Effect of prebiotic intake on gut microbiota, intestinal permeability and glycemic control in children with type 1 diabetes: study protocol for a randomized controlled trial
The gut microbiome plays a key role in health but is increasingly recognized as a contributor to various disease states when an imbalance or dysbiosis occurs. Both animal and human studies found a difference in microbial composition between those that develop type 1 diabetes from those that did not develop diabetes [1]. In animal studies, interventions that change the gut microbiota can alter immune response and can play a role in the development of type 1 diabetes [2]. In children with type 1 diabetes (DM1), alterations in gut microbiota have been identified [3–6]. For example, bifidobacteria have previously been found to negatively correlate with beta-cell autoimmunity in Finnish children with diabetes-related autoantibodies [3] and in Spanish children with DM1 [6]. Faecalibacterium prausnitzii, a butyrate-producing bacterium, has been shown to have some anti-inflammatory effects and has been found to be decreased in children with diabetes-related autoantibodies [3].
Prebiotics are defined as selectively fermented ingredients that result in specific changes in the composition and/or activity of the gastrointestinal microbiota, thus conferring benefit(s) upon host health [7]. Prebiotics have been shown to increase the abundance of both bifidobacteria and Faecalibacterium prausnitzii [8] and, therefore, may help correct defects in the gut microbial environment associated with DM1 development and progression. Beyond reducing dysbiosis in the gut microbial environment, prebiotics have also been shown to improve glucose tolerance via mechanisms that likely include enhanced production and secretion of the incretin glucagon-like peptide 1 (GLP-1) [9]. Indeed, prebiotics improved hemoglobin A1c (HbA1c), postprandial glycemic excursion and inflammatory markers in patients with type 2 diabetes [9, 10]. To date however, there have been no studies examining the effect of using prebiotics to alter gut microbiota and intestinal permeability in children with DM1 and whether such changes can improve glycemic control.
In addition to increased incretin production, prebiotics may improve glycemia through its action on intestinal mucosal barrier function and gut microbiota [11–14]. Both animal and human studies have linked gut microbiota to metabolic dysregulation. Patients with diabetes have distinct gut microbiota in comparison to healthy individuals [3, 4], with a higher gram-negative to gram-positive bacterial ratio and a lower abundance of bifidobacteria, an important microbial population with many health benefits [1, 15, 16].
In animal studies, diabetes is also associated with increased gut permeability, allowing bacterial lipopolysaccharides (LPS) from gram-negative bacteria to translocate into the systemic circulation, causing metabolic endotoxemia, triggering pro-inflammatory cytokine secretion and insulin resistance [17–19]. Animal studies showed that prebiotic treatment dose-dependently increases bifidobacteria [20], reduces gut permeability and endotoxemia [21, 22] and improves glucose tolerance [23]. Indeed, bifidobacteria abundance negatively correlates with serum LPS, fasting insulin and glucose [21]. Prebiotics also enhance GLP-2 production, which restores tight junction protein expression and reduces gut permeability [18]. Hence, prebiotics may improve glucose homeostasis by two separate mechanisms: (1) up-regulating GLP-1 to improve beta-cell mass and function, and (2) altering gut microbiota and permeability to a less pro-inflammatory phenotype, improving insulin sensitivity. In humans, bacterial endotoxin activity has been shown to be associated with insulin resistance [24]. However, direct manipulation of gut microbiota in humans and its impact on gut permeability and glycemic control has not been studied, and whether these mechanisms also operate in humans is unknown.
Prebiotics are a potentially novel, inexpensive, low-risk treatment addition for DM1 that may improve glycemic control by changes in gut microbiota, gut permeability and inflammation. This pilot study will provide critical proof of concept data for future trials looking at the efficacy of using prebiotics as an adjunct in the management of DM1 to improve glycemic control.
The primary objective of this study is to determine the effect of a 12-week dietary intervention with 8 g/day of prebiotic intake compared to placebo on glycemic control as measured by HbA1c in children diagnosed with DM1 for at least one year. The secondary objective is to determine the gut microbiota composition in children diagnosed with DM1 consuming prebiotic versus placebo. Further, we aim to examine the differences in gut permeability, serum inflammatory markers, glucagon-like peptide 1 (GLP-1) and GLP-2 and C-peptide in children diagnosed with DM1 consuming prebiotics versus placebo and to assess for diabetes-related adverse reactions (i.e. severe hypoglycemia and diabetic ketoacidosis) associated with use of prebiotics in children with DM1.