miR‐10b‐5p rescues leaky gut linked with gastrointestinal dysmotility and diabetes

Abstract

Background/AimDiabetes has substantive co‐occurrence with disorders of gut‐brain interactions (DGBIs). The pathophysiological and molecular mechanisms linking diabetes and DGBIs are unclear. MicroRNAs (miRNAs) are key regulators of diabetes and gut dysmotility. We investigated whether impaired gut barrier function is regulated by a key miRNA, miR‐10b‐5p, linking diabetes and gut dysmotility.MethodsWe created a new mouse line using the Mb3Cas12a/Mb3Cpf1 endonuclease to delete mir‐10b globally. Loss of function studies in the mir‐10b knockout (KO) mice were conducted to characterize diabetes, gut dysmotility, and gut barrier dysfunction phenotypes in these mice. Gain of function studies were conducted by injecting these mir‐10b KO mice with a miR‐10b‐5p mimic. Further, we performed miRNA‐sequencing analysis from colonic mucosa from mir‐10b KO, wild type, and miR‐10b‐5p mimic injected mice to confirm (1) deficiency of miR‐10b‐5p in KO mice, and (2) restoration of miR‐10b‐5p after the mimic injection.ResultsCongenital loss of mir‐10b in mice led to the development of hyperglycemia, gut dysmotility, and gut barrier dysfunction. Gut permeability was increased, but expression of the tight junction protein Zonula occludens‐1 was reduced in the colon of mir‐10b KO mice. Patients with diabetes or constipation‐ predominant irritable bowel syndrome, a known DGBI that is linked to leaky gut, had significantly reduced miR‐10b‐5p expression. Injection of a miR‐10b‐5p mimic in mir‐10b KO mice rescued these molecular alterations and phenotypes.ConclusionsOur study uncovered a potential pathophysiologic mechanism of gut barrier dysfunction that links both the diabetes and gut dysmotility phenotypes in mice lacking miR‐10b‐5p. Treatment with a miR‐10b‐5p mimic reversed the leaky gut, diabetic, and gut dysmotility phenotypes, highlighting the translational potential of the miR‐10b‐5p mimic.

Sustained Effectiveness and Safety of Therapeutic miR-10a/b in Alleviating Diabetes and Gastrointestinal Dysmotility without Inducing Cancer or Inflammation in Murine Liver and Colon

“…Our results indicate that the long-term treatment of HFHSD-induced diabetic mice subcutaneously injected with miR-10a/b mimics can effectively rescue both diabetes and GI dysmotility without indication for increased risk of cancer development and inflammation induction. These efficacy and safety data are consistent with our previous studies [16,17] that highlighted the pivotal role of miR-10a/b-5p in regulating glucose homeostasis and GI motility as well as the promising efficacy of miR-10a/b mimics in reversing diabetes and GI dysmotility without induction of cancer.…”

“…We further found that loss of miR-10b-5p in KIT + β cells and ICC in Kit-mir-10b KO mice led to diabetes and GI dysmotility, revealing a novel miR-10b-KLF11-KIT pathway that regulates glucose homeostasis and GI motility [16]. In addition, we found that miR-10a-5p mimic and miR-10b-5p mimic (miR-10a/b mimics) intervention effectively reversed these pathological phenotypes in the multiple models of diabetic mice by restoration of β cells and ICC, highlighting the potential utilization of miR-10a/b mimics in therapeutic applications [16,17].…”

“…miR-10a/b are also essential for intestinal barrier function, which is crucial for GI and metabolic homeostasis [2]. Our previous study revealed that global mir-10b KO mice displayed impaired intestinal barrier function, characterized by a disorganized epithelial barrier and increased gut permeability [17]. Intervention with a miR-10b mimic in these mice rescued the hyperglycemic GI dysmotility and leaky gut phenotype through remodeling epithelial cells, thereby maintaining GI homeostasis and metabolic health [17].…”

“…Our previous research has shed light on the essential role of miR-10a-5p and miR-10b-5p (miR-10a/b-5p) in pancreatic β cells and ICC [16,17]. We discovered that miR-10a/b-5p are the most highly expressed in receptor tyrosine kinase protein KIT + ICC in healthy mice and drastically depleted in ICC in diabetic ob/ob mice [16].…”

Screening and identification of key biomarkers associated with endometriosis using bioinformatics and next generation sequencing data analysis

“…CCND2 [1083], VCAM1 [761], PDGFB (platelet derived growth factor subunit B) [1059], PTCH1 [1098], FOXQ1 [1044], IGF2BP1 [1162], ACTC1 [1192], DAPK1 [947], hsa-mir-2110 [1676], hsa-mir-10b-5p [1677], TCF3 [1678], NR1I2 [1679] and TRIM28 [1680] have been shown to be associated with inflammation. Studies have shown that CCND2 [1495], VCAM1 [1462], PTPRD (protein tyrosine phosphatase receptor type D) [1496], PRKCB (protein kinase C beta) [1476], IGF2BP1 [1545], hsa-mir-200a-3p [1681] and hsa-mir-10b-5p [1682] are an important biomarkers of diabetes mellitus. VCAM1 [110], PDGFB (platelet derived growth factor subunit B) [121], IGF2BP1 [162], DAPK1 [183] and hsa-mir-17-5p [1683] are a potential markers for the detection and prognosis of endometriosis.…”