A mechanism by which gut microbiota elevates permeability and inflammation in obese/diabetic mice and human gut
| Autor: | Sidharth P Mishra, Bo Wang, Shalini Jain, Jingzhong Ding, Jared Rejeski, Cristina M Furdui, Dalane W Kitzman, Subhash Taraphder, Christian Brechot, Ambuj Kumar, Hariom Yadav |
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| Rok vydání: | 2023 |
| Předmět: | |
| Zdroj: | Gut. :gutjnl-2022 |
| ISSN: | 1468-3288 0017-5749 0286-9659 |
| DOI: | 10.1136/gutjnl-2022-327365 |
| Popis: | ObjectiveAmple 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.DesignIn 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.ResultsWe 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-3pby enhancing ARID3a binding on the miR promoter. IncreasedmiR-101a-3pdecreased 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/Zo1axis.ConclusionOverall, 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 numberNCT02869659andNCT03269032. |
| Databáze: | OpenAIRE |
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