Protective Role of Pre-/ Post-biotics on Gut Inflammation, Dysbiosis, and Life Quality in Rett Syndrome (Biotics_RTT)

Quality of Life Clinical Trial

— Biotics_RTT  

Official title:

Protective Effects of Pre- and Post-biotics on Gut Inflammation, Microbiota Diversity, Epileptogenesis, and Quality of Life in Rett Syndrome

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05420805
• Other study ID #: NCT
• Status: Completed
• Phase: N/A
• Start date: April 1, 2022
• Est. completion date: February 28, 2023

Study information

• Verified date: April 2023
• Source: Azienda Ospedaliera Universitaria Senese
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The study will examine the potential efficacy and safety of two pre- and post-biotics on markers for gut inflammation and intestinal microbiota ecology in patients with Rett syndrome. Moreover, this trial will search for possible effects on epileptogenesis and quality of life.

Description:

The gastrointestinal tract is the major site of exposure to environmental molecules where 1) dietary components are chemically transformed by the microbiota, and 2) gut-derived metabolites are disseminated to all organs, including the brain. The human gut microbiota directly affects human health, and its alteration can lead to gastrointestinal abnormalities and inflammation. Indeed, accumulating clinical and experimental evidences indicate that the gut microbiota impacts behavior, modulates neurotransmitter production in the gut and brain, influences brain development and myelination patterns. Specific gut-derived metabolites, such as 4-ethylphenyl sulfate (4-EPS) and isoamylamine (IAA) are known to alter brains activity and anxiety behavior in mice and/ or promoting neural cell death leading to cognitive decline. Rett syndrome (RTT; Online Mendelian Inheritance in Man, OMIM number #312750) is a severe and progressive neurological disorder that almost exclusively affects females with an incidence of ~1:10,000 live births. Loss-of-function mutations of the X-linked methyl-CpG binding protein 2 (MeCP2) gene is the major cause (approximately 90 %) of classical cases of RTT. Although a rare disorder, RTT represents a leading cause of severe cognitive impairment in the female gender. Affected individuals commonly show a period of apparent early normal development, followed by regression of hand and/or communication skills, and subsequent development of hand stereotypies, while gait is often abnormal in those who are learning to walk.

Despite a wide phenotypic variability, RTT is commonly associated with epilepsy, sleep disturbances, and gastrointestinal dysfunction thus suggesting a link between RTT's gastrointestinal abnormalities and the gut microbiota.

RTT is associated with a dysbiosis of both the bacterial and fungal component of the gut microbiota, suggesting that MeCP2 loss-of-function can favour the establishment of a peculiar microbial community with altered production of short chain fatty acids (SCFAs) possibly contributing to the RTT gastrointestinal physiopathology.

Modulation of the systemic inflammatory response using pre- and post-biotics is advocated as a possible global therapeutic approach in neurological diseases such as Alzheimer's dementia.

Alpha-lactalbumin (ALAC), is the predominant whey protein in human milk, provides essential amino acids for protein synthesis in the developing neonates. Its supplementation in adults are associated with improved cognition, better memory and sleep. The bioactive properties of ALAC relate to antimicrobial activity, pre-biotic features and epithelial restoration via selective apoptosis activity. Moreover, the antibacterial peptides released from ALAC during digestion can exert immunostimulatory effects inducing phagocytic activity. Overall, ALAC shows reduction of inflammation and oxidative stress status as well as improvement of insulin resistance and increase in the synthesis of brain serotonin, a central nervous system neurotransmitter with well-known antiepileptic activity.

Butyrate, a bacterial metabolite and one of the main SCFAs, exhibits a broad range of pharmacological activities including microbiome modulating, anti-inflammatory, metabolic pathway regulating and anti-oxidant actions.

This body of knowledge supports testing pre- and post-biotics strategies for benefit in individuals with Rett syndrome with the goal of translating potential new treatments from experimental models to clinical practice. Results of this study could lead to the first approved pre- / post-biotics treatment for common co-morbidities in the disorder.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 28
• Est. completion date: February 28, 2023
• Est. primary completion date: February 28, 2023
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 3 Years and older

Eligibility

Inclusion Criteria:

• Diagnosis of classic/typical Rett syndrome (and proven loss-of-function mutation of the MeCP2 gene) with gastrointestinal dysfunction and/or positive history of epilepsy

• Female gender (age > / = 3 years old)

• Ability to obtain written informed consent from their parent(s)/legal guardian(s)

• Stable medications for at least 4 weeks prior to the baseline visit.

Exclusion Criteria:

• Diagnosis not fitting into the Rett syndrome consensus guidelines

• Nonpathogenic MECP2 mutation or mutations in non-MECP2 genes (i.e., cyclin-dependent kinase 5, CDKL5; forkhead box protein G1, FOXG1)

• Male gender

• Percutaneous endoscopic gastrostomy (PEG) tube

• Proven hypersensitivity to one or more components of the dietary supplements (X-biotics)

• Unstable concomitant medications less than 4 weeks prior to enrollment visit.

• Concomitant antibiotic therapy at the enrollment. In the case of antibiotic therapy, a 4-weeks washout period will be undertaken.

• Rejection of the informed consent form by the parents/caregivers and/or lack of compliance to the Study procedures.

Related Conditions & MeSH terms

• Dysbiosis
• Epilepsy
• Inflammation
• Quality of Life
• Rett Syndrome
• Syndrome

Intervention

Dietary Supplement:
• ALAC, inulin, FOS, and sodium butyrate
Pre- and post-biotic supplementation will be administered for 3 month period (i.e. 12 weeks) given the filling out of a supplementation diary by parents/caregivers. At the scheduled visits/ phone contacts (i.e., baseline, 4 weeks and 12 weeks), systemic inflammation, intestinal inflammation, and gut microbiome characterization as well as treatment compliance, clinical and dietary intake will be assessed. A seizure diary will be provided to parents/caregivers in order to check the frequency and entity of the critical episodes. An EEG recording will be performed at enrollment (or within 6 months prior to the baseline visit).
• Sodium butyrate and zinc oxide
Post-biotic supplementation will be administered for 3 month period (i.e. 12 weeks) given the filling out of a supplementation diary by parents/caregivers. At the scheduled visits/ phone contacts (i.e., baseline, 4 weeks and 12 weeks), systemic inflammation, intestinal inflammation, and gut microbiome characterization, as well as treatment compliance, clinical and dietary intake will be assessed. A seizure diary will be provided to parents/caregivers in order to check the frequency and entity of the critical episodes. An EEG recording will be performed at enrollment (or within 6 months prior to the baseline visit).

Locations

Country	Name	City	State
Italy	Policlinico "S. Maria alle Scotte" Azienda Ospedaliera Universitaria Senese	Siena

Sponsors (3)

Lead Sponsor	Collaborator
Azienda Ospedaliera Universitaria Senese	European Institute of Oncology, Kolfarma s.r.l. - Italy

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Quality of life and gastrointestinal health	Change in well-being indices [Quality of Life Inventory-Disability Questionnaire (QI-Disability), Gastrointestinal Health Questionnaire (GHQ), Bristol Stool Chart (BSC), Rome III scoring, Sleep Disturbance Scale for Children Questionnaire (SDSC)]; [QI-Disability: lower scores indicate a worse outcome, BSC: type 1-2 indicate constipation, type 3-4 normal, and type 5-7 diarrhea), Rome III scoring: higher scores indicate a worse outcome, SDSC: higher scores indicate a worse outcome]	Change at 3 months from baseline of each interventional arm
Other	Quality of life and illness severity	Change in clinical severity [Rett Syndrome Behaviour Questionnaire (RSBQ) and Motor Behavioural Assessment Scale (MBAS)] (higher scores of RSBQ and MBAS indicate a worse outcome)	Change at 3 months from baseline of each interventional arm
Primary	Systemic inflammation	Change in circulating pro-inflammatory or change in anti-inflammatory cytokine levels	Change at 3 months from baseline of each interventional arm
Primary	Gut inflammation	Change in fecal calprotectin levels	Change at 3 months from baseline of each interventional arm
Primary	Gut dysbiosis	Change in intestinal microbiota biodiversity	Change at 3 months from baseline of each interventional arm
Secondary	Epileptogenesis	Change in frequency and/or severity of epileptic seizures (a seizure diary provided to parents/caregivers at the baseline visit)	Change at 3 months from baseline of each interventional arm