that it gives us insight into one way that the gut microbiota may be communicating with the brain. It can be used as a framework for developing future intervention studies that further support this proposed mechanism,” Dilger added.

“Initially, we set out to characterize relationships between the gut microbiota, blood biomarkers and brain metabolites, but once we looked at the relationships identified in our study, they kept leading us to independently reported findings in the autism literature. We remain cautious and do not want to overstate our findings without support from clinical intervention trials, but we hypothesize that this could be a contributing factor to autism’s heterogenous symptoms,” Mudd said.

Interestingly, in the time since the researchers wrote the paper, other publications have also reported relationships between ruminococcus and measures of brain development, supporting the idea that this might be a promising area for future research.

Dilger noted, “We admit this approach is limited by only using predictive models. Therefore, the next step is to generate empirical evidence in a clinical setting. So, it’s important to state that we’ve only generated a hypothesis here, but it’s exciting to consider the progress that may be made in the future based on our evidence in the pre-clinical pig model.”

Linking mental health, gut microbiome

Beyond brain development and ASD, researchers are also trying to gain a better understanding of how the gastrointestinal microbiome may help psychiatrists treat mental health disorders such as depression, according to a review in Frontiers in Psychiatry.

From a psychiatric standpoint, the underlying causes of depression are still not fully understood, and depression remains difficult to treat, in some cases. Given increasing interest in the role of the microbiome in a range of human health issues, this has led many researchers to also investigate potential links between mental health and the microbiome, specifically the microbial flora in the gut.

"The main idea of our review is that there is strong communication between the gastrointestinal tract and the brain and that changes to the microbiome/gut/brain axis could be associated with the etiology of different neuropsychiatric disorders such as depression," said Juan M. Lima-Ojeda, lead author of the review and a physician and researcher at the University of Regensburg in Germany.

Lima-Ojeda and his colleagues reviewed the body of literature on the role of the gut microbiome with a particular emphasis on the connections formed among the microbiome, the gut and the brain.

The brain and the gastrointestinal tract are bidirectionally linked through the central nervous system, endocrine system and immune system, he said, and perturbations to any of these systems can have repercussions across the others, in turn potentially influencing a person's overall well-being.

Their findings included evidence that the gut microbiome's formation and influence begin already in the very earliest stages of life in utero. Some of the reviewed publications propose that the interactions between the brain and gut are influential, if not possibly more important, during neurodevelopment, suggesting that depressive syndromes might be traced back to imbalances during neurodevelopment.

However, Lima-Ojeda additionally uncovered evidence that depression may also be attributable to disturbances to the gut microbiome at any point during a person's life, which can be due to stress, diet and/or medications.

These findings promote the idea that attention to nutrition and diet may be a practical and effective complement to existing strategies for the treatment of depression.