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

Authors: THAPA, SANTOSH - Texas Children'S Hospital; VENKATACHALAM, ALAMELU - Texas Children'S Hospital; KHAN, NABEEL - Baylor College Of Medicine; NAQVI, MOHAMMED - Baylor College Of Medicine; BALDERAS, MIRIAM - Texas Children'S Hospital; RUNGE, JESSICA - Texas Children'S Hospital; HAAG, ANTHONY - Texas Children'S Hospital; HOCH, KATHLEEN - Texas Children'S Hospital; GLAZE, DANIEL - Baylor College Of Medicine; LUNA, RUTH - Texas Children'S Hospital; MOTIL, KATHLEEN - Children'S Nutrition Research Center (CNRC)

Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/22/2021
Publication Date: 5/6/2021
Citation: Thapa, S., Venkatachalam, A., Khan, N., Naqvi, M., Balderas, M., Runge, J.K., Haag, A., Hoch, K.M., Glaze, D.G., Luna, R.A., Motil, K.J. 2021. Assessment of the gut bacterial microbiome and metabolome of girls and women with Rett Syndrome. PLoS ONE. 16(5):e0251231. https://doi.org/10.1371/journal.pone.0251231.
DOI: https://doi.org/10.1371/journal.pone.0251231

Interpretive Summary: Our research seeks to understand the impact of diet on gastrointestinal health and quality of life in children and young adults. We characterized the composition of the intestinal microbiome and metabolome in children and young adults with Rett syndrome (RTT), a rare genetic disorder, because more than 90% of individuals affected with this disorder develop gastrointestinal problems that affect their health and quality of life. Our findings of greater bacterial richness and diversity among individuals who consumed table foods compared with those who received a milk-based formula suggest a potential benefit of a vegetable-rich, fiber-rich diet. Our findings of lower dietary, fecal, and plasma glutamate concentrations, the latter in association with abdominal gas bloating, raises the possibility of altered bacterial neurochemistry and neurologic dysfunction as a source of gastrointestinal symptoms in these individuals. These observations are important because dietary interventions that favorably alter intestinal microbial profiles may provide therapeutic benefit to healthy children and adolescents commonly affected with functional gastrointestinal disorders.

Technical Abstract: 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. 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. 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. 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 gamma-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. 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 dys-function. Nevertheless, alterations in the gut metabolome may provide clues to the patho-physiology of gastrointestinal problems in RTT.