Stress disrupts gut and brain barriers by reducing key microbial metabolites, study finds

A new study reports that a single, brief exposure to stress is associated with a rapid reduction of beneficial compounds produced by gut bacteria. The research, published in the journal Brain, Behavior, & Immunity – Health, also found that these same compounds, when tested in a laboratory setting, appear to protect the cellular barriers of both the gut and the brain from damage. The findings offer new insight into the immediate biological responses to stress, highlighting a potential mechanism through which even short-term stressors might influence our physiology.

Scientists are increasingly interested in the gut-brain axis, the complex network of communication between the gastrointestinal system and the brain. This system includes not only nerves and hormones, but also immune signals and microbial products. One of the key components in this system is a group of substances called short-chain fatty acids, which are produced when gut bacteria digest dietary fiber.

These fatty acids—mainly butyrate, acetate, and propionate—can influence gut health, inflammation, brain function, and even mood. While much attention has been paid to how stress affects the body over time, less is known about how the gut and brain respond to short bursts of stress. The current study set out to examine whether acute stress changes short-chain fatty acid production, and how those changes might influence the function of protective barriers in the body.

“We have long been interested in the impact of stress on signalling in the gut-brain axis. This is a two-way street in that while gut microbes can tune the host stress response, stress exposures can also change the composition and function of the gut microbiota. Much less is known in this context about how acute stress, the building blocks of chronic stress, modify the gut. Essentially, we wanted to know what was going on in the stressed gut,” explained study author Gerard Clarke, a professor of neurobehavioral science at the University College Cork and co-author of Microbiota Brain Axis: A Neuroscience Primer.

To explore this, the researchers exposed mice to a 15-minute period of restraint stress. They used both conventional mice, germ-free mice raised without any gut microbes, and germ-free mice that had been re-colonized with gut bacteria. After the stress exposure, the team measured the levels of various short-chain fatty acids and other related compounds in the animals’ lower intestines. The researchers also tested the effects of these compounds on cellular models that mimic the gut and blood-brain barriers, which are crucial in preventing harmful substances from entering sensitive tissues.

In the animals exposed to stress, levels of butyrate and acetate dropped significantly in the lower intestinal contents, especially in conventional and colonized germ-free mice. These changes appeared quickly, within 45 minutes of the stress exposure. The researchers also found that stress reduced levels of dietary sugar breakdown products and other microbial metabolites. These findings suggest that acute stress disrupts the fermentation processes that gut bacteria use to produce beneficial compounds, which could have downstream effects on host health.

“One of the intriguing findings here is that the consequences of an acute stress exposure is visible in the gut very quickly as alterations in microbial metabolites,” Clarke told PsyPost. “These results build on earlier work from our lab to potentially explain how an acute psychosocial stressor can impact intestinal permeability.”

To understand whether these stress-induced reductions had functional consequences, the researchers turned to laboratory cell models. They applied varying concentrations of butyrate, acetate, and propionate to layers of gut and brain cells grown in the lab. The goal was to see whether these compounds could protect against barrier disruption triggered by lipopolysaccharide, a bacterial molecule known to increase permeability and inflammation.

The results showed that certain concentrations of butyrate and acetate helped maintain barrier function, both in intestinal and brain cell models. For example, pretreatment with butyrate at 1 and 10 millimoles significantly prevented gut barrier damage, while acetate at 10 millimoles also had protective effects. Some concentrations of acetate, however, appeared to worsen permeability, indicating that its effects may vary depending on dose and context.

The protective effects were linked to changes in tight junction proteins, which help hold the barrier cells together. One of these proteins, ZO-1, was reduced by the bacterial challenge, but this reduction was partially reversed by treatment with the short-chain fatty acids. Microscopy showed that butyrate and propionate increased both the abundance and structural complexity of ZO-1 proteins at the junctions between cells, forming wavy “ruffles” that may represent a more active or flexible barrier. In contrast, acetate did not increase ruffling but still helped restore overall protein levels.

The researchers also looked at how these fatty acids influenced the activity of receptors known to respond to them. Specifically, butyrate increased the expression of FFAR2 and FFAR3, two receptors involved in immune and barrier regulation. These receptors are believed to play a role in maintaining the health of the gut lining, and mice lacking them show higher permeability and more inflammation. The current results suggest that short-chain fatty acids may help stabilize the gut barrier partly by activating these protective signaling pathways.

In addition to looking at how fatty acids protect barrier function, the researchers also tried to understand why stress reduces their levels in the first place. By analyzing the breakdown products of dietary sugars in the intestines, they found that stress reduced the availability of key substrates that bacteria use to make short-chain fatty acids.

The data also suggested that stress might shift microbial activity toward producing other compounds, such as polyols, or increase host absorption of fatty acids before they accumulate in the lower intestine. Some changes in microbial energy metabolism were also observed, depending on whether the animals had gut microbes or not. These findings point to a broad disturbance in the gut environment after stress, which could influence both microbial activity and the availability of beneficial compounds to the host.

“Our gut microbes are like little factories, with production lines pumping out microbial metabolites,” Clarke said. “One of the key messages is that the experience of stress can also be felt by our gut microbes and one of the consequences of this is alterations in the production of these microbial metabolites, in this case a reduction in short-chain fatty acids. Our results using in vitro models show that these microbial metabolites, like butyrate, are important to maintain gut and blood-brain barrier function.”

The findings offer new insight into how even short-term stress can alter gut-brain signaling, but the researchers acknowledge some limitations. The experiments used cell culture models to test barrier integrity, which cannot fully capture the complexity of living organisms.

“We used in vitro studies to understand if short-chain fatty acids could be effectors of intestinal permeability alterations in the gut and the brain, but these are a very simple approximations of what is happening at these sites in the whole organism within the context of microbiota-gut-brain axis signalling,” Clarke explained. “We have recently noted that more sophisticated options like human induced pluripotent stem cells (hiPSCs) offer a more innovative model to advance these studies in the future.”

The researchers emphasized that understanding how acute stress affects microbial metabolites like short-chain fatty acids may help explain how the gut-brain axis contributes to stress-related health problems. Since these metabolites are influenced by diet and microbial composition, they could become targets for new therapies aimed at supporting gut and brain barrier function during stress. For example, interventions that boost butyrate production or mimic its protective effects might help buffer against stress-induced damage.

“We still need to understand what happens in the stressed gut when these acute stress exposures are experienced repeatedly and chronically, and if adaptive or maladaptive consequences emerge that will be important for stress-related disorders,” Clarke said.

“This is all down to the great work of a really talented postdoctoral researcher, Dr. Cristina Rosell-Cardona,” he added. “Cristina is now an INSPIRE fellow at APC Microbiome Ireland and is going on to look at the impact of microbial metabolites in depression, a stress-related disorder with alterations in microbiota-gut-brain axis signalling.”

The study, “Acute stress-induced alterations in short-chain fatty acids: Implications for the intestinal and blood brain barriers,” was authored by Cristina Rosell-Cardona, Sarah-Jane Leigh, Emily Knox, Emanuela Tirelli, Joshua M. Lyte, Michael S. Goodson, Nancy Kelley-Loughnane, Maria R. Aburto, John F. Cryan, and Gerard Clarke.