Assessment of the gut bacterial microbiome and metabolome of girls and women with Rett Syndrome

Abstract

Background Gastrointestinal problems affect the health and quality of life of individuals with Rett syndrome (RTT) and pose a medical hardship for their caregivers. We hypothesized that the variability in the RTT phenotype contributes to the dysbiosis of the gut microbiome and metabolome in RTT, predisposing these individuals to gastrointestinal dysfunction. Objectives We characterized the gut bacterial microbiome and metabolome in girls and young women with RTT (n = 44) and unaffected controls (n = 21), and examined the relation between the composition of the microbiome and variations in the RTT phenotype. Methods Demographics and clinical information, including growth and anthropometric measurements, pubertal status, symptoms, clinical severity score, bowel movement, medication use, and dietary intakes were collected from the participants. Fecal samples were collected for analysis of the gut microbiome using Illumina MiSeq-based next-generation sequencing of the 16S rRNA gene followed by bioinformatics analysis of microbial composition, diversity, and community structure. Selected end-products of microbial protein metabolism were characterized by liquid chromatography-mass spectrometry. Results The gut bacterial microbiome differed within the RTT cohort based on pubertal status (p<0.02) and clinical severity scores (p<0.02) of the individuals and the type of diet (p<0.01) consumed. Although the composition of the gut microbiome did not differ between RTT and unaffected individuals, concentrations of protein end-products of the gut bacterial metabolome, including γ-aminobutyric acid (GABA) (p<0.001), tyrosine (p<0.02), and glutamate (p<0.06), were lower in the RTT cohort. Differences in the microbiome within RTT groups, based on symptomatic anxiety, hyperventilation, abdominal distention, or changes in stool frequency and consistency, were not detected. Conclusions Although variability in the RTT phenotype contributes to the dysbiosis of the gut microbiome, we presently cannot infer causality between gut bacterial dysbiosis and gastrointestinal dysfunction. Nevertheless, alterations in the gut metabolome may provide clues to the pathophysiology of gastrointestinal problems in RTT.

Literature Cases Summarized Based on Their Polysomnographic Findings in Rett Syndrome

“…Transmission of endogenous glutamate concentrations was proven to play a role in characterizing the durations of sleep and wakefulness [ 63 ]. In human research, fecal glutamate has been shown to be significantly lower in RTT females than unaffected controls [ 64 ]. although the specific mechanisms of REM sleep remain unclear [ 59 ].…”

Metabolomic Fingerprint of Mecp2-Deficient Mouse Cortex: Evidence for a Pronounced Multi-Facetted Metabolic Component in Rett Syndrome

“…It is metabolized by the gut microbiome [ 106 ]. In RTT, the gut microbiome, depending on clinical severity score, has been reported to shift towards a less diverse and pro-inflammatory composition [ 38 , 107 ]. This may result in an altered bioavailability of non-metabolized rutin in Mecp2 −/y mice.…”

“…Metabolomic studies in RTT are currently in their early stages but bear the potential to provide global insights into pathogenic mechanisms. Recently, the suitability of this approach was demonstrated in a first metabolomics study on RTT patient-derived blood samples [ 37 ], and the characterization of the gut microbiome and metabolome in RTT patients [ 38 ]. An earlier pilot metabolic screening in male Mecp2 -null ( Mecp2 −/y ) mice analyzed full brain extracts by means of high-resolution magnetic resonance spectroscopy.…”

Gut microbiota profiles in mental disorders and their association with behavior in children and adolescents.

“…Due to the small number of published articles, we decided not to exclude the studies which involved both children and young adults. Adult patients were included in one AN study, two ADHD studies, MDD and Rett syndrome study [16][17][18][19][20].…”

“…Only one study published to date involved children and adolescents with RTT along with young women [20]. Alpha diversity as well as beta diversity between patients and healthy controls did not differ signi cantly.…”