Journal Article

Increased circulating butyrate and ursodeoxycholate during probiotic intervention in humans with type 2 diabetes

Tyagi, Surabhi, Souza, Michael, Sieber, Christian M. K., Kolterman, Orville, Justice, Nicholas, McMurdie, Paul J., Eid, John, Gines, Jessica, Stoeva, Magdalena K., Nemchek, Madeleine, Skennerton, Connor T.

2022

Overview

Background An increasing body of evidence implicates the resident gut microbiota as playing a critical role in type 2 diabetes (T2D) pathogenesis. We previously reported significant improvement in postprandial glucose control in human participants with T2D following 12-week administration of a 5-strain novel probiotic formulation (‘WBF-011’) in a double-blind, randomized, placebo controlled setting (NCT03893422). While the clinical endpoints were encouraging, additional exploratory measurements were needed in order to link the motivating mechanistic hypothesis - increased short-chain fatty acids - with markers of disease. Results Here we report targeted and untargeted metabolomic measurements on fasting plasma ( n  = 104) collected at baseline and end of intervention. Butyrate and ursodeoxycholate increased among participants randomized to WBF-011, along with compelling trends between butyrate and glycated haemoglobin (HbA1c). In vitro monoculture experiments demonstrated that the formulation’s C. butyricum strain efficiently synthesizes ursodeoxycholate from the primary bile acid chenodeoxycholate during butyrogenic growth. Untargeted metabolomics also revealed coordinated decreases in intermediates of fatty acid oxidation and bilirubin, potential secondary signatures for metabolic improvement. Finally, improvement in HbA1c was limited almost entirely to participants not using sulfonylurea drugs. We show that these drugs can inhibit growth of formulation strains in vitro. Conclusion To our knowledge, this is the first description of an increase in circulating butyrate or ursodeoxycholate following a probiotic intervention in humans with T2D, adding support for the possibility of a targeted microbiome-based approach to assist in the management of T2D. The efficient synthesis of UDCA by C. butyricum is also likely of interest to investigators of its use as a probiotic in other disease settings. The potential for inhibitory interaction between sulfonylurea drugs and gut microbiota should be considered carefully in the design of future studies.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Akkermansia muciniphila / Anaerobutyricum hallii / Bile / Bile acids / Bile Acids and Salts - analysis / Bile Acids and Salts - blood / Bile Acids and Salts - metabolism / Bilirubin / Biological Microscopy / Biomedical and Life Sciences / Blood Glucose - drug effects / Butyrate / Butyrates - analysis / Butyrates - blood / Butyrates - metabolism / Care and treatment / Chenodeoxycholate / Clinical trials / Clostridium butyricum / Clostridium butyricum - metabolism / Deoxycholic acid / Diabetes / Diabetes mellitus (non-insulin dependent) / Diabetes Mellitus, Type 2 - blood / Diabetes Mellitus, Type 2 - drug therapy / Diabetes Mellitus, Type 2 - microbiology / Drug development / Drug interaction / Drugs / Experiments / Fatty acids / Fatty Acids, Volatile - analysis / Fatty Acids, Volatile - blood / Fatty Acids, Volatile - metabolism / Feces / Feces - chemistry / Gastrointestinal Microbiome - drug effects / Glycated Hemoglobin A - analysis / Health aspects / Hemoglobin / Humans / Intermediates / Intestinal microflora / Life Sciences / Metabolism / Metabolites / Metabolomics / Microbiology / Microbiomes / Microbiota / Microbiota (Symbiotic organisms) / Monoculture / Mycology / Oxidation / Parasitology / Pathogenesis / Plasma / Probiotics / Probiotics - metabolism / Probiotics - therapeutic use / Sulfonylurea / Sulfonylurea Compounds - therapeutic use / Testing / Type 2 diabetes / Ursodeoxycholic Acid - analysis / Ursodeoxycholic Acid - blood / Ursodeoxycholic Acid - metabolism / Virology