In the current study, we have extended our model of SBS in the mouse to a greater magnitude of resection with the intent of demonstrating greater adaptive changes. If this were the case, we would anticipate that genetic alterations responsible for adaptation would be magnified, thereby leading to easier detection of target genes responsible for this important response. Unfortunately, this was not the case as changes in both mucosal morphology and kinetics of enterocyte turnover were similar despite the greater amount of bowel resected.
As expected, we noted an increased mortality associated with increased resection. Others have found 75% SBR in the mouse to be even more lethal. For example, our group has previously published a 16% survival in mice 3 weeks after 75% SBR, with most of the mice dying within the first three days after operation (5
). Other researchers in our lab have recorded a 55% survival 7 days after 75% SBR (unpublished data). The 75% SBR model is likely more morbid due to the more advanced degree of SBS and dehydration that ensues. Indeed, we have verified that the animals have noticeably worse diarrhea and lose more weight following 75% SBR than after 50% SBR.
As expected, the remnant bowel adapted after mice underwent 75% SBR relative to intraoperative levels. The findings of augmented crypt depth, villus length, proliferative rate, and apoptotic indices all parallel previously reported measures of adaptation following 50% SBR in mice (4
). These data represent the first study regarding the extent of small intestinal resections and the magnitude of adaptation in the mouse. Prior studies had been done in rats (12
). Perhaps the best evidence that greater bowel resections induce increasingly more robust adaptation responses comes from Hanson’s work published in 1977 (13
). They performed resections ranging from 10%-80% in rats (n=5 in each group). Similar to our findings, they reported that greater resections led to increased weight loss after 30 days.
On the other hand, this group found that greater resections resulted in enhanced intestinal adaptation as gauged by increased remnant bowel wet weights and proliferative rates in crypts. Hanson et al sampled tissue 3cm distal to the anastomosis, a comparable location to our PO tissue harvest site in mice. However, they performed a mid-SBR while we have performed a proximal-SBR. Although seemingly unlikely, this difference may account for the different findings between groups. They also sampled tissue from another, fixed point – 3 cm proximal to the cecum. Interestingly, in the distal ileum they found a plateau-effect seen for proliferative rates between 10-70% SBR’s; only 80% SBR led to greater proliferative rates. Perhaps our findings were not too dissimilar from Hanson’s, as our tissue from 75% SBR mice was harvested in the distal ileum, as well.
We identified two other studies that directly tested the impact different resection lengths had on adaptation (12
). Our lab has published on 25%, 50%, and 75% SBR’s in rats (12
). We showed that increasingly greater resections lead to increased ileal wet weights, but no change in proliferative rates in the remnant bowel. Intriguingly, serum taken from these rats was capable of stimulating enterocyte proliferation in vitro
, but there was no effect of the extent of resection on the magnitude of proliferation. Lanzoni et al tested 60%, 70%, 80%, and 90% SBR’s in rats (14
). They found that the 80% and 90% SBR’s caused more weight loss than the lesser resections. Although they claim that adaptive parameters increased with greater resections, no statistical analyses were performed to support this claim. In addition, villus growth calculated from IO to PO groups appears similar across groups.
Our inability to demonstrate enhanced adaptation after SBR could be due to the increased technical limitations of performing the intestinal anastomosis during the 75% SBR. Due to the reduced size of the distal ileum, these mice are more likely to develop bowel obstruction postoperatively. Although no animals exhibited overt evidence of obstruction at harvest, it is possible that mice after 75% SBR have subclinical partial obstruction that does not manifest, but, nevertheless, impairs the distal bowel’s adaptive response. We observed a more profound state of SBS in mice that underwent 75% SBR. Perhaps, these mice lack the nutritional reserve to mount a more robust adaptation response than the 50% SBR mice. It must be considered that adaptation responses may be species-specific. As such, the findings of the present study may not be directly transferable to the clinical setting. Indeed, little is understood regarding adaptation in humans. Most knowledge has been derived from various animal studies with different species, sites, and extents of intestinal resection.
The present study does have limitations. First of all, the 50% SBR and 50% sham operations were preformed by a different surgeon (SWL) than the 75% SBR and 75% sham procedures (DW). On the other hand, the magnitude of adaptive change in the 50% group of the present study is no different than multiple other prior studies done in our laboratory. The ability to perform greater lengths of intestinal resection in the present report undoubtedly reflects the large experience gained in our laboratory over the past several years. Despite improved operative techniques and survival with this model, the extent of adaptation remains fixed. Another factor to consider is the timing for adaptation to occur. While we have previously demonstrated that adaptation reaches a significant peak after seven days following a 50% SBR (5
), we have not performed the same time course study following a 75% SBR. It is possible that adaptation plateaus after 50% SBR before it does after 75% SBR and, therefore, seven days may not be long enough to observe different adaptation responses between the groups.
Since our murine model affords the opportunity to directly test the significance of various genes in the genesis of adaptation, we sought to characterize the influence of resection specifically in this model. Regardless of its limitations, this study does indicate that SBR greater than 50% in mice is complicated by increased morbidity and mortality. This is accompanied by seemingly little evidence of enhanced parameters of adaptation. We therefore conclude that performing resections greater than 50% in mice to study the mechanisms underlying adaptation is not useful. Although we have yet to test if any of the signaling cascades associated with adaptation are altered by greater resections, it seems doubtful given the similar morphometric scale of adaptation.