Gut microbiota profile in CDKL5 deficiency disorder patients as a potential marker of clinical severity

Abstract

CDKL5 deficiency disorder (CDD) is a neurodevelopmental condition characterized by global developmental delay, early-onset seizures, intellectual disability, visual and motor impairments. Unlike Rett Syndrome (RTT), CDD lacks a clear regression period. CDD patients frequently encounter gastrointestinal (GI) disturbances and exhibit signs of subclinical immune dysregulation. However, the underlying causes of these conditions remain elusive. Emerging studies indicate a potential connection between neurological disorders and gut microbiota, an area completely unexplored in CDD. We conducted a pioneering study, analyzing fecal microbiota composition in CDD patients and their healthy relatives. Notably, differences in intestinal bacterial diversity and composition were identified in CDD patients. We further investigated microbiota changes based on the severity of GI issues, seizure frequency, sleep disorders, food intake type, impairment in neuro-behavioral features (assessed through the RTT Behaviour Questionnaire – RSBQ), and ambulation capacity.Our findings hint at a potential connection between CDD, microbiota, and symptom severity. This study marks the first exploration of the gut-microbiota-brain axis in CDD patients. It adds to the growing body of research emphasizing the role of the gut microbiota in neurodevelopmental disorders and opens doors to potential interventions that target intestinal microbes with the aim of improving the lives of CDD patients.

Multi-Site Investigation of Gut Microbiota in CDKL5 Deficiency Disorder Mouse Models: Targeting Dysbiosis to Improve Neurological Outcomes

“…A significant increase in gut Proteobacteria associated with neuroinflammation, and accompained by exploration impairment and anxiety-like behavior was observed in a mouse model of diet induced obesity (47). Importantly, an enrichment in Enterobacteriaceae was observed in patients affected by CDD and manifesting severe GI disturbances compared to patients with mild to normal GI features (16), indicating similarities in the gut microbiota profile of mouse model and human subjects.…”

“…Alpha diversity was decreased at P25 and P32 in the Berlin vivarium, and a tendency for a decrease was observed in Pisa at the same ages. Similarly, in an Italian cohort of patients affected by CDD, fecal microbiota alpha diversity was diminished compared to healthy individuals (16). The Pisa CDKL5 KO mouse also displayed specific alterations in the gut microbiota: taxa belonging to the Phylum Proteobacteria were significantly enriched in these mice, at both P25 and P32 (i.e.…”

“…Indeed, ASD patients display alterations in the composition of the gut microbiota (13) as well as RTT patients (14,15). Importantly, we have recently discovered differences in biodiversity and composition of intestinal microbes in a cohort of Italian patients affected by CDD (16). Disturbances in the composition or equilibrium of the gut microbiota, termed dysbiosis, have been associated with inflammatory bowel disease (IBD), metabolic disturbances, and even neuropsychiatric conditions (17–20).…”