The Effects of Limosilactobacillus reuteri LR-99 Supplementation on Body Mass Index, Social Communication, Fine Motor Function, and Gut Microbiome Composition in Individuals with Prader–Willi Syndrome: a Randomized Double-Blinded Placebo-Controlled Trial

Abstract

Prader–Willi syndrome (PWS) is a rare genetic disorder associated with developmental delay, obesity, and neuropsychiatric comorbidities. Limosilactobacillus reuteri (Lactobacillus reuteri, Lact. reuteri) has demonstrated anti-obesity and anti-inflammatory effects in previous studies. In the present study, we aim to evaluate the effects of Lact. reuteri supplementation on body mass index (BMI), social behaviors, and gut microbiota in individuals with PWS. We conducted a 12-week, randomized, double-blind, placebo-controlled trial in 71 individuals with PWS aged 6 to 264 months (64.4 ± 51.0 months). Participants were randomly assigned to either receive daily Lact. reuteri LR-99 probiotic (6 × 1010 colony forming units) or a placebo sachet. Groupwise differences were assessed for BMI, ASQ-3, and GARS-3 at baseline, 6 weeks, and 12 weeks into treatment. Gut microbiome data was analyzed with the QIIME2 software package, and predictive functional profiling was conducted with PICRUSt-2. We found a significant reduction in BMI for the probiotic group at both 6 weeks and 12 weeks relative to the baseline (P < 0.05). Furthermore, we observed a significant improvement in social communication and interaction, fine motor function, and total ASQ-3 score in the probiotics group compared to the placebo group (P < 0.05). Altered gut microbiota was observed in the probiotic group to favor weight loss and improve gut health. The findings suggest a novel therapeutic potential for Lact. reuteri LR-99 probiotic to modulate BMI, social behaviors, and gut microbiota in Prader–Willi syndrome patients, although further investigation is warranted.Trial registration Chinese Clinical Trial Registry: ChiCTR1900022646

Recommendations for the diagnosis and management of childhood Prader-Willi syndrome in China

“…At present, the management of PWS is based on symptoms. It was reported that Limosilactobacillus reuteri probiotic could be used to modulate BMI, social behaviors, and gut microbiota in patients with PWS, although further investigation was warranted [ 115 ]. Oxytocin (OXT) and its analogue, carbetocin, are extensively studied in PWS clinical trials and have shown potential for treating both hyperphagia and behavior problems in pediatric PWS, although future investigations should confirm the previous study findings with extended follow-up periods within larger, well-defined clinical cohorts and also determine long-term effects and safety [ 116 , 117 ].…”

Targeting the Gut Microbiome in Prader-Willi Syndrome

“…For this purpose, a literature review up until July 2021 was carried out using PubMed database searches with the following terms: "Prader-Willi syndrome" and "gut/intestinal microbiome/microbiota". We identified 13 publications that included both observational [25][26][27][28] and interventional studies [29][30][31][32][33], a study protocol [34], and three studies based on secondary analyses of microbiome data from previously published articles [35][36][37]. Publications were classified based on their evidence level in accordance with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology, considering the lowest evidence level "Expert opinion" (score 4) and the highest evidence level "High quality meta-analysis, systematic reviews of randomized controlled trials (RCTs), or RCTs with a very low risk of a bias" (score 1 ++ ) [38].…”

“…To this date, four randomized controlled clinical studies have evaluated the effects of probiotic supplementation in individuals with PWS using two different bacterial species, namely B. lactis and L. reuteri without significant adverse events (Table 2) [30][31][32][33]. Additionally, a study implementing a dietary intervention with prebiotics and a fiber-rich diet has also been reported [29].…”

“…Recently, a larger clinical trial designed to test two different probiotic strains in a crossover fashion has been completed; results were independently evaluated for each bacterial strain and reported in two different publications as parallel-group clinical studies [32,33]. First, the authors conducted a randomized, double-blind, placebo-controlled 12-week trial to evaluate the efficacy of B. lactis (BL-11) on weight, height, and psychological measurements [33].…”

“…While no major changes were found in psychological measurements, the authors reported improvement of the clinician's view of the patient's global functioning measured by the Clinical Global Impression Improvement (CGI-I) scale. The second study consisted in a 12-week randomized, double-blind, placebo-controlled trial providing Limosilactobacillus reuteri (LR-99) in a cohort of 71 individuals with PWS aged 5.4 ± 4.3 years [32]. Probiotic supplementation significantly reduced BMI and improved social communication, social interaction, and fine motor function.…”