Nearly 40% of patients suffering from inflammatory bowel disease (IBD) also suffer from psychiatric disorders such as depression and anxiety. While the gut-brain axis is believed to drive these symptoms, the mechanisms have been unclear.
Now, a new study from scientists at Humanitas University in Italy, shows the presence of a vascular barrier in a region of the brain called the choroid plexus—a complex network of capillaries lined by specialized cells that serve as a barrier between the circulating blood and the fluid that bathes the brain and spinal cord (cerebrospinal fluid).
The study showed that this plexus vascular barrier (PVB) is closed in response to gut inflammation, isolating the brain from the rest of the body. While locking down access to the brain protects the brain from inflammation, the authors provided evidence that it also leads to cognitive and psychiatric symptoms associated with IBD.
These findings identify a potential pathogenic link between IBD and mental comorbidities and were reported in an article in the journal Science, titled, “Identification of a choroid plexus vascular barrier closing during intestinal inflammation.”
Senior authors on the study, Maria Rescigno, PhD, professor, and Simona Lodato, PhD, assistant professor, both at Humanitas University said: “This study opens new areas of research in other pathologies of the central nervous system that are connected with increased intestinal permeability, including neurodegenerative diseases and neurodevelopmental disorders, including autism spectrum disorders.”
The team previously identified a gut vascular barrier (GVB) that controls the spread of bacteria from the gut to the liver during gut inflammation. The GVB, the authors noted, connects our body with the external world so that nutrients and small molecules can be absorbed and assimilated but bacteria and large toxic molecules can be prevented from entering the liver. When the gut is inflamed, the GVB becomes more permeable allowing inflammation to spread beyond the gut.
In their current study, first author Sara Carloni, PhD, and colleagues showed, in response to gut inflammation, lipopolysaccharides released by bacteria played a pivotal role in closing the PVB. Using a mouse model of intestinal inflammation, the team showed that the PVB closes after the GVB opens, through the upregulation of a molecular pathway—the Wnt-beta catenin signaling pathway. This locks down the access of large molecules to the brain.
Experimentally locking the endothelial cells that form the PVB in a mouse model through genetic manipulations, the scientists observed the mice exhibit anxiety-like behavior and deficits in recognizing novel objects that indicate impaired short-term episodic memory. Based on these observations, the authors concluded, closing the PVB correlates with mental deficits. “IBD-related mental symptoms may thus be the consequence of a deregulated gut-brain vascular axis.”
The scientists used a multidisciplinary approach to investigate the role of the plexus barrier, spanning from genetics to behavior and from immunology to omics. “Single-cell RNA sequencing technology allowed us to identify the cell types in the choroid plexus that quickly respond to intestinal inflammation. This led to the identification of capillary endothelial cells as the first cells to respond and the discovery of an unappreciated vascular network that connects the brain with the body,” noted Rescigno and Lodato.
The authors said these findings could be leveraged to develop therapeutic targets in treating behavioral disorders.