Article ; Online: Insulin resistance per se drives early and reversible dysbiosis-mediated gut barrier impairment and bactericidal dysfunction
Molecular Metabolism, Vol 57, Iss , Pp 101438- (2022)
2022
Abstract: Objective: A common feature of metabolic diseases is their association with chronic low-grade inflammation. While enhanced gut permeability and systemic bacterial endotoxin translocation have been suggested as key players of this metaflammation, the ... ...
| Abstract | Objective: A common feature of metabolic diseases is their association with chronic low-grade inflammation. While enhanced gut permeability and systemic bacterial endotoxin translocation have been suggested as key players of this metaflammation, the mechanistic bases underlying these features upon the diabesity cascade remain partly understood. Methods: Here, we show in mice that, independently of obesity, the induction of acute and global insulin resistance and associated hyperglycemia, upon treatment with an insulin receptor (IR) antagonist (S961), elicits gut hyperpermeability without triggering systemic inflammatory response. Results: Of note, S961-treated diabetic mice display major defects of gut barrier epithelial functions, such as increased epithelial paracellular permeability and impaired cell-cell junction integrity. We also observed in these mice the early onset of a severe gut dysbiosis, as characterized by the bloom of pro-inflammatory Proteobacteria, and the later collapse of Paneth cells antimicrobial defense. Interestingly, S961 treatment discontinuation is sufficient to promptly restore both the gut microbial balance and the intestinal barrier integrity. Moreover, fecal transplant approaches further confirm that S961-mediated dybiosis contributes at least partly to the disruption of the gut selective epithelial permeability upon diabetic states. Conclusions: Together, our results highlight that insulin signaling is an indispensable gatekeeper of intestinal barrier integrity, acting as a safeguard against microbial imbalance and acute infections by enteropathogens. |
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| Keywords | Insulin resistance ; Gut barrier ; Dysbiosis ; Antimicrobial defenses ; Internal medicine ; RC31-1245 |
| Language | English |
| Publishing date | 2022-03-01T00:00:00Z |
| Publisher | Elsevier |
| Document type | Article ; Online |
| Database | BASE - Bielefeld Academic Search Engine (life sciences selection) |
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