Duodenal <i>Anaerobutyricum soehngenii</i> infusion stimulates GLP-1 production, ameliorates glycaemic control and beneficially shapes the duodenal transcriptome in metabolic syndrome subjects: a randomised double-blind placebo-controlled cross-over study.

Abstract

Although gut dysbiosis is increasingly recognised as a pathophysiological component of metabolic syndrome (MetS), the role and mode of action of specific gut microbes in metabolic health remain elusive. Previously, we identified the commensal butyrogenic <i>Anaerobutyricum soehngenii</i> to be associated with improved insulin sensitivity in subjects with MetS. In this proof-of-concept study, we investigated the potential therapeutic effects of <i>A. soehngenii</i> L2-7 on systemic metabolic responses and duodenal transcriptome profiles in individuals with MetS. In this randomised double-blind placebo-controlled cross-over study, 12 male subjects with MetS received duodenal infusions of <i>A. soehngenii</i>/ placebo and underwent duodenal biopsies, mixed meal tests (6 hours postinfusion) and 24-hour continuous glucose monitoring. <i>A. soehngenii</i> treatment provoked a markedly increased postprandial excursion of the insulinotropic hormone glucagon-like peptide 1 (GLP-1) and an elevation of plasma secondary bile acids, which were positively associated with GLP-1 levels. Moreover, <i>A. soehngenii</i> treatment robustly shaped the duodenal expression of 73 genes, with the highest fold induction in the expression of regenerating islet-protein 1B (<i>REG1B</i>)-encoding gene. Strikingly, duodenal <i>REG1B</i> expression positively correlated with GLP-1 levels and negatively correlated with peripheral glucose variability, which was significantly diminished in the 24 hours following <i>A. soehngenii</i> intake. Mechanistically, Reg1B expression is induced upon sensing butyrate or bacterial peptidoglycan. Importantly, <i>A. soehngenii</i> duodenal administration was safe and well tolerated. A single dose of <i>A. soehngenii</i> improves peripheral glycaemic control within 24 hours; it specifically stimulates intestinal GLP-1 production and <i>REG1B</i> expression. Further studies are needed to delineate the specific pathways involved in REG1B induction and function in insulin sensitivity. NTR-NL6630.