The effect of impaired angiogenesis on intestinal function following massive small bowel resection

Abstract

Purpose Intestinal adaptation involves villus lengthening, crypt deepening, and increased capillary density following small bowel resection (SBR). Mice lacking the proangiogenic chemokine CXCL5 have normal structural adaptation but impaired angiogenesis. This work evaluates the impact of incomplete adaptive angiogenesis on the functional capacity of the intestine after SBR. Methods CXCL5 knockout (KO) and C57BL/6 wild-type (WT) mice underwent 50% SBR. Magnetic resonance imaging measured weekly body composition. Intestinal absorptive capacity was evaluated through fecal fat analysis. Gene expression profiles for select macronutrient transporters were measured via RT-PCR. Postoperative crypt and villus measurements assessed for structural adaptation. Submucosal capillary density was measured through CD31 immunohistochemistry. Results Comparable postoperative weight gain occurred initially. Diminished weight gain, impaired fat absorption, and elevated steatorrhea occurred in KO mice after instituting high-fat diet. Greater postoperative upregulation of ABCA1 fat transporter occurred in WT mice, while PEPT1 protein transporter was significantly downregulated in KO mice. KO mice had impaired angiogenesis but intact structural adaptation. Conclusion After SBR, KO mice display an inefficient intestinal absorption profile with perturbed macronutrient transporter expression, impaired fat absorption, and slower postoperative weight gain. In addition to longer villi and deeper crypts, an intact angiogenic response may be required to achieve functional adaptation to SBR.

Both epidermal growth factor and insulin-like growth factor receptors are dispensable for structural intestinal adaptation

“…The EGFR/IGFR-IKO mice had an impaired angiogenic response following SBR, but this did not appear to altar the structural features of adaptation. Similarly, we have previously found that impaired angiogenesis does not affect structural adaptation, however, intestinal function is impaired [19, 41]. This observation confirms previous suggestions that structural and functional intestinal adaptation are independent processes [42].…”

Single-Cell Analysis Reveals Regional Reprogramming during Adaptation to Massive Small Bowel Resection in Mice

“…Because the duodenum and jejunum absorb the majority of nutrients under normal conditions, we propose that this "regional reprogramming," driven by transcriptional proximalization, is a critical component of the adaptation response to SBR. This is a novel principle, as the typically studied structural adaptation, while increasing absorptive surface area, does not necessarily facilitate functional adaptation 5 . Rather than simple tissue hyperplasia, as others have suggested 66 , we demonstrate that enterocyte-level alterations in transcriptional profiles occurs after SBR, in order to mimic proximal SI function.…”

“…This model is relevant to clinical SGS, as structural adaptation correlates with oral tolerance and weaning from PN observed in human patients 4 . At the same time, structural adaptation does not intrinsically predict functional adaptation, as perturbed weight gain and steatorrhea affect mice deficient in CXCL5 after SBR, despite normal structural adaptation 5 . This leads us to conclude that additional factors beyond simple tissue hyperplasia are at play, which are likely underscored by molecular changes at the single-cell level.…”

The Pathogenesis of Resection-Associated Intestinal Adaptation

“…In a subsequent series of experiments, CXCL-5 null mice were found to have impaired intestinal lipid absorption after SBR. 102 It therefore is plausible to conclude that the angiogenic response to intestinal resection is more important for functional, rather than structural, adaptation.…”