Small Bowel Resection Operation Research Articles

Comparison of outcomes in small bowel surgery for Crohn’s disease: a retrospective NSQIP review

IntroductionDespite advances in medical therapy, approximately 33% of Crohn’s disease (CD) patients will need surgery within 5 years after initial diagnosis. Several surgical approaches to CD have been proposed including small bowel resection, strictureplasty, and combined surgery with resection plus strictureplasty. Here, we utilize the American College of Surgeons (ACS) national surgical quality registry (NSQIP) to perform a comprehensive analysis of 30-day outcomes between these three surgical approaches for CD.MethodsThe authors queried the ACS-NSQIP database between 2015 and 2020 for all patients undergoing open or laparoscopic resection of small bowel or strictureplasty for CD using CPT and IC-CM 10. Outcomes of interest included length of stay, discharge disposition, wound complications, 30-day related readmission, and reoperation.ResultsA total of 2578 patients were identified; 87% of patients underwent small bowel resection, 5% resection with strictureplasty, and 8% strictureplasty alone. Resection plus strictureplasty (combined surgery) was associated with the longest operative time (p = 0.002). Patients undergoing small bowel resection had the longest length of hospital stay (p = 0.030) and the highest incidence of superficial/deep wound infection (44%, p = 0.003) as well as the highest incidence of sepsis (3.5%, p = 0.03). Small bowel resection was found to be associated with higher odds of wound complication compared to combined surgery (OR 2.09, p = 0.024) and strictureplasty (1.9, p = 0.005).ConclusionOur study shows that various surgical approaches for CD are associated with comparable outcomes in 30-day related reoperation and readmission, or disposition following surgery between all three surgical approaches. However, small bowel resection displayed higher odds of developing post-operative wound complications.

A novel maladaptive unfolded protein response as a mechanism for small bowel resection-induced liver injury.

The unfolded protein response (UPR) is a complex adaptive signaling pathway activated by the accumulation of misfolded proteins in the endoplasmic reticulum (ER). ER stress (ERS) triggers a cascade of responses that converge upon C/EBP homologous protein (CHOP) to drive inflammation and apoptosis. Herein, we sought to determine whether liver injury and fibrosis after small bowel resection (SBR) were mediated by a maladaptive hepatic ERS/UPR. C57BL/6 mice underwent 50% proximal SBR or sham operation. Markers of liver injury and UPR/ERS pathways were analyzed. These were compared with experimental groups including dietary fat manipulation, tauroursodeoxycholic acid (TUDCA) treatment, distal SBR, and global CHOP knockout (KO). At 10 wk, proximal SBR had elevated alanine aminotransferase/aspartate aminotransferase (ALT/AST) (P < 0.005) and greater hepatic tumor necrosis factor-α (TNFα) (P = 0.001) and collagen type 1 α1 (COL1A1) (P = 0.02) than shams. SBR livers had increased CHOP and p-eIF2α, but were absent in activating transcription factor 4 (ATF4) protein expression. Low-fat diet (LFD), TUDCA, and distal SBR groups had decreased liver enzymes, inflammation, and fibrosis (P < 0.05). Importantly, they demonstrated reversal of hepatic UPR with diminished CHOP and robust ATF4 signal. CHOP KO-SBR had decreased ALT but not AST compared with wild-type (WT)-SBR (P = 0.01, P = 0.12). There were no differences in TNFα and COL1A1 (P = 0.09, P = 0.50). SBR-induced liver injury, fibrosis is associated with a novel hepatic UPR/ERS response characterized by increased CHOP and decreased ATF4. LFD, TUDCA, and ileocecal resection rescued the hepatic phenotype and reversed the UPR pattern. Global CHOP KO only partially attenuated liver injury. This underscores the significance of disruptions to the gut/liver axis after SBR and potentiates targets to mitigate the progression of intestinal failure-associated liver disease.NEW & NOTEWORTHY The unfolded protein response (UPR) is a complex signaling cascade that converges upon C/EBP-homologous protein (CHOP). Under conditions of chronic cellular stress, the UPR shifts from homeostatic to proapoptotic leading to inflammation and cell death. Here, we provide evidence that small bowel resection-induced liver injury and fibrosis are mediated by a maladaptive hepatic UPR. Low-fat diet, TUDCA treatment, and ileocecal resection rescued the hepatic phenotype and reversed the UPR pattern.

Postoperative complications and hospital costs following small bowel resection surgery.

Postoperative complications after major gastrointestinal surgery are a major contributor to hospital costs. Thus, reducing postoperative complications is a key target for cost-containment strategies. We aimed to evaluate the relationship between postoperative complications and hospital costs following small bowel resection. Postoperative complications were recorded for 284 adult patients undergoing major small bowel resection surgery between January 2013 and June 2018. Complications were defined and graded according to the Clavien-Dindo classification system. In-hospital cost of index admission was calculated using an activity-based costing methodology; it was reported in US dollars at 2019 rates. Regression modeling was used to investigate the relationships among a priori selected perioperative variables, complications, and costs. The overall complication prevalence was 81.6% (95% CI: 85.7-77.5). Most complications (69%) were minor, but 22.9% of patients developed a severe complication (Clavien-Dindo grades III or IV). The unadjusted median total hospital cost for patients with any complication was 70% higher than patients without complications (median [IQR] USD 19,659.64 [13,545.81-35,407.14] vs. 11,551.88 [8,849.46-15,329.87], P < 0.001). The development of 1, 2, 3, and ≥ 4 complications increased hospital costs by 11%, 41%, 50%, and 195%, respectively. Similarly, more severe complications incurred higher hospital costs (P < 0.001). After adjustments were made (for the Charlson Comorbidity Index, anemia, surgical urgency and technique, intraoperative fluid administration, blood transfusion, and hospital readmissions), a greater number and increased severity of complications were associated with a higher adjusted median hospital cost. Patients who experienced complications had an adjusted additional median cost of USD 4,187.10 (95% CI: 1,264.89-7,109.31, P = 0.005) compared to those without complications. Postoperative complications are a key target for cost-containment strategies. Our findings demonstrate a high prevalence of postoperative complications following small bowel resection surgery and quantify their associated increase in hospital costs. Australian Clinical Trials Registration number: 12620000322932.

Small Bowel Resection Increases Paracellular Gut Barrier Permeability via Alterations of Tight Junction Complexes Mediated by Intestinal TLR4

BackgroundShort bowel syndrome resulting from small bowel resection (SBR) is associated with significant morbidity and mortality. Many adverse sequelae including steatohepatitis and bacterial overgrowth are thought to be related to increased bacterial translocation, suggesting alterations in gut permeability. We hypothesized that after intestinal resection, the intestinal barrier is altered via toll-like receptor 4 (TLR4) signaling at the intestinal level. MethodsB6 and intestinal-specific TLR4 knockout (iTLR4 KO) mice underwent 50% SBR or sham operation. Transcellular permeability was evaluated by measuring goblet cell associated antigen passages via two-photon microscopy. Fluorimetry and electron microscopy evaluation of tight junctions (TJ) were used to assess paracellular permeability. In parallel experiments, single-cell RNA sequencing measured expression of intestinal integral TJ proteins. Western blot and immunohistochemistry confirmed the results of the single-cell RNA sequencing. ResultsThere were similar number of goblet cell associated antigen passages after both SBR and sham operation (4.5 versus 5.0, P > 0.05). Fluorescein isothiocyanate–dextran uptake into the serum after massive SBR was significantly increased compared with sham mice (2.13 ± 0.39 ng/μL versus 1.62 ± 0.23 ng/μL, P < 0.001). SBR mice demonstrated obscured TJ complexes on electron microscopy. Single-cell RNA sequencing revealed a decrease in TJ protein occludin (21%) after SBR (P < 0.05), confirmed with immunostaining and western blot analysis. The KO of iTLR4 mitigated the alterations in permeability after SBR. ConclusionsPermeability after SBR is increased via changes at the paracellular level. However, these alterations were prevented in iTLR4 mice. These findings suggest potential protein targets for restoring the intestinal barrier and obviating the adverse sequelae of short bowel syndrome.

Alterations in pancreatic islet cell function in response to small bowel resection.

After 50% proximal small bowel resection (SBR) in mice, we have demonstrated hepatic steatosis, impaired glucose metabolism without insulin resistance, and increased pancreatic islet area. We sought to determine the consequences of SBR on pancreatic β-cell morphology, proliferation, and expression of a key regulatory hormone, glucagon-like peptide-1 (GLP-1). C57BL/6 mice underwent 50% SBR or sham operation. At 10 wk, pancreatic insulin content and secretion was measured by ELISA. Immunohistochemistry was performed to determine structural alterations in pancreatic α-and β-cells. Western blot analysis was used to measure GLP-1R expression, and immunoassay was used to measure plasma insulin and GLP-1. Experiments were repeated by administering a GLP-1 agonist (exendin-4) to a cohort of mice following SBR. After SBR, there was pancreatic islet hypertrophy and impaired glucose tolerance. The proportion of α and β cells was not grossly altered. Whole pancreas and pancreatic islet insulin content was not significantly different; however, SBR mice demonstrated decreased insulin secretion in both static incubation and islet perfusion experiments. The expression of pancreatic GLP-1R was decreased approximately twofold after SBR, compared with sham and serum GLP-1, was decreased. These metabolic derangements were mitigated after administration of the GLP-1 agonist. Following massive SBR, there is significant hypertrophy of pancreatic islet cells with morphologically intact α- and β-cells. Significantly reduced pancreatic insulin release in both static and dynamic conditions demonstrate a perturbed second phase of insulin secretion. GLP-1 is a key mediator of this amplification pathway. Decreased expression of serum GLP-1 and pancreatic GLP-1R in face of no change in insulin content presents a novel pathway for enteropancreatic glucose regulation following SBR.NEW & NOTEWORTHY Metabolic changes occur following intestinal resection; however, the effects on pancreatic function are unknown. Prior studies have demonstrated that glucagon-like protein-1 (GLP-1) signaling is a crucial player in the improved insulin sensitivity after bariatric surgery. In this study, we explore the effect of massive small bowel resection on gut hormone physiology and provide novel insights into the enteropancreatic axis.

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

Background & AimsThe small intestine (SI) displays regionality in nutrient and immunological function. Following SI tissue loss (as occurs in short gut syndrome, or SGS), remaining SI must compensate, or “adapt”; the capacity of SI epithelium to reprogram its regional identity has not been described. Here, we apply single-cell resolution analyses to characterize molecular changes underpinning adaptation to SGS.MethodsSingle-cell RNA sequencing was performed on epithelial cells isolated from distal SI of mice following 50% proximal small bowel resection (SBR) vs sham surgery. Single-cell profiles were clustered based on transcriptional similarity, reconstructing differentiation events from intestinal stem cells (ISCs) through to mature enterocytes. An unsupervised computational approach to score cell identity was used to quantify changes in regional (proximal vs distal) SI identity, validated using immunofluorescence, immunohistochemistry, qPCR, western blotting, and RNA-FISH.ResultsUniform Manifold Approximation and Projection-based clustering and visualization revealed differentiation trajectories from ISCs to mature enterocytes in sham and SBR. Cell identity scoring demonstrated segregation of enterocytes by regional SI identity: SBR enterocytes assumed more mature proximal identities. This was associated with significant upregulation of lipid metabolism and oxidative stress gene expression, which was validated via orthogonal analyses. Observed upstream transcriptional changes suggest retinoid metabolism and proximal transcription factor Creb3l3 drive proximalization of cell identity in response to SBR.ConclusionsAdaptation to proximal SBR involves regional reprogramming of ileal enterocytes toward a proximal identity. Interventions bolstering the endogenous reprogramming capacity of SI enterocytes—conceivably by engaging the retinoid metabolism pathway—merit further investigation, as they may increase enteral feeding tolerance, and obviate intestinal failure, in SGS.

Intestinal resection-associated metabolic syndrome

BackgroundShort 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. MethodsMale 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. ResultsSBR 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. ConclusionsAfter 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.

Farnesoid X Receptor Agonist Treatment Alters Bile Acid Metabolism butExacerbates Liver Damage in a Piglet Model of Short-BowelSyndrome.

Background & AimsOptions for the prevention of short-bowel syndrome–associated liver disease (SBS-ALDs) are limited and often ineffective. The farnesoid X receptor (FXR) is a newly emerging pharmaceutical target and FXR agonists have been shown to ameliorate cholestasis and metabolic disorders. The aim of this study was to assess the efficacy of obeticholic acid (OCA) treatment in preventing SBS-ALDs.MethodsPiglets underwent 75% small-bowel resection (SBS) or sham surgery (sham) and were assigned to either a daily dose of OCA (2.4 mg/kg/day) or were untreated. Clinical measures included weight gain and stool studies. Histologic features were assessed. Ultraperformance liquid chromatography tandem mass spectrometry was used to determine bile acid composition in end point bile and portal serum samples. Gene expression of key FXR targets was assessed in intestinal and hepatic tissues via quantitative polymerase chain reaction.ResultsOCA-treated SBS piglets showed decreased stool fat and altered liver histology when compared with nontreated SBS piglets. OCA prevented SBS-associated taurine depletion, however, further analysis of bile and portal serum samples indicated that OCA did not prevent SBS-associated alterations in bile acid composition. The expression of FXR target genes involved in bile acid transport and synthesis increased within the liver of SBS piglets after OCA administration whereas, paradoxically, intestinal expression of FXR target genes were decreased by OCA administration.ConclusionsAdministration of OCA in SBS reduced fat malabsorption and altered bile acid composition, but did not prevent the development of SBS-ALDs. We postulate that extensive small resection impacts the ability of the remnant intestine to respond to FXR activation.

Small Bowel Resection Induces Long-Term Changes in the Enteric Microbiota of Mice

PurposeThe enteric microbiome is known to play a major role in healthy gut homeostasis and several disease states. It may also contribute to both the intestinal recovery and complications that occur in patients with short bowel syndrome. The extent and nature of alterations to the gut microbiota following intestinal resection, however, are not well studied in a controlled setting. The purpose of this investigation is to characterize the effects of massive small bowel resection on the murine enteric microflora. MethodsWild-type C57BL6 mice, following a week of acclamation to a liquid rodent diet, underwent either 50 % proximal small bowel resection (SBR) or a sham operation. Mice were sacrificed, and enteric contents from the small bowel, cecum, and stool were harvested at 7 and 90 days post-operatively. DNA was isolated, and the V3–V5 regions of the 16s rRNA gene amplified and pyrosequenced on a Roche 454 platform. Sequences were clustered into operation taxonomic units and classified. Communities were then analyzed for diversity and phylogenic composition. ResultsIn the long-term group, the microbes inhabiting the ileum of mice undergoing SBR and sham operation differed significantly at the genus level (p < 0.001). Small bowel contents collected before and after SBR also differed significantly (p = 0.006). This was driven by an increase in Lactobacillus and decrease in Enterobacteriaceae species in mice undergoing SBR. No difference was seen in the long-term stool or in stool, cecal, or ileal contents in the short-term. No difference in microbial community diversity was found in any group. ConclusionBowel resection induces long-term changes in the microbial community of the murine ileum, but not at more distal sites of the gastrointestinal tract. The increase in Lactobacillus encountered small bowel of resected mice correlates with limited previous studies. These changes may reflect an adaptive response of the microbiota to maximize energy extraction, but further studies are needed to establish the role played by this altered community.

CXCL5 is required for angiogenesis, but not structural adaptation after small bowel resection

PurposeIntestinal adaptation is the compensatory response to massive small bowel resection (SBR) and characterized by lengthening of villi and deepening of crypts, resulting in increased mucosal surface area. Previous studies have demonstrated increased villus capillary blood vessel density after SBR, suggesting a role for angiogenesis in the development of resection-induced adaptation. Since we have previously shown enhanced expression of the proangiogenic chemokine CXCL5 after SBR, the purpose of this study was to determine the effect of disrupted CXCL5 expression on intestinal adaptation. MethodsCXCL5 knockout (KO) and C57BL/6 wild type (WT) mice were subjected to either a 50% proximal SBR or sham operation. Ileal tissue was harvested on postoperative day 7. To assess for adaptation, villus height and crypt depth were measured. Submucosal capillary density was measured by CD31 immunohistochemistry. ResultsBoth CXCL5-KO and WT mice demonstrated normal structural features of adaptation. Submucosal capillary density increased in the WT but not in the KO mice following SBR. ConclusionCXCL5 is required for increased intestinal angiogenesis during resection-induced adaptation. Since adaptive villus growth occurs despite impaired CXCL5 expression and enhanced angiogenesis, this suggests that the growth of new blood vessels is not needed for resection-induced mucosal surface area expansion following massive SBR.

High-Fat Diet Enhances Villus Growth During the Adaptation Response to Massive Proximal Small Bowel Resection

Previous studies have shown that high-fat diet (HFD) enhances adaptation if provided immediately following small bowel resection (SBR). The purpose of this study was to determine if HFD could further enhance villus growth after resection-induced adaptation had already taken place. C57/Bl6 mice underwent a 50 % proximal SBR or sham operation and were then provided a standard rodent liquid diet (LD) ad lib. After a typical period of adaptation (7 days), SBR and sham-operated mice were randomized to receive either LD or HFD (42 % kcal fat) for an additional 7 days. Mice were then harvested, and small intestine was collected for analysis. Adaptation occurred in both SBR groups; however, the SBR/HFD had significantly increased villus height compared to SBR/LD. Reverse transcription–polymerase chain reaction of villus enterocytes showed a marked increase in CD36 expression in the SBR/HFD group compared with SBR/LD mice. While exposure to increased enteral fat alone did not affect villus morphology in sham-operated mice, HFD significantly increased villus growth in the setting of resection-induced adaptation, supporting the clinical utility of enteral fat in augmenting adaptation. Increased expression of CD36 suggests a possible mechanistic role in dietary fat metabolism and villus growth in the setting of short gut syndrome.

Enterocyte expression of epidermal growth factor receptor is not required for intestinal adaptation in response to massive small bowel resection

PurposeIntestinal adaptation after massive small bowel resection (SBR) permits improved absorption of enteral nutrition despite significant loss of bowel length. Epidermal growth factor (EGF) and its receptor (EGFR) have previously been established to play major roles in the pathogenesis of adaptation. This study tested the hypothesis that EGFR signaling within the epithelial cell compartment (enterocytes) is required for intestinal adaptation. MethodsWe developed a tamoxifen-inducible Villin-Cre/LoxP recombinant system for enterocyte-directed EGFR deletion using EGFR-floxed mice. Epidermal growth factor receptor–null mice and wild-type littermates underwent either 50% proximal SBR or sham operation. Ileal tissue was harvested on postoperative day 7. To assess for adaptation, villus height and crypt depth as well as rates of crypt cell proliferation and apoptosis were measured. ResultsAdaptation after SBR occurred normally, as demonstrated by significant increases in villus height, crypt depth, and crypt proliferative and apoptotic index in both the wild-type and EGFR-null mice. ConclusionEnterocyte EGFR expression is not required for the adaptation response to massive SBR. This novel finding suggests that enterocyte proliferation during adaptation is regulated by EGFR signaling in cells other than enterocytes, perhaps within the mesenchymal cell compartment of the bowel wall via factor(s) that are presently unknown.

Regulation of Retinoblastoma Protein (Rb) by p21 Is Critical for Adaptation to Massive Small Bowel Resection

BackgroundAdaptation following massive intestinal loss is characterized by increased villus height and crypt depth. Previously, we demonstrated that p21-null mice do not adapt after small bowel resection (SBR). As retinoblastoma protein (Rb) levels are elevated in p21-null crypt cells, we first sought to determine whether Rb is required for normal adaptation. Next, we tested whether Rb expression is responsible for blocked adaptation in p21-nulls. MethodsGenetically manipulated mice and wild-type (WT) littermates underwent either 50% SBR or sham operation. The intestine was harvested at 3, 7, or 28 days later and intestinal adaptation was evaluated. Enterocytes were isolated and protein levels evaluated by Western blot and quantified by optical density. ResultsRb-null mice demonstrated increased villus height, crypt depth, and proliferative rate at baseline, but there was no further increase following SBR. Deletion of one Rb allele lowered Rb expression and restored resection-induced adaptation responses in p21-null mice. ConclusionRb is specifically required for resection-induced adaptation. Restoration of adaptation in p21-null mice by lowering Rb expression suggests a crucial mechanistic role for Rb in the regulation of intestinal adaptation by p21.

A changing trend in the management of patients with newly diagnosed Crohn’s disease

Epidemiologic shift with rising incidence of Crohn's disease (CD) has been reported in recent studies. To determine disease behaviour and therapeutic interventions undertaken in newly diagnosed patients with CD. Patients diagnosed with CD between January 2006 and June 2008 were included. Disease type, location, degree of involvement and type of therapeutic interventions were recorded. A total of 78 patients were included. Colonic, ileo-colonic, terminal ileal and isolated small bowel disease were present in 37, 27, 9 and 5 patients, respectively. Disease phenotype was inflammatory, stenosing and fistulising in 42, 30 and 6 patients, respectively. Surgery was required in 22 patients, including right hemicolectomy (n = 8), subtotal colectomy (n = 4), segmental colonic resection (n = 2), segmental small bowel resection (n = 2), appendectomy (n = 2) and perianal surgery (n = 4). Fourteen patients underwent surgery at the time of diagnosis. Laparoscopic surgery was performed in 14 patients. A significant proportion of newly diagnosed patients with CD underwent surgical intervention on their first admission to hospital. This may signify a changing trend in the management approach.

Short- and long-term effects of small bowel resection: a unique histological study in a piglet model of short bowel syndrome

If we are to develop successful interventions to improve clinical outcomes for short bowel syndrome patients we require (1) knowledge of changes within the epithelial population following small bowel resection (SBR) and (2) an idea of when these changes occur to inform on the timing of potential interventions aimed at enhancing the adaptive response. The aim of this study was to produce a temporal map of epithelial changes within the crypt and villus at early and late adaptation phases. Four-week-old piglets underwent a 75% SBR or sham operation and were studied at 2, 4 and 6 weeks post-operation to allow analysis of early and late adaptation responses. Piglets received polymeric infant formula (PIF). Immunohistochemistry with specific cell markers was used to quantitate intestinal cell types and the total cell numbers. Changes within the crypt were temporally dependent on an early significant increase in enterocytes and proliferative cells not sustained at 6 weeks. Goblet cell numbers were increased at all time points. Despite a significant increase in total villus cell numbers at 6 weeks there was no change in specific cell types. We observed two distinct phases of cellular change following SBR. An early increase in enterocytes and proliferative cells was not reflected in increased weight gain indicating the early increase represents immature enterocytes. Interventions aimed at increasing differentiation of the rapidly changing crypt population would allow for an earlier increase in absorption.

Morphological and functional changes in the colon after massive small bowel resection

Purpose Anecdotal evidence suggests that the colon plays an important role after small bowel resection (SBR). However, colonic changes have not previously been studied. The aim of this study was to characterize morphological and functional changes within the colon after SBR and elucidate the influence of diet complexity on adaptation. Method In study 1, 4-week-old piglets underwent a 75% SBR or sham operation and were studied at 2, 4, and 6 weeks postoperation to allow analysis of early and late adaptation responses. Piglets received a polymeric infant formula (PIF). In study 2, SBR piglets received an elemental diet and were studied at 6 weeks postoperation and compared with SBR + PIF piglets from study 1. For both studies, immunohistochemistry was used to quantitate intestinal cell types. Changes in functional proteins were measured by Western blot, enteroendocrine/peptide YY (PYY), enterocyte/liver fatty acid binding protein (L-FABP), and goblet cells/trefoil factor 3 (TFF3). Results In study 1, early and late adaptation-related changes were observed after SBR. Early adaptation included increased numbers of enterocytes ( P = .0001), whereas late adaptation included increased proliferative cell numbers ( P = .02). Enteroendocrine, goblet, and apoptotic cells numbers were significantly elevated in the resected group at all time-points studied ( P < .05). Functional changes included increased levels of L-FABP ( P = .04) and PYY ( P = .03). There was no change in TFF3 expression. In study 2, feeding with an elemental diet resulted in suboptimal adaptation as evidenced by reduced rate of weight gain and significant reductions in total cell numbers ( P = .0001), proliferative ( P = .0001) and apoptotic cells ( P = .04), enteroendocrine cells ( P = .001), and PYY expression ( P .004). Conclusion These findings indicate that significant morphological and functional changes occur in the colon after massive SBR and that these occur as early and late adaptation responses. Elemental diet was associated with suboptimal adaptation suggesting an effect of diet complexity on colonic adaptation.

On “Pathogenesis and Management of Postoperative Ileus” (Clin Colon Rectal Surg 2009;22:47–50)

I read with great interest the article in your Volume 22 issue by Carroll and Alavi regarding the pathogenesis and management of postoperative ileus (POI).1 Alvimopan was reviewed by the authors and concluded to show “promise in reducing POI, but needs more rigorous investigation.” Alvimopan has been extensively evaluated for the management of gastrointestinal (GI) recovery (POI) in five large, randomized, double-blind, placebo-controlled phase 3 clinical trials (>3,000 patients). The results from these clinical trials have all been published in peer-reviewed journals.2,3,4,5,6 Furthermore, alvimopan was ultimately approved by the U.S. Food and Drug Administration in 2008 to accelerate the time to upper and lower GI recovery following partial large or small bowel resection surgery with primary anastomosis.7 Although the information presented in the article is accurate, it is also incomplete. This additional information, which was not referenced in the original article, may help provide perspective to the reader about the current state of development of alvimopan. Thank you for the opportunity to comment on this interesting paper by Carroll and Alavi.

Murine Functional Liver Mass is Reduced Following Partial Small Bowel Resection

IntroductionLiver mass is regulated in precise proportion to body mass in health and is restored by regeneration following acute injury. Despite extensive experimental analyses, the mechanisms involved in this regulation have not been fully elucidated. Previous investigations suggest that signals from the bowel may play an important role. The purpose of the studies reported here was to determine the effect of proximal partial small bowel resection on liver mass in a murine model. MethodsMice were subjected to a 50% proximal small bowel resection or sham surgery followed by primary anastomosis, then sacrificed at serial times for determination of liver:body mass ratio and analyses of liver tissue. ResultsLiver:body weight ratio was significantly decreased 72 h after small bowel resection, and this decrease correlated with reduced functional liver mass as assessed by determination of total hepatic tissue protein and alanine transaminase (ALT) activity. Liver from bowel-resected animals demonstrated increased expression of LC3-II, a marker of autophagy, and also of pro-apoptotic Bax compared to anti-apoptotic Bcl-2. ConclusionThese data support a role for signals from the intestine in liver mass regulation, and they have potential implications regarding the pathogenesis of liver injury following small bowel resection.

P21 waf1/cip1 deficiency does not perturb the intestinal crypt stem cell population after massive small bowel resection

Background After small bowel resection (SBR), adaptation is initiated in intestinal crypts where stem cells reside. Prior studies revealed SBR-induced enterocyte proliferation requires the expression of p21 waf1/cip1. As deficient expression of p21 waf1/cip1 has been shown to result in reduced numbers of hematopoietic stem cells. We sought to test the hypothesis that p21 waf1/cip1deficiency similarly perturbs the intestinal stem cell population after SBR. Methods Control ( n = 21; C57Bl/6) and p21 waf1/cip1-null mice ( n = 30) underwent 50% proximal SBR or sham operation. After 3 days, the ileum was harvested and the crypt stem cell population evaluated by counting crypt base columnar cells on histologic sections, determining the expression of Musashi-1 and Lgr5, and profiling the transcriptional expression of 84 known stem cell genes. Results There were no significant differences in crypt base columnar cells, expression of Musashi-1 or Lgr5, or in stem cell gene expression after SBR in control mice. Furthermore, there were no differences in these markers between controls and p21 waf1/cip1-null mice. Conclusion In contrast with bone marrow stem cells, the stem cell population of the gut is unaffected by deficient expression of p21 waf1/cip1. Additional mechanisms for the role of p21 waf1/cip1 in small bowel proliferation and adaptation after massive SBR must be considered.

New drug to restore bowel function approved under new FDA rules

FDA approved a new drug on May 20 to help restore normal bowel function after some types of abdominal surgery under new rules that allow several safety-related restrictions. The drug, to be marketed as Entereg, is indicated for use in hospitalized patients 18 years or older who have undergone partial large or small bowel resection surgery. Under FDA’s new Risk Evaluation and Mitigation Strategy (REMS) rules, the product may be given only to inpatients at specially certified facilities. Adolor Corporation manufactures the drug, which has the generic name alvimopan and is a peripherally acting μ-opioid-receptor antagonist, according to the Exton, Pennsylvania, company. FDA says patients may not receive more than 15 doses of the product. The drug agency states that it is approving Entereg with REMS restrictions to make sure the drug’s benefits outweigh the risks. Use of the drug is restricted to patients in the hospital. All patients receiving the drug are to be entered in a registry. Health care providers, including pharmacists, must participate in educational training on all REMS drugs, according to rules published on March 27 in the Federal Register.