Small studies in rodents and humans hint at an answer
by Erman Misirlisoy, PhD
The human gut contains a host of life forms with their own genes that make up our gut microbiome. Over 10 trillion microorganisms live inside human intestines, with some recent estimates putting the number as high as 39 trillion. That means people have more microbes in their large intestine than human cells throughout their body. The human gut is also home to a sophisticated network of over 100 million neurons, which many experts refer to as the body’s “second brain.”
These microbial environments are now revealing new insights about psychology and behavior.
Gut flora is an indispensable army of microbes that assist in metabolism and support people’s immunity, but scientists have only recently begun to uncover the fast-acting connections between the gut and brain. In mice, it takes only two nerve cells for communications to travel from the intestines to the brain stem. This means the gut and brain can communicate with each other in a few seconds or less, rather than relying on slower signals that require the release of hormones. The human gut can also send signals about the presence of nutrients and microbes to the brain, and the brain can use this information to help control metabolism, digestion, and satiety. In a sense, the gut is the human body’s largest sensory organ.
Scientists say the relationship between the gut and brain could play a role in thoughts and feelings. In a recent study, a team of researchers in Philadelphia systematically tested whether microbiota in the guts of rats could influence their emotions and psychological vulnerabilities.
The researchers took a group of rats and split them into two groups: a social conflict group and a relaxed group. While the relaxed rats simply rested in their own territory, the social conflict rats were placed into the territory of another aggressive rat in order to arouse a stressful interplay. The researchers analyzed fecal samples from all of the rats to compare the different microbiota at home in their guts.
Among the social conflict group, two types of rats emerged. Some were confident and resilient when intruding on the territory of another rat, taking a long time to express any sign of defeat. Others were vulnerable and were quicker to surrender by lying on their backs for around three seconds.
After repeated social conflicts over multiple days, the gut flora in the rats began to change. Compared to both the relaxed rats who experienced no conflict and the resilient rats who stood up confidently to the challenge, the vulnerable rats had more of a microorganism called Actinobacteria in their gut. They also had higher levels of microbes called Bacilli and Clostridia, but less Bacteroidia, than the rats in the relaxed group. In contrast, the resilient rats’ guts looked more similar to the relaxed rats. Although some microbial effects of stress could be identified in all social conflict rats, stress had the strongest impact on the gut bacteria of the vulnerable rats.
But what do these changes mean? To better understand some of the functional consequences, the researchers narrowed their attention to the balance of Bacilli versus Clostridia in each rat’s gut. Bacilli microorganisms include several anti-inflammatory species, while Clostridia are often linked to inflammation, so a healthy response to the inflammatory effects of stress could be an increased ratio of Bacilli to Clostridia. Fitting with this theory, the resilient rats showed an increased ratio of Bacilli to Clostridia over their multiple days of social conflict, and a significantly higher ratio compared to relaxed rats on their final day of testing. In contrast, the vulnerable rats showed no adaptive change in this ratio.
This is all interesting, but it doesn’t say much about the consequences of actively manipulating an animal’s internal microorganism balance. To answer this more practical question, the researchers took the microorganisms from either the resilient or vulnerable rats and transferred them into the guts of relaxed rats. After six days of transfer, the relaxed rats started to show relevant changes in the makeup of their gut flora.
“It’s far too early to confidently say whether any particular supplement could meaningfully enhance our lives, but the limited evidence that we do have paints an optimistic picture.”
More importantly, the transplanted rats also started to change their behavior. In a forced swimming test, the rats who received microbiota from vulnerable rats displayed more signs of depressive behavior, as they were quicker to give up on swimming in favor of wading with their heads above water.
How were the gut bacteria influencing the behavior of vulnerable transplant rats? When studying an area of the brain known as the ventral hippocampus, the researchers found increased activity in cells that are known to be involved in protecting the central nervous system. They also found increased levels of corticosterone — a hormone involved in immune and stress responses — in the rats’ plasma. These immune responses, regulated by a changing gut microbiome, may have caused the depression-related behaviors and stress responses.
These results from the rats show that it is biologically plausible to assume that gut flora may contribute to mood and behavior, the scientists say, but that does not necessarily mean that the effects apply similarly to humans. Although human studies are still rare, some research supports a link between gut flora and psychiatric symptoms. Analysis of fecal samples from people with clinical depression suggests that they have more microbes like Enterobacteriaceae and Alistipes than non-depressed people, but less Faecalibacterium. And the less Faecalibacterium they have, the more severe their depression symptoms appear.
Could probiotic supplements – which are thought to increase healthy microbes in the gut – have any meaningful effects on human mental well-being? Again, while studies are rare, several early examples suggest that taking some supplements may reduce anxiety and psychological distress compared to taking a placebo treatment. In one study, specific probiotic yogurts and capsules improved self-reported outcomes in questionnaire measures of general health and also improved scores on scales that measure depression and anxiety. Conventional yogurt and placebo capsules had no such effect. In another study, healthy women who took a probiotic milk product twice a day for four weeks showed brain activity changes that may protect against negative emotional sensitivity compared to women who took a placebo milk product. None of these studies confirm that probiotic changes can help mood, but scientists are interested.
Prebiotics, which act by fertilizing the internal growth of particular microbiota, rather than directly inserting the microbiota themselves, may have similar effects to probiotics. In one study from 2015, 45 healthy volunteers took a daily dose of either a prebiotic or placebo treatment for three weeks. People on the probiotics had a lower level of cortisol – a hormone linked to stress — in their morning saliva samples. They were also more likely to automatically prioritize positive rather than negative emotional information in a behavioral task that measured their attention.
While there are some early signs hinting at a potential role for probiotics or prebiotics in improving mental health in the future, it is far too early to confidently say whether any particular supplement could meaningfully enhance people’s lives. For now, more studies on humans are needed, in particular using measures of mental well-being that extend beyond questionnaires and include assessments of daily behavior.
A better understanding of the mechanisms that link the behavior of microbiota in the gut to the functions of the brain is needed as well. Even in rat studies, where scientists have more direct access to fine-grained physiological processes, they still haven’t fully mapped out how a stressful environment stimulates the growth of particular microbial communities in the gut.
There’s a long way to go before entertaining the possibility of buying yogurts to improve emotional well-being and cognitive performance. That said, as the medical community learns more about the functions and evolution of the human microbiome, a new medical tool kit for treating mental health problems may emerge.