SUBEPITHELIAL MICRORNA EXPRESSION DURING ADAPTATION TO MASSIVE SMALL BOWEL RESECTION
Adam Bajinting*1,3,4, Kristen Seiler3,4, Matt Kanke2, Michael T. Shanahan2, Praveen Sethupathy2, Brad W. Warner3,4
1St. Louis University School of Medicine, St. Louis, MO; 2Cornell University College of Veterinary Medicine, Ithaca, NY; 3Department of Surgery, Washington University in St. Louis School of Medicine, St. Louis, MO; 4Divison of Pediatric Surgery, St. Louis Children's Hospital, St. Louis, MO
Background: Intestinal adaptation is a physiological response to shortened gut following a massive small bowel resection (SBR). Adaptation is characterized by lengthened villi and deepened crypts to compensate for lost absorptive surface area. While the morphological and certain functional aspects are well characterized at the epithelial level, changes occurring in the subepithelium (subepithelial tissue, or SET) are poorly understood. Understanding contributions of SET to intestinal adaptation is potentially important because SET has previously been shown to drive intestinal stem cell (ISC) proliferation and epithelial regeneration in other damage-response scenarios. To begin addressing this gap in our understanding of adaptation, we analyzed the microRNA (miRNA) profile of SET from mice that underwent SBR vs sham surgery. miRNA are small noncoding segments of RNA that regulate expression at target regions of the transcribed genome. Clinically miRNAs may be a potential way to modify the genetic expression landscape of the gut in order to accelerate intestinal adaptation in patients suffering from short bowel syndrome (SBS).
Methods: C57BL/6 mice were subjected to 50% proximal SBR or sham operation. At day 3 after surgery (a time of crypt hypertrophy and increase epithelial proliferation), SET from remnant ileum was harvested and analyzed for miRNA expression.
Results: Using a cut off value of p =/< 0.5, we identified 18 miRNA that were differently expressed between SET from sham and SBR mice. The top nine miRNAs upregulated in SBR or downregulated in SBR are presented in Tables 1 and 2 respectively. Literature was queried for what is known about these miRNAs, revealing that they may be involved in angiogenic, immune, metabolic, stem cell, and proliferative responses following SBR. Moreover, we identified miRNAs that are involved in the regenerative processes of other organs.
Conclusion: Here, we demonstrate that the miRNA expression profiles of SET between sham and SBR mice are significantly different. Moreover, the identified miRNAs that are involved in the regenerative process of other organs has led us to believe the potential role of SET in the intestinal regenerative response. Given SET's role in epithelial regeneration and the potential for miRNA to be used clinically to accelerate intestinal adaptation, this analysis sets the groundwork for future mechanistic studies on the relationship between miRNA and SBS.
Table 1. Unregulated miRNA in SET for SBR vs. SHAM mice
| miRNA Id | Relative Expression SBR vs. SHAM | p Value | Known function of miRNA |
| mmu-mir-365-1-3p | 5.705 | 0.045 | Associated with heart regeneration after removal of the left ventricular apex |
| mmu-mir-423-5p | 2.935 | 0.025 | Promotes gluconeogenesis and hyperglycemia via repressing the AKT pathway |
| mmu-mir-342-5p | 2.921 | 0.007 | Linked to Th1- and Th2-type inflammation |
| mmu-mir-30c-2-3p | 2.380 | 0.014 | Supports intestinal epithelial proliferation/ inhibits differentiation |
| mmu-mir-155-5p | 2.309 | 0.002 | Mediates food allergen related inflammation in intestine; induced during macrophage inflammatory response |
| mmu-mir-127-3p_-_1 | 2.199 | 0.002 | Upregulated in non-alcoholic hepatic steatosis |
| mmu-mir-99a-5p | 1.778 | 0.007 | Promotes M2 activated macrophages |
| mmu-mir-145-3p | 1.759 | 0.021 | Inhibits SOX9 in mesenchymal stem cells which allows for preservation of stem cell niche in chondrocytes |
| mmu-mir-9-1-5p | 1.335 | 0.027 | Inhibits insulin secretion |
Table 2. Downregulated miRNA in SET for SBR vs. SHAM mice
| miRNA Id | Relative Expression SBR vs. SHAM | p value | Known function of miRNA |
| mmu-let-7g-5p_+_1 | 0.605 | 0.040 | Upregulation represses the stem cell phenotype in intestinal epithelium |
| mmu-let-7g-5p_-_1 | 0.590 | 0.050 | Upregulation represses the stem cell phenotype in intestinal epithelium |
| mmu-mir-361-5p_-_1 | 0.497 | 0.003 | Silences VEGFA |
| mmu-mir-361-5p | 0.486 | 0.012 | Silences VEGFA |
| mmu-mir-132-3p | 0.462 | 0.018 | Found in adipocytes and associated with obesity-associated inflammation, and insulin resistance |
| mmu-mir-103-1-3p | 0.261 | 0.023 | Upon IGF-1 stimulated crypt cell proliferation, has been shown to be downregulated in crypt cells. |
| mmu-mir-107-3p | 0.260 | 0.009 | Increases insulin sensitivity |
| mmu-mir-130a-3p | 0.256 | 0.032 | Increases insulin sensitivity |
| mmu-mir-24-1-3p | 0.230 | 0.049 | Free fatty acid-induced fat accumulation, marker of metabolic syndrome |
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