Intestinal resection-associated metabolic syndrome

Abstract

Background: Short bowel syndrome occurs following massive small bowel resection (SBR) and is one of the most lethal diseases of childhood. We have previously demonstrated hepatic steatosis, altered gut microbiome, and increased fat deposition in our murine model of SBR. These novel findings prompted us to investigate potential alterations in glucose metabolism and systemic inflammation following intestinal resection.

Methods: Male C57BL6 mice underwent 50% proximal SBR or sham operation. Body weight and composition were measured. Fasting blood glucose (FBG), glucose, and insulin tolerance testing were performed. Small bowel, pancreas, and serum were collected at sacrifice and analyzed.

Results: SBR mice gained less weight than shams after 10weeks. Despite this, FBG in resected mice was significantly higher than sham animals. After SBR, mice demonstrated perturbed body composition, higher blood glucose, increased pancreatic islet area, and increased systemic inflammation compared with sham mice. Despite these changes, we found no alteration in insulin tolerance after resection.

Conclusions: After massive SBR, we present evidence for abnormal body composition, glucose metabolism, and systemic inflammation. These findings, coupled with resection-associated hepatic steatosis, suggest that massive SBR (independent of parenteral nutrition) results in metabolic consequences not previously described and provides further evidence to support the presence of a novel resection-associated metabolic syndrome.

Keywords: Hepatic steatosis; Short bowel syndrome; Small bowel resection.

Figure 1

Mice gain significantly less weight, maintaining fat mass and losing lean mass after 50% small bowel resection (SBR) compared with sham operated animals. Male C57BL6 mice underwent 50% proximal SBR or sham operation. (A) They were weighed weekly for 10 weeks. (B) Body composition obtained at week 10 was compared to that obtained at week five to visualize late body composition change. ANOVA for operation p< 0.0002. Sidak’s Multiple comparisons presented on weight graph. *p <0.05, **p=0.001,*** p <0.0007, **** p <0.0001, N= 9–14

Figure 2

Glucose homeostasis is impaired 5 weeks after massive small bowel resection (SBR). Male C57BL6 mice underwent 50% proximal SBR or sham operation. Fasting blood glucose (FBG, A) was measured after overnight fast and after a 2mg/g body weight glucose load provided by either intraperitoneal (IPGTT, B) or oral gavage (OGTT, C). Finally, (D) Peak blood glucose levels directly correlated to fasting blood glucose. ANOVA was used to analyze trends over time comparing operations. P<0.0002 for IPGTT and P< 0.002 for oral GTT. Sidak’s multiple comparisons are presented on charts. *p <0.05, **p <0.001, ***p <0.0003, ****p <0.0001, n=18–19 for FBG, n=5–8 for GTT, n=13 pairs for correlation

Figure 3

Fasting blood glucose remains elevated at 10 weeks after small bowel resection without alteration of peripheral insulin tolerance. Male C57BL6 mice underwent 50% proximal SBR or sham operation. At 10 weeks after operation, (A) fasting blood glucose was measured after overnight fast. (B) Mice were given a 0.75 U/kg body weight insulin load via intraperitoneal injection and blood glucose was determined over the course of 120 minutes. *p=0.002, N=11–13 for FBG, N=5–9 for ITT

Figure 4

Pancreatic islet area is significantly increased after massive SBR. Male C57BL6 mice underwent sham operation A) or 50% proximal small bowel resection (SBR) and were sacrificed at 5 weeks after operation. Tissue was fixed in formalin, paraffin embedded, and stained with hematoxylin and eosin. Slides are presented at 10X magnification. A) Representative microscopic section of pancreas from Sham operated mouse. Arrowheads denote islets. B) Representative microscopic section of pancreas from mouse at 5 weeks following SBR. Arrowheads denote islets. C) Quantification of total pancreas area and islet area was performed in Image-J software (C). *p<0.01 n=4–7.

Figure 5

Small bowel resection results in elevated TNF α at 10 weeks after small bowel resection. Male C57BL6 mice underwent sham operation, A) or 50% proximal small bowel resection (SBR). Serum was collected via cardiac puncture at the time of sacrifice (10 weeks after operation). Serum was analyzed for TNFα, IL-6 and IL-1β using an electrochemiluminescence immunoassay. P<0.05, N= 4–13 (sham), N=9 (SBR)