A mechanism by which gut microbiota elevates permeability and inflammation in obese/diabetic mice and human gut
2023/03/22 by Sidharth P. Mishra, Sidharth P Mishra, Bo Wang +12 · 29 citations
Biochemistry, Genetics and Molecular Biology · Medicine · Neuroscience · #Gut microbiota and health #Clostridium difficile and Clostridium perfringens research #Barrier Structure and Function Studies
paper · pdf · doi:10.1136/gutjnl-2022-327365
Abstract
Objective Ample evidence exists for the role of abnormal gut microbiota composition and increased gut permeability (‘leaky gut’) in chronic inflammation that commonly co-occurs in the gut in both obesity and diabetes, yet the detailed mechanisms involved in this process have remained elusive. Design In this study, we substantiate the causal role of the gut microbiota by use of faecal conditioned media along with faecal microbiota transplantation. Using untargeted and comprehensive approaches, we discovered the mechanism by which the obese microbiota instigates gut permeability, inflammation and abnormalities in glucose metabolism. Results We demonstrated that the reduced capacity of the microbiota from both obese mice and humans to metabolise ethanolamine results in ethanolamine accumulation in the gut, accounting for induction of intestinal permeability. Elevated ethanolamine increased the expression of microRNA- miR-101a-3p by enhancing ARID3a binding on the miR promoter. Increased miR-101a-3p decreased the stability of zona occludens-1 ( Zo1 ) mRNA, which in turn, weakened intestinal barriers and induced gut permeability, inflammation and abnormalities in glucose metabolism. Importantly, restoring ethanolamine-metabolising activity in gut microbiota using a novel probiotic therapy reduced elevated gut permeability, inflammation and abnormalities in glucose metabolism by correcting the ARID3a/ miR-101a / Zo1 axis. Conclusion Overall, we discovered that the reduced capacity of obese microbiota to metabolise ethanolamine instigates gut permeability, inflammation and glucose metabolic dysfunctions, and restoring ethanolamine-metabolising capacity by a novel probiotic therapy reverses these abnormalities. Trial registration number NCT02869659 and NCT03269032 .
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