The study, published in the journal Cell Reports, is a collaboration between Scuola Sant’Anna with the interdisciplinary Health Science Center, Scuola Normale Superiore with the Biology Laboratory, the University of Pisa, CNR and the Max Planck Institute in Berlin.
CDKL5 Deficiency Disorder (CDD) is a rare and severe genetic disease that predominantly affects girls, causing drug-resistant epilepsy, profound delays in motor and cognitive development, and visual impairments. Until now, therapies have mainly focused on the brain, but an unexpected breakthrough may come from a study led by the Scuola Superiore Sant’Anna in Pisa, with Francesca Damiani, a Ph.D. student at the Laboratory of Biology at the Scuola Normale Superiore (BIO@SNS), as first author: for the first time, it has been demonstrated that an imbalance in the gut microbiota (the collection of bacteria that inhabit our intestines) plays a causal role in some of the neurological symptoms of CDKL5 deficiency disorder. The study is published in the journal Cell Reports.
“It was surprising to discover such a strong and causal link between the gut and neurological manifestations in this disease. Looking to the gut to understand and treat a brain disorder is no longer science fiction,” says Paola Tognini, a researcher at the Interdisciplinary Health Science Center of the Scuola Superiore Sant’Anna in Pisa.
The research analyzed CDD model subjects, finding that the composition of their gut microbiota was profoundly different from that of healthy subjects, especially during the early stages of development. But the research went even further. By administering antibiotics targeting the “altered” microbiota, there was a marked improvement in neuronal responses and behavior in the affected subjects. During laboratory experiments conducted by Francesca Damiani, the gut microbiota from the CDD models was transplanted into healthy models. Surprisingly, the healthy models that received the “sick” microbiota began to develop some of the typical symptoms of CDD. This provides direct evidence that the altered microbiota is not merely a consequence of the disease but actively influences its neurological symptoms.
“Our data suggest that microbiota alterations are not just a side effect, but play an active role. This gives us a completely new therapeutic target: by modulating the gut microbiota, for example with targeted probiotics, specific diets, or even microbiota transplants, we may be able to improve patients’ quality of life and enhance the effectiveness of other therapies,” explains Paola Tognini.
“Despite our extensive experience studying CDD,” says Tommaso Pizzorusso, Full Professor of Neurobiology at the Scuola Normale Superiore and director of Bio@SNS, “this research has been eye-opening. For the first time, we have clear evidence of how limiting it is to focus on just one organ when studying diseases. It is essential to broaden our perspective and investigate systemic interconnections, such as the gut-brain axis, to fully understand the causes and manifestations of neuropsychiatric disorders.”
The study also involved Maria Grazia Giuliano (SSSA), Elena Putignano from the CNR Institute of Neuroscience in Pisa, Andrea Tognozzi, a Ph.D. student at the University of Pisa, and Sara Cornuti (SNS). The analysis across different models was made possible through collaboration with Vera Kalscheuer and Vanessa Suckow from the Max Planck Institute in Berlin.
Here the link to the article: https://www.cell.com/cell-reports/fulltext/S2211-1247(25)00317-1
Pictured are researchers Andrea Tognozzi, Elena Putignano, Paola Tognini, and Sara Cornuti.
