Anaerobutyricum soehngenii improves glycemic control and other markers of cardio-metabolic health in adults at risk of type 2 diabetes

Abstract

Anaerobutyricum soehngenii (previously Eubacterium hallii) is a butyrate-producing next-generation beneficial microbe generally recognized as safe. Several short-term intervention trials by A. soehngenii L2-7 have shown improvement of insulin sensitivity in prediabetic subjects and type 2 diabetes patients. To determine the long-term cardiometabolic benefits and safety, we performed a 3-month double-blind, randomized placebo-controlled intervention in 98 prediabetic insulin-resistant adults in Europe and U.S. with daily administration of encapsulated cells of A. soehngenii CH-106, a tetracycline-sensitive isogenic derivative of strain L2-7. Compared to placebo, A. soehngenii-treated subjects showed significantly reduced glycemic variability (1% reduction in the coefficient of variation; p = 0.01) and improved glycemic control (6% reduction in the overall net glycemic action-1; p < 0.05), including reduced serum glycated hemoglobin (HbA1c) levels when including the 4-week washout period (1 mmol/mol reduction; p < 0.05). Moreover, diastolic blood pressure was significantly reduced in all A. soehngenii-treated subjects (3 mm Hg; p < 0.05). The study product was well-tolerated and had no effect on the global intestinal microbiota composition, including alpha and beta-diversity, besides an increased abundance of A. soehngenii in the treatment group, indicative of compliance. The U.S. participants, compared to those in Europe, responded best, notably in the oral glucose tolerance tests (15% improvement in the area-under-the curve of plasma glucose levels; p = 0.039) or coefficient of variation (reduction of 3.1%; p < 0.05). This potentially relates to a more severe prediabetic state in U.S. subjects, associated with significantly reduced (1.5-3.5-fold) relative abundance of Bifidobacterium, Coprococcus, Ruminococcus spp. and two-fold increased relative abundance of Lachnoclostridium spp. In conclusion, daily oral supplementation with A. soehngenii was safe and improved various markers of glycemic control, reduced HbA1c levels and diastolic blood pressure, indicating a novel microbiome-based approach to improve cardio-metabolic health in adults at risk for developing type 2 diabetes.Clinical trial reg. no. NCT04529473, clinicaltrials.govSocial media summary 120 characters: Anaerobutyricum soehngenii supplementation improves #cardio-metabolic health in subjects at risk for type 2 #diabetes.

Keywords: Anaerobutyricum; butyrate-producing bacteria; continuous glucose measurement; glycemic control; intestinal microbiota; next-gen beneficial microbes; prediabetes; responder analysis; type 2 diabetes.

Graphical abstract

Figure 1.

Effect of A. soehngenii supplementation on (a) iAUC after OGTT, (b) delta change iAUC, (c) HbA1c, and (d) delta HbA1c between week 0 and week 16. Analyses performed using a linear mixed effects model. p < 0.05 was considered statistically significant. Abbreviations used: IAUC =  incremental area under the curve; OGTT = Oral glucose tolerance test.

Figure 2.

Effect of A. soehngenii supplementation on glycemic variability metrics. (a) Coefficient of variance (CV), (b) delta change CV, (c) continuous overall net glycemic action (CONGA), and (d) delta CONGA between. All analyses performed using a linear mixed effects model. p < 0.05 was considered statistically significant.

Figure 3.

Effect of A. soehngenii supplementation on (a) systolic blood pressure, (b) diastolic blood pressure, and (c) change in diastolic blood pressure between week 0 and week 12. Delta analyses performed using a linear regression model on total dataset and linear mixed effects models for within group comparisons. p < 0.05 was considered statistically significant.

Figure 4.

Gut microbiota analysis based on 16S rRNA amplicon sequencing and qPCR. The overall principal coordinate analysis (PCoA) of the microbiota composition (α-diversity based on Bray–Curtis dissimilarity) in the A. soehngenii-treated and placebo groups before (a) and after intervention (b) are shown, revealing significant center-based effects. (c) The ratio of A. soehngenii CH-106 rRNA over total bacterial rRNA at time points visit 3 (week 0 – baseline) and visit 6 (week 12 – end of the intervention). (d) The bacterial signature that differentiates the gut microbiota of the European (EU) and U.S. participants at baseline with relevant fold-change, p-value and false discovery rate (FDR).

Figure 5.

Distribution of the improvement in serum HbA1C over baseline in the intervention group (a). The signature with the most representative taxa that differentiate responders and non-responders is shown with relevant fold-change, p-value and false discovery rate (FDR) (b).