Improvements to postprandial glucose control in subjects with type 2 diabetes: a multicenter, double blind, randomized placebo-controlled trial of a novel probiotic formulation

Abstract

Introduction: A growing body of evidence suggests that specific, naturally occurring gut bacteria are under-represented in the intestinal tracts of subjects with type 2 diabetes (T2D) and that their functions, like gut barrier stability and butyrate production, are important to glucose and insulin homeostasis. The objective of this study was to test the hypothesis that enteral exposure to microbes with these proposed functions can safely improve clinical measures of glycemic control and thereby play a role in the overall dietary management of diabetes.

Research design and methods: We evaluated whether a probiotic comprised of these anaerobic bacteria would enhance dietary management by (1) manufacturing two novel probiotic formulations containing three (WBF-010) or five (WBF-011) distinct strains in a Current Good Manufacturing Practice (cGMP) facility, (2) establishing consistent live-cell concentrations, (3) confirming safety at target concentrations dispensed in both animal and human studies and (4) conducting a 12-week parallel, double-blind, placebo-controlled, proof-of-concept study in which subjects previously diagnosed with T2D (n=76) were randomly assigned to a two times a day regimen of placebo, WBF-010 or WBF-011.

Results: No safety or tolerability issues were observed. Compared with the placebo group, subjects administered WBF-011 (which contains inulin, Akkermansia muciniphila, Clostridium beijerinckii, Clostridium butyricum, Bifidobacterium infantis and Anaerobutyricum hallii) significantly improved in the primary outcome, glucose total area under the curve (AUC): -36.1 mg/dL/180 min, p=0.0500 and also improved in secondary outcomes, glycated hemoglobin (A1c): -0.6, glucose incremental-AUC: -28.6 mg/dL/180 min.

Conclusions: To our knowledge, this is the first randomized controlled trial to administer four of the five strains to human subjects with T2D. This proof-of-concept study (clinical trial number NCT03893422) shows that the intervention was safe and well tolerated and that supplementation with WBF-011 improves postprandial glucose control. The limited sample size and intersubject variability justifies future studies designed to confirm and expand on these observations.

Keywords: diabetes mellitus, Type 2; fatty acids; glycated hemoglobin A.

Conflict of interest statement

Competing interests: All authors are employees and stock/stock option shareholders of Pendulum Therapeutics, Inc (formerly known as ‘Whole Biome Inc.’). OK owns stock in GlySens, Inc, has stock options in ViaCyte, Inc, and is a consultant to NuSirt BioPharma, Circius, and NanoPrecision Medical.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Summary of trial. (A) CONSORT flow diagram of subject enrollment, allocation, and follow-up counts. A total of 76 subjects were randomized at one of six US study sites and allocated by block to one of three experimental arms. Withdrawal from study participation was similar across arms, whereas those on placebo were more likely to discontinue the intervention. (B) Ingredients present in respective formulation capsules. Specific per-strain viability is provided in online supplementary table S1. A description of study formulation production is provided in online supplementary text S4. (C) Graphical summary of glucose control measurement outcomes. Primary endpoint was total glucose AUC0-180 min, while incremental glucose AUC0-180 min and A1c were key secondary measures. Additional detail is provided in table 2 and online supplementary figure S1. AUC, area under the curve.

Figure 2

Rates of detection of probiotic strains via qPCR at each of four collection timepoints. Each point indicates the fraction of subjects in a study arm that had at least two replicates with positive detection. Light gray box indicates the y-axis range of proportions observed in samples from subjects randomized to the placebo group. Point shape distinguishes separate primer-pairs for the same strain. Primer sequences are defined in online supplementary table S1. All stool homogenate samples were measured in at least quadruplicate reactions for each primer-pair.

Figure 3

Summary of subject-wise changes in stool SCFAs. Each point in each panel represents a different subject in the study. (A) Change in the stool butyrate fraction of total SCFA (acetate, propionate, butyrate), shown as the per-subject Log10-ratio of week-12 to baseline. (B) Changes in the millimolar concentration in stool. Changes are represented as baseline subtracted from week-12 (median difference for technical replicate pairs). Panels separate the values for each SCFA. Further detail is provided in online supplementary text S4. SCFA, short-chain fatty acid.