The gut talks to the brain: a study coordinated by the Sant'Anna School of Advanced Studies in Pisa shows how imbalances in the gut microbiota are the cause of certain neurodevelopmental disorders

The study, published in the journal Cell Reports, is the result of a collaboration between the Sant'Anna School, the Scuola Normale Superiore, the University of Pisa, the CNR, and the Max Planck Institute in Berlin. “By modulating the gut microbiota, we may be able to improve patients' quality of life and enhance the effectiveness of other therapies,” says Paola Tognini, a researcher at the Interdisciplinary Health Science Center.

CDKL5 deficiency disorder (CDD) is a rare and severe genetic disease that mainly affects girls, causing encephalopathy, drug-resistant epilepsy, severe delays in motor and cognitive development, and visual problems. Until now, therapies have focused mainly on the brain, but an unexpected breakthrough could come from a study coordinated by the Scuola Superiore Sant'Anna in Pisa and published in the journal Cell Reports: for the first time, it has been shown that an imbalance in the gut microbiota (the collection of bacteria that populate our intestines) plays a causal role in some neurological symptoms of CDKL5 deficiency disorder.

“It was surprising to discover such a close and causal link between the gut and neurological manifestations in this disease. Looking to the gut to understand and treat a brain disease is no longer science fiction,” says Paola Tognini, researcher at the Interdisciplinary Health Science Center of the Sant'Anna School of Advanced Studies in Pisa and coordinator of the study.

Microbiota treatments lead to improved neural responses
 

The research analyzed model subjects for CDD and found that the composition of their gut microbiota was profoundly different from that of healthy subjects, especially in the early stages of development. But the research went further. By administering antibiotics against the “altered” microbiota, there was a clear improvement in neural responses and behavior in the affected subjects. 
 

During experiments conducted by Francesca Damiani, a PhD student at the BIO@SNS laboratory of the Scuola Normale Superiore and first author of the study, the gut microbiota of CDD models was transplanted into healthy models. Surprisingly, the healthy models that received the 'diseased' microbiota began to develop some of the typical symptoms of CDD. This is direct evidence that the altered microbiota is not just a consequence of the disease, but actively influences its neurological symptoms.

“Our data suggest that microbiota alterations are not a mere side effect but play an active role. This offers us a completely new target: by modulating the gut microbiota, for example with targeted probiotics, specific diets, or even microbiota transplantation, we may be able to improve patients' quality of life and enhance the effectiveness of other therapies,” explains Paola Tognini.

Collaboration with Normale, Unipi, CNR, and Max Planck Institute

The study was conducted by Maria Grazia Giuliano (SSSA), Elena Putignano from the Institute of Neuroscience at CNR in Pisa, Andrea Tognozzi, PhD student at the University of Pisa, Sara Cornuti (SNS), and Tommaso Pizzorusso, director of the BIO@SNS Laboratory at the Scuola Normale Superiore. The analysis in the different models was carried out thanks to the collaboration with Vera Kalscheuer and Vanessa Suckow of the Max Planck Institute in Berlin.
 

“Despite our long experience in the study of CDD,” says Tommaso Pizzorusso, full professor of Neurobiology at the Scuola Normale Superiore, ”this research has opened our eyes. For the first time, we have clear evidence of how limiting it is to focus on a single organ when studying diseases. It is essential to broaden our perspective and investigate systemic interconnections, such as the gut-brain connection, in order to fully understand the causes and manifestations of neuropsychiatric diseases.”

This study was developed thanks to the interaction and financial support of the patients' families, who came together in the association CDKL5 Insieme Verso la Cura (Together Towards a Cure): a synergy that highlights the importance of the link between research and patients.