Discussion
metabolic endotoxemia, T2DM
ADVERSE REACTIONS, SECONDARY, ADVERSE EVENTS, RECRUITMENT
Metformin intolerance is an important clinical barrier to care and a potentially modifiable target for adjunctive treatment in Y-T2DM. This novel pilot study evaluated the tolerability and feasibility of using a prebiotic supplement and microbiome modulator at the time of metformin treatment initiation and dose escalation. The prebiotic supplement was feasible and well tolerated in youth and was not associated with increased GI symptoms or adverse reactions. Participants tolerated the rapid metformin dose escalation without adverse events. Our findings are consistent with studies in adults supporting prebiotics as adjunctive therapy in adults on metformin pharmacotherapy (Prebiotics and dietary adjuncts to traditional medicines in Y-T2DM are attractive candidates for addressing the complex multi-faceted care considerations in youth, with studies already suggesting beneficial glycemic effects when combining prebiotics and polyphenols with metformin in adults with T2DM (Notably, this study filled an important knowledge gap by demonstrating, for the first time in Y-T2DM, distinct metformin-induced shifts in gut microbiota signatures after one week of monotherapy or in combination with prebiotics. These findings extend previous studies in adults indicating metformin-induced shifts in microbiota occurred within 24 hours of drug initiation (The short term combination of metformin/prebiotic supplementation also resulted in potentially beneficial microbial shifts towards greater enrichment in some SCFA producing bacteria such as These foundational findings support the design of larger studies to evaluate whether the shifts in microbiome could be associated with metabolic improvement in Y-T2DM. Incremental trends for improved glucose and triglyceride homeostasis were observed during Phase 1 of our trial and abolished during the Phase 2 open-label period. A strength of this study, therefore, was to demonstrate that detailed metabolic phenotyping combining ecological momentary assessments of glycemia (CGM) and standardized mixed meal tests, were useful for identifying targets for metabolic phenotyping. The rigorous double-blind crossover design and controlled feeding periods during Phase 1 reduced the chances of carry-over effects in metformin, dietary intake, and prebiotics. The run-in and washout periods exceeded the five half-lives needed to eliminate metformin from the plasma and red blood cell compartments and minimized the carry-over effects of metformin and prebiotic changes in the microbiota. The cross-over study design also accounted for interindividual heterogeneity in microbiome signatures and host-environmental effects, increasing the ability to identify small microbiota shifts.Generalizability of this pilot study was restricted by the small sample size with limited recruitment and product availability secondary to COVID-19 pandemic 2020-2022. Participants also had few GI symptoms at baseline and additional studies will be needed to determine the effectiveness in youth with increased frequency and/or severity of GI symptoms. Other limitations include multiple exploratory metabolic and microbiome analyses with a lack of correlation with stool metabolites such as short-chain fatty acids. Additionally, metformin treatment is associated with reduced lipopolysaccharide (LPS) and improvements in metabolic endotoxemia (