The Effect of Impaired Angiogenesis on Intestinal Function Following Massive Small Bowel Resection
Purpose: Intestinal adaptation is characterized by structural changes within the remnant bowel following massive small bowel resection (SBR). These changes include lengthening of villi, deepening of crypts, and increased submucosal capillary density. Mice lacking the proangiogenic chemokine CXCL5 have normal structural features of adaptation, but lack the reactive angiogenesis. We expand on our previous work to evaluate the impact of this incomplete adaptive response on the functional capacity of the small intestine after massive SBR.
Methods: CXCL5 knock out (KO, n=12) and C57BL/6 wild type (WT, n=9) mice underwent a 50% SBR. Postoperatively, mice were weighed regularly for up to 35 days. Magnetic resonance imaging (MRI) was used to measure body composition at baseline and once weekly until sacrifice. Intestinal absorptive ability was indirectly measured through fecal fat analysis. Gene expression profiles for select fat (CD36, MTTP, APOB, ABCA1, DGAT2, and ABCG5) and protein (PEPT1) transporters in isolated intestinal villus cells were measured using RT-PCR. Crypt depth and villus height from ileal tissue were measured at the completion of the study to assess for adaptation. Submucosal capillary density was also measured by CD31 immunohistochemistry.
Results: Comparable postoperative weight gain was observed between CXCL5 WT and KO mice. However, diminished weight gain was observed in the CXCL5 KO mice after institution of a high fat diet (HFD) without any noted group differences in percent fat or lean body mass composition, as measured by MRI (Figure 1). When compared with WT, CXCL5 KO mice exhibited impaired fat absorption (90.26% ±0.58 SEM vs. 92.16% ±0.55 SEM, p=0.027) and greater steatorrhea (18.38% ±1.21 SEM vs. 14.01% ±0.88 SEM, p=0.006) while on HFD. Postoperative upregulation of the ABCA1 fat transporter was more pronounced in WT mice (p=0.029), while PEPT1, the major protein transporter, was downregulated only in the KO group (p=0.018). Consistent with prior studies, increased villus height and crypt depth were noted in both groups, while the increased submucosal capillary density was noted only among the WT mice.
Conclusion: CXCL5 KO mice without normal neovascularization response after SBR display an inefficient intestinal absorption characterized by perturbed macronutrient transporter expression, impaired fat absorption, and slower postoperative weight gain. In addition to longer villi and deeper crypts, an intact angiogenic response is required to achieve a functional adaptive response to massive intestinal loss.
Figure 1: A) Percent weight change between CXCL5 WT and KO mice. Asterisk designate significant differences (p<0.05) on the indicated POD. B, C) Comparable percent lean body mass and fat between WT and KO mice. LD=liquid diet; HFD=High fat diet.