The effects of prebiotics on gastrointestinal side effects of metformin in youth: A pilot randomized control trial in youth-onset type 2 diabetes

Abstract

Disclosure summaryDr. Yadav is Chief Scientific Officer and Co-Founder of Postbiotics Inc and has no conflict of interest with this work. All other authors have no conflicts of interest to disclose.BackgroundMetformin is the only approved first-line oral glucose lowering agent for youth with type 2 diabetes mellitus (Y-T2DM) but often causes gastrointestinal (GI) side effects, which may contribute to reduced treatment adherence and efficacy. Prebiotic intake may reduce metformin’s side effects by shifting microbiota composition and activity.ObjectiveThe aims of this study were to determine the feasibility and tolerability of a prebiotic supplement to improve metformin-induced GI symptoms and explore the changes in glycemia and shifts in the microbiota diversity.MethodsIn a two-phase pilot clinical trial, we compared, stool frequency and stool form every 1-2 days, and composite lower GI symptoms (weekly) at initiation of daily metformin combined with either a daily prebiotic or a placebo shake in a 1-week randomized double-blind crossover design (Phase 1), followed by a 1-month open-labeled extension (Phase 2). Plasma glycemic markers and stool samples were collected before and after each phase.ResultsSix Y-T2DM (17.2 ± 1.7y (mean ± SD), 67% male, BMI (42 ± 9 kg/m2), HbA1c (6.4 ± 0.6%)) completed the intervention. Stool frequency, stool composition, and GI symptom scores did not differ by group or study phase. There were no serious or severe adverse events reported, and no differences in metabolic or glycemic markers. After one week Phase 1metformin/placebo Proteobacteria, Enterobacteriaceae, and Enterobacteriales were identified as candidate biomarkers of metformin effects. Principle coordinate analyses of beta diversity suggested that the metformin/prebiotic intervention was associated with distinct shifts in the microbiome signatures at one week and one month.ConclusionAdministration of a prebiotic fiber supplement during short-term metformin therapy was well tolerated in Y-T2DM and associated with modest shifts in microbial composition. This study provides a proof-of-concept for feasibility exploring prebiotic-metformin-microbiome interactions as a basis for adjunctive metformin therapy.Clinical trial registrationhttps://clinicaltrials.gov/, identifier NCT04209075.

Role of prebiotics and probiotics in the prevention of the gastrointestinal side effects of metformin among the type 2 diabetic patients

“…This finding of the research was also backed by various studies that were performed in the different regions of the globe. [16][17][18] This study also noted that metformin induced GI side effects frequency was higher with high dose of metformin.…”

“…This imbalance in the gut flora could be the cause of metformin-induced GI side effects. 16,17 Various researches have presented that use of prebiotics and probiotics along with metformin balance the gut flora imbalance induced by alone use of metformin and consequently the metformin-induced GI side effects gets settled. 17,18 GI side effects of metformin and role of prebiotics and probiotics use in the prevention of metformin-induced GI side effects are under-studied in the different regions of Pakistan, especially in the locality of this research.…”

An Update on Prebiotics and on Their Health Effects

“…In a recent study [80], a commercial formula, composed of inulin and glucans, was tested on young patients affected by type 2 diabetes and the main effect was a modulation of gut microbiota after 1 week and 1 month, while stool frequency and gastro-intestinal symptoms were not affected.…”

Targeting metabolic pathways: a novel therapeutic direction for type 2 diabetes

“…Studies have shown that changes in the gut microbiome of T2DM include not only changes in the number, composition and diversity of the microbiota, but also changes in the levels of metabolites in the gut microbiome, which can inhibit insulin release and lead to the development of T2DM ( Bao et al., 2023 ). Second, changes in the gut microbiome are relevant to the treatment of T2DM: in the treatment of patients with T2DM, the use of probiotics and prebiotics can regulate the balance of the gut microbiome, thereby improving insulin resistance and blood glucose levels in patients with T2DM ( Paul et al., 2022 ; Chen et al., 2023 ; Dixon et al., 2023 ). Again, the mechanism of action of intestinal flora changes in T2DM: intestinal flora can influence the development and progression of T2DM through a variety of mechanisms, including altering nutrient metabolism, affecting the intestinal barrier and immune system, and influencing neurological regulation ( Tawulie et al., 2023 ).…”