A newly discovered vascular brain barrier that blocks the passage of inflammatory molecules triggered by gut bacteria may be why patients with inflammatory bowel disease (IBD) are at increased risk for certain mental health disorders, including anxiety and depression, early research suggests.
The discovery, which was based on a preclinical model, could lead to new therapeutic targets that could have applications for both gastrointestinal and psychiatric conditions, investigators note.
The research team, which was led by immunologist Maria Rescigno, PhD, and neuroscientist Simona Lodato, PhD, both from Humanitas University, Milan, Italy, notes that the barrier resides in the choroid plexus, a region of the brain that is involved in filtering cerebrospinal fluid. The researchers found that the region closes in response to inflammatory molecules produced in reaction to the presence intestinal bacteria in patients with gut disorders.
Lodato told Medscape Medical News that the brain’s choroid plexus vascular barrier, along with another barrier between the gut and liver, known as the gut vascular barrier, appear to control the movement of molecules along the gut-brain axis.
“We show that in addition to the epithelial barrier in the choroid plexus, there is a functional vascular barrier that only becomes evident in blocking entry of various inflammatory molecules under conditions of systemic inflammation,” Lodato said.
“This interruption of the gut-brain interaction has developed to protect the brain from inflammation. Why this happens is not yet known, but it is likely to prevent epileptic seizures and imbalanced neuronal activity,” added Rescigno.
The study was published online October 22 in Science.
The Gut a Root Cause of Mental Illness?
Nearly 40% of patients with IBD also experience depression and anxiety. It was once thought that these conditions arose because of patients’ difficulties in coping with their disease, said Rescigno.
“People with these disorders conventionally thought to be caused by an imbalance in the brain may actually find the root cause is located in the intestine. This is the first time these symptoms have been associated with the choroid plexus vascular brain barrier and its closure,” she noted.
Rescigno added that subtle, rather than overt, inflammation may be all that’s required for closure of the choroid plexus and the subsequent effects on mental health.
In 2015, Rescigno’s group first described the gut vascular barrier that protects the systemic circulation from gut bacteria or associated bacteria-derived molecules. During intestinal inflammation, such as occurs in IBD, this barrier is compromised and becomes more permeable. This allows microbes to pass across the epithelium of the gut barrier and enter the systemic circulation, including the liver and spleen, explained Rescigno.
Rescigno and Lodato then explored whether this systemic inflammatory condition was connected to the brain along a gut-brain axis and found that it was.
The researchers tested the hypothesis that central nervous system symptoms may be due to vascular changes at the interface between the gut or the brain and elsewhere in the body.
“We set out to test whether opening of the gut vascular barrier would allow gut bacteria to trigger the release of inflammatory molecules that spread to more distant areas, possibly leading to a deficiency of certain nutrients and precipitating mental disorders,” they said.
An experimental preclinical model of the choroid plexus vascular barrier closure led to anxiety-like behavior, as well as short-term memory loss. That this behavior occurred independently of inflammation suggested that it was likely a response to closure itself, they note.
In the noninflammatory state, the epithelium of the choroid plexus filters molecules. Those that are ≤70 kDa are allowed to pass through to the brain. However, the investigators found that during systemic inflammation, this filtration stops, and the blood capillaries of the choroid plexus prevent entry of inflammatory molecules such as cytokines.
Lodato speculated that when the vascular barrier of the choroid plexus shuts off during the systemic inflammatory state, it responds by bathing the brain in cerebrospinal fluid.
“When the choroid plexus closes, like a door slamming shut, then communication between the brain and the rest of the body is halted. This means that the brain is deprived of certain nutrients and other beneficial molecules that usually enter via the cerebrospinal fluid or enriched of potentially dangerous ones, as drainage could also be affected,” she said.
If confirmed in further studies, these results may open the way to new interventions.
“A Significant Leap Forward”
Commenting on the findings for Medscape Medical News, David T. Rubin, MD, professor of medicine at the University of Chicago, in Chicago, Illinois, noted that the study’s results represent “a significant leap forward” and that it highlights “another important cost to uncontrolled gut inflammation that is the potential for worsened mental health disorders.”
Rubin, whose research involves measuring metabolites of the dietary amino acid tryptophan, including melatonin and serotonin, in patients with IBD, added that the findings offer a possible explanation for the association of both Crohn’s disease and ulcerative colitis with anxiety and depressive disorders.
“There was a belief that the association was in the opposite direction, that the mental health disorder was causing or worsening the gut inflammation, but this has been disavowed,” Rubin said.
“Most recently, the recognition that the major sources of serotonin and other metabolites of tryptophan that come from the gut microbiome has led to the hypothesis that the inflamed bowel and dysbiotic gut biome may in fact be driving the mental health disorders due to the effect of neurotransmitter imbalance,” he added. Rubin also suggested that the shutdown of the choroid plexus vascular barrier may contribute to this imbalance but that that needs additional study.
“This further supports my ongoing contention that the gut really is the center of the universe,” said Rubin.
Also commenting on the findings for Medscape Medical News, Miguel Rigueiro, MD, professor in the Department of Medicine in the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, said, “There’s an implication that anxiety and depression and other behavioral health disorders may be explained by this mechanism. If that is the case, there may be a way to target medications against the choroid plexus and potentially treat depression or anxiety.”
This prospect was echoed by Rubin, who said, “The clinical implication is that treatment of gut inflammation may restore a balance to the neurotransmitters and resolve anxiety or depressive disorders.”
To identify new therapeutic targets, investigators will study the regions and circuits of the brain that are more susceptible to this closure of the choroid plexus, said Lodato.
“If these regions are associated with depression or other psychosocial disorders, then this new understanding around the choroid plexus vascular barrier might eventually have implications for helping treat such disorders,” she noted.
Reflecting a general shift from a brain-centric view of some psychosocial disorders to an intestinal-centric one, Lodato added, “The brain cannot be considered in isolation. It is part of a much larger body, and we need to think this way.”
Rescigno, Lodato, and Rubin report no relevant financial relationships. Regueiro has served on advisory boards and as consultant for AbbVie, Janssen, UCB, Takeda, Pfizer, Miraca Labs, Amgen, Celgene, Seres, Allergan, Genentech, Gilead, Salix, Prometheus, Lilly, TARGET Pharma Solutions, ALFASIGMA, SpA, and Bristol-Meyer Squibb.
Science. 2021;374:439-448. Abstract
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