Increased Enterocyte Apoptosis Research Articles

Impaired FXR-CPT1a signaling contributes to parenteral nutrition-induced villus atrophy in short-bowel syndrome.

Parenteral nutrition (PN)-induced villus atrophy is a major cause of intestinal failure (IF) for children suffering from short bowel syndrome (SBS), but the precise mechanism remains unclear. Herein, we report a pivotal role of farnesoid X receptor (FXR) signaling and fatty acid oxidation (FAO) in PN-induced villus atrophy. A total of 14 pediatric SBS patients receiving PN were enrolled in this study. Those patients with IF showed longer PN duration and significant intestinal villus atrophy, characterized by remarkably increased enterocyte apoptosis concomitant with impaired FXR signaling and decreased FAO genes including carnitine palmitoyltransferase 1a (CPT1a). Likewise, similar changes were found in an in vivo model of neonatal Bama piglets receiving 14-day PN, including villus atrophy and particularly disturbed FAO process responding to impaired FXR signaling. Finally, in order to consolidate the role of the FXR-CPT1a axis in modulating enterocyte apoptosis, patient-derived organoids (PDOs) were used as a mini-gut model in vitro. Consequently, pharmacological inhibition of FXR by tauro-β-muricholic acid (T-βMCA) evidently suppressed CPT1a expression leading to reduced mitochondrial FAO function and inducible apoptosis. In conclusion, impaired FXR/CPT1a axis and disturbed FAO may play a pivotal role in PN-induced villus atrophy, contributing to intestinal failure in SBS patients.

S3023 Mesenteric Lymphadenopathy From Recurrent Giardiasis: A Rare Cause of Small Bowel Obstruction in a Patient With X Linked Agammaglobulinemia

Introduction: Giardiasis, the most common parasitic infection of the human intestine, is caused by the binucleated protozoan parasite Giardia duodenalis (G intestinalis, giardia lamblia). This infection is commonly reported in developing countries; however, it remains one of the most common parasitic infections in the United States. This infection is also often found in populations with immunodeficiency disorders, such as X Linked agammaglobulinemia. Here, we discuss the case of a patient with X linked agammaglobulinemia who presented with a rare complication of small bowel obstruction (SBO) due to recurrent giardiasis. Case Description/Methods: A 59-year-old male with medical history of X linked agammaglobulinemia, bronchiectasis, COPD, iron deficiency anemia, intestinal malabsorption presented with the complaints of abdominal discomfort and intractable vomiting. The patient also reported similar complaints in the past. Review of systems unremarkable. Initial lab tests revealed leukocytosis (WBC 14.5 K/micro-L), Na 133 mmol/L, K 4.0 mmol/L, BUN 17 mg/dl, Cr 1.17 mg/dl, LFT with in normal limits. X Ray abdomen suggestive of ileus rather than small bowel obstruction. Stool studies positive for calprotectin and lactoferrin. EGD showed giardiasis, colonoscopy biopsies negative for IBD and cancer. CT Abd is unremarkable except for persistent prox. Jejunal luminal narrowing. MR Enterography positive for mesenteric lymphadenopathy causing persistent small bowel obstruction (Fig 1). Discussion: X linked agammaglobulinemia is an inherited immunodeficiency disorder characterized by a failure to produce mature B lymphocytes and antibodies. Because of the lack of antibodies, patients most often present with recurrent upper respiratory tract infections, followed by gastrointestinal infections. Patients with giardiasis present with chronic diarrhea, bloating, nausea and vomiting. Functional dyspepsia, irritable bowel syndrome and cancer are additional intestinal manifestations of giardiasis. The pathophysiology is thought to be due increased enterocyte apoptosis, intestinal barrier dysfunction, malabsorption and increased intestinal transit rates caused by the host’s pathogen immune response. SBO from giardiasis is very rarely reported and has been hypothesized to relate to altered intestinal motility. More research is needed to study the details of the mechanism causing this complication.Figure 1.: Massively distended small bowel loops (shown by orange arrow).

Роль неинвазивных маркеров повреждения энтероцитов и повышенной проницаемости в патогенезе целиакии

Celiac disease (CD) is an immune-mediated enteropathy characterized by atrophy/damage to the mucous membrane of the small intestine in genetically susceptible individuals in response to gluten administration. In CD morphology, atrophy is the result of increased enterocyte apoptosis due to autoimmune inflammation. Since the enterocyte is an anatomical and functional unit of the mucous membrane of the small intestine, responsible for the barrier function and for the absorption of nutrients, to understand the pathogenesis of CD, the study of the processes of restoration of the mucosa is of paramount importance. Antibodies to tissue transglutaminase, antibodies to deamidated gliadin peptides, antibodies to endomysium, which are used to monitor disease activity and represent the body's immune response, can only indirectly indicate the degree of damage/recovery of enterocytes. During histological examination it is not always possible to assess the degree of damage at the cellular level, taking into account the complexity of the interpretation of morphological changes and patchiness of mucosa damage. In recent years, researchers have paid much attention to new markers of mucosa permeability, which include: I-FABP − a marker reflecting damage to enterocytes, citrulline − a marker of the functional mass of enterocytes, zonulin − a marker of increased mucosa permeability and alpha-1-antitrypsin − a marker reflecting the failure of the barrier function of the small intestine and protein loss. Using of these markers will help optimize the algorithm for non-invasive diagnostics of CD, improve monitoring of disease activity, and will also usefull for understanding the processes of mucosa recovery.

Toll-like receptor 4-mediated lymphocyte influx induces neonatal necrotizing enterocolitis.

The nature and role of the intestinal leukocytes in necrotizing enterocolitis (NEC), a severe disease affecting premature infants, remain unknown. We now show that the intestine in mouse and human NEC is rich in lymphocytes that are required for NEC development, as recombination activating gene 1–deficient (Rag1–/–) mice were protected from NEC and transfer of intestinal lymphocytes from NEC mice into naive mice induced intestinal inflammation. The intestinal expression of the lipopolysaccharide receptor TLR4, which is higher in the premature compared with full-term human and mouse intestine, is required for lymphocyte influx through TLR4-mediated upregulation of CCR9/CCL25 signaling. TLR4 also mediates a STAT3-dependent polarization toward increased proinflammatory CD3+CD4+IL-17+ and reduced tolerogenic Foxp3+ Treg lymphocytes (Tregs). Th17 lymphocytes were required for NEC development, as inhibition of STAT3 or IL-17 receptor signaling attenuated NEC in mice, while IL-17 release impaired enterocyte tight junctions, increased enterocyte apoptosis, and reduced enterocyte proliferation, leading to NEC. Importantly, TLR4-dependent Th17 polarization could be reversed by the enteral administration of retinoic acid, which induced Tregs and decreased NEC severity. These findings identify an important role for proinflammatory lymphocytes in NEC development via intestinal epithelial TLR4 that could be reversed through dietary modification.

Intestinal phenotype in mice overexpressing a heparin-binding EGF-like growth factor transgene in enterocytes

Primary objective. Heparin-binding EGF-like growth factor (HB-EGF) protects the intestine from damage in animals. Future clinical trials of HB-EGF may involve administration of repeated doses of HB-EGF. Since HB-EGF activates EGF receptors which have been implicated in tumor development, we examined the effects of HB-EGF overexpression in the intestine.Research design. We generated transgenic (TG) mice in which the human HB-EGF gene is driven by the villin promoter to overexpress HB-EGF along the crypt-villous axis from the duodenum to the colon.Results. HB-EGF TG mice have increased enterocyte proliferation balanced by increased enterocyte apoptosis. Despite prolonged overexpression of HB-EGF, no evidence of intestinal hyperplasia or tumor formation occurs. Although HB-EGF TG mice have no significant phenotypic alterations under basal conditions, they have increased resistance to intestinal injury.Conclusions. Prolonged intestinal HB-EGF overexpression results in no significant phenotypic alterations under basal conditions, but confers protection against intestinal injury.

A Critical Role for TLR4 in the Pathogenesis of Necrotizing Enterocolitis by Modulating Intestinal Injury and Repair

Necrotizing enterocolitis (NEC) is the leading cause of death from gastrointestinal disease in preterm infants and is characterized by translocation of LPS across the inflamed intestine. We hypothesized that the LPS receptor (TLR4) plays a critical role in NEC development, and we sought to determine the mechanisms involved. We now demonstrate that NEC in mice and humans is associated with increased expression of TLR4 in the intestinal mucosa and that physiological stressors associated with NEC development, namely, exposure to LPS and hypoxia, sensitize the murine intestinal epithelium to LPS through up-regulation of TLR4. In support of a critical role for TLR4 in NEC development, TLR4-mutant C3H/HeJ mice were protected from the development of NEC compared with wild-type C3H/HeOUJ littermates. TLR4 activation in vitro led to increased enterocyte apoptosis and reduced enterocyte migration and proliferation, suggesting a role for TLR4 in intestinal repair. In support of this possibility, increased NEC severity in C3H/HeOUJ mice resulted from increased enterocyte apoptosis and reduced enterocyte restitution and proliferation after mucosal injury compared with mutant mice. TLR4 signaling also led to increased serine phosphorylation of intestinal focal adhesion kinase (FAK). Remarkably, TLR4 coimmunoprecipitated with FAK, and small interfering RNA-mediated FAK inhibition restored enterocyte migration after TLR4 activation, demonstrating that the FAK-TLR4 association regulates intestinal healing. These findings demonstrate a critical role for TLR4 in the development of NEC through effects on enterocyte injury and repair, identify a novel TLR4-FAK association in regulating enterocyte migration, and suggest TLR4/FAK as a therapeutic target in this disease.

Epidermal Growth Factor Receptor Signaling Regulates Bax and Bcl-w Expression and Apoptotic Responses During Intestinal Adaptation in Mice

Normal intestinal adaptation to massive small-bowel resection requires intact epidermal growth factor receptor signaling and consists of increased enterocyte proliferation and apoptosis. Although emphasis has been placed on understanding the regulation of proliferation, few studies have evaluated the mechanism and contribution of apoptosis to the adaptation response. We sought to test the hypothesis that epidermal growth factor receptor signaling regulates specific Bcl-2 family members (Bax and Bcl-w) to direct apoptosis and adaptation after massive small-bowel resection. Laser capture microdissection microscopy permitted measurement of Bax and Bcl-w messenger RNA expression in crypt and villus enterocytes in control conditions and under epidermal growth factor receptor-inhibited (waved-2 mice) or stimulated (epidermal growth factor transgenic mice) conditions after a 50% small-bowel resection or sham operation. Resection-induced adaptation was then studied in Bax-null and Bcl-w-null mice under control circumstances and after epidermal growth factor receptor stimulation. When compared with Bcl-w, the most significant expression changes were observed with Bax and took place within crypt enterocytes. Epidermal growth factor receptor stimulation resulted in a decreased ratio of Bax to Bcl-w expression and decreased rates of apoptosis. Bax-null mice had no apoptosis response to small-bowel resection and displayed an amplified adaptation response to the administration of epidermal growth factor. Bcl-w-null mice had poor survival and impaired adaptation to small-bowel resection, an effect that was rescued by crossbreeding these mice with epidermal growth factor transgenic mice. The crypt expression of Bax and Bcl-w is influenced by epidermal growth factor receptor signaling and is key for the regulation of apoptosis. Epidermal growth factor receptor stimulation, coupled with apoptosis inhibition, may provide a novel strategy to amplify adaptation responses in patients after massive intestinal loss.

Characteristics of Human Calicivirus Enteritis in Intestinal Transplant Recipients

The human caliciviruses, which include Norwalk-like viruses (or Noroviruses) and Sapporo viruses, commonly cause epidemic and endemic viral gastroenteritis of short duration in healthy individuals. However, the impact of human calicivirus in immunosuppressed populations has not been established. The authors report five pediatric patients who developed human calicivirus enteritis after intestinal transplantation. Infection was documented with repetitive reverse transcription polymerase chain reaction testing with nucleotide sequencing of tissue and lumen fluid specimens. A single strain, type Miami Beach, affected all patients in the hospital with an apparent index case. A potential mode of transmission was not defined. Severe osmotic or secretory diarrhea necessitated intravenous fluid therapy for 40 days or more in three of the five infants. Concurrent or recent subclinical allograft infection with adenovirus in two patients was associated with more severe symptoms. Virus excretion exceeded 80 days in two patients. Differentiation of human calicivirus enteritis from allograft rejection was difficult, as both disorders were associated with increased enterocyte apoptosis and inflammation. Intensification of immunosuppressive therapy because of suspected rejection appeared to prolong symptoms. These findings demonstrate that human calicivirus can be a significant pathogen in intestinal transplant recipients and potentially in other immunocompromised patients.

Mechanisms of postburn intestinal barrier dysfunction in the rat: roles of epithelial cell renewal, E-cadherin, and neutrophil extravasation.

Our group has previously shown that the intestinal epithelium exhibits increased postburn barrier permeability and bacterial translocation associated with deranged neutrophil activity. The purpose of this investigation is to explore possible underlying intestinal structural mechanisms, leading to those functional changes with emphasis on (1) neutrophil influx and extravasation in the intestinal lamina propria 1-3 days after burn and (2) enterocyte proliferation, migration, apoptosis, and E-cadherin junctional epithelium levels 3 days after burn. Freshly isolated ileum specimens were quick frozen, then cut by a cryostat into 30-micron-thick sections. Sections from day 1 postburn rats were immunostained with (1) anti-granulocyte or anti-elastase antibodies to assess neutrophil influx or (2) combined anti-granulocyte and anti-von Willebrand factor double immunolabeling to compare levels of neutrophil extravasation. Sections from day 3 postburn rats were immunostained with (1) bromodeoxyuridine immunohistochemistry 1, 3, 6, or 18 hrs after bromodeoxyuridine injection to assess enterocyte proliferation and migration, (2) cytokeratin-18 M30-immunohistochemistry to compare levels of enterocyte apoptosis, and (3) E-cadherin immunohistochemistry to compare junctional E-cadherin integrity. Ileal myeloperoxidase activity and bacterial translocation of Enterococcus faecalis were assessed biochemically and by E. faecalis-specific bacterial cultures, respectively, in day 3 postburn rats. : Research laboratories in a medical center and an academic institution. Male Sprague-Dawley rats given sham treatment or treatment as a burn model with full-thickness skin scald over 30% total body surface area. We report (1) increased levels of neutrophil influx and extravasation in villi lamina propriae, including elastase-positive cells (postburn day 1), (2) heightened levels of intestinal myeloperoxidase activity (postburn day 3), (3) decreased levels of epithelial cell proliferation, migration, and E-cadherin (postburn day 3), and (4) increased enterocyte apoptosis and E. faecalis bacterial translocation (postburn day 3). Based on these structural and functional abnormalities, we propose a mechanism for burn injury-related intestinal barrier dysfunction that includes increased trans- and para-cellular leakage caused by impaired enterocyte renewal and decreased junctional E-cadherin levels subsequent to increased neutrophil influx and extravasation within the villus lamina propria microenvironment.

Enterocyte apoptosis and TPN-associated intestinal mucosal atrophy: a view of the chicken or the egg?

Enterocyte apoptosis and TPN-associated intestinal mucosal atrophy: a view of the chicken or the egg?

Enterocyte apoptosis after enterectomy in mice is activated independent of the extrinsic death receptor pathway.

Intestinal adaptation following small bowel resection (SBR) is associated with greater rates of enterocyte apoptosis by unknown mechanism(s). Because postresection adaptation is associated with increased translocation of luminal bacteria, we sought to characterize the role for the extrinsic, death receptor pathway for the activation of enterocyte apoptosis after massive SBR. We first performed SBR or sham operations in mice, and the temporal expression of caspases 8, 9, and 3, death receptors tumor necrosis factor receptor-1 (TNFR1) and Fas and corresponding ligands (TNF and Fas ligand) was determined in the remnant intestine at various postoperative time points. Ileal TNFR1 and Fas expression were then measured after SBR in the setting of increased (waved-2 mice) or decreased (exogenous EGF administration) apoptosis. Finally, intestinal adaptation and apoptosis were recorded in the remnant ileum after SBR in TNFR1-null and Fas-null mice. The expression of death receptor family proteins and caspases demonstrated only modest changes after SBR and did not correlate with the histological appearance of apoptosis. In the setting of accelerated apoptosis, TNFR1 and Fas expression were paradoxically decreased. Apoptotic and adaptive responses were preserved in both TNFR1-null and Fas-null mice. These results suggest that the mechanism for increased enterocyte apoptosis following massive SBR does not appear to involve the extrinsic, death receptor-mediated pathway.

Cytolytic mechanisms of intraepithelial lymphocytes in coeliac disease (CoD).

The effector arm of the mucosal immune system comprises lymphocytes scattered at intraepithelial and lamina propria levels. Intraepithelial lymphocytes (IEL) are a large population of oligoclonal resting cells which exhibit phenotypic and functional characteristics of cytolytic T cells when activated. Several mechanisms have been demonstrated to account for their cytotoxicity. Among them, one is mediated by perforin and granzyme molecules, another is mediated by Fas ligand (FasL) which delivers apoptotic signals through Fas receptor on target cells. There is good evidence that a flat intestinal mucosa may be produced by activated T cells. The aim of our study was to evaluate FasL and perforin expression by IEL, and its possible correlation with the increased enterocyte apoptosis in coeliac mucosa. Endoscopic duodenal biopsy specimens from 10 untreated coeliac patients, 10 treated coeliac patients, and 10 biopsied controls were evaluated for enterocyte apoptosis by terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine triphosphate nick end label method, for perforin expression by immunohistochemistry, and for FasL expression by immunocytochemistry. In untreated CoD there was a significant increase of percentage of both FasL+ and perforin+ IEL which positively correlated with enterocyte apoptosis in comparison with controls. All these parameters were significantly lower in treated CoD, even though they did not normalize. Our study demonstrates that in untreated CoD FasL and perforin expression by IEL is increased, and significantly correlates with the level of enterocyte apoptosis.

Increased enterocyte apoptosis and Fas-Fas ligand system in celiac disease.

Our aim was to evaluate whether increased enterocyte apoptosis was responsible for mucosal flattening in celiac disease (CD), and, since the mechanisms responsible for tissue injury in this condition are unknown, we studied the possibility that the Fas-Fas ligand (FasL) system may be involved. Endoscopic duodenal biopsy specimens from 12 patients with untreated and 12 with treated CD and 12 control subjects were evaluated for enterocyte apoptosis by the terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine triphosphate nick-end labeling assay and for Fas and FasL expression by immunohistochemistry. A coculture of isolated enterocytes (targets) and purified lamina propria mononuclear cells (LPMCs) (effectors) was performed in the absence or presence of an antagonistic ZB4 anti-Fas antibody. We found a significant correlation between the degree of villous atrophy, morphometrically evaluated, and the level of enterocyte apoptosis, suggesting that mucosal flattening is a consequence of exaggerated epithelial cell death. Most celiac enterocytes express Fas, and LPMCs express FasL. The abolishment of enterocyte apoptosis observed in the presence of ZB4 antibody suggests that enterocytes are potential targets of lymphocyte infiltrate. These results directly demonstrate that FasL-mediated apoptosis is a major mechanism responsible for enterocyte death in CD.

Ceramide involvement in the signal transduction leading to increased enterocyte apoptosis in celiac disease

Ceramide involvement in the signal transduction leading to increased enterocyte apoptosis in celiac disease

Ceramide involvement in the signal transduction leading to increased enterocyte apoptosis in celiac disease

Ceramide involvement in the signal transduction leading to increased enterocyte apoptosis in celiac disease

Bax is required for increased enterocyte apoptosis after massive small bowel resection

Background: Massive small bowel resection (SBR) increases rates of both enterocyte proliferation and apoptosis. Previous studies have demonstrated increased intestinal expression of proapoptotic bax mRNA and protein, as well as the appearance of an 18-kd bax cleavage product within 12 hours of SBR. This study tested the hypothesis that bax is required for postresection increases in enterocyte apoptosis. Methods: Male bax-null and C57Bl/6 (control) mice underwent either a 50% proximal SBR or sham operation. After 3 days, the remnant ileum was harvested and weighed. Apoptotic indexes, proliferation indexes, villus heights, and crypt depths were determined. Results: The usual adaptive increases in ileal wet weight, crypt depth, and rate of proliferation occurred in both the control and bax-null mice. Resection significantly increased the rate of apoptosis in the control mice; however, it failed to alter the apoptotic index in the bax-null mice. Conclusions:Bax is necessary for the increase in apoptosis that occurs after SBR, but its absence has no significant effect on short-term adaptation. These findings suggest that enterocyte proliferation and apoptosis are differentially regulated during intestinal adaptation. (Surgery 2000;128:165-70.)

Epidermal growth factor alters the bax:bcl-w ratio following massive small bowel resection.

Following massive small bowel resection (SBR), the expression of bax and bcl-w is associated with increased enterocyte apoptosis. Epidermal growth factor (EGF) has been shown to enhance enterocyte proliferation and retard apoptosis in the adapting bowel. This study examined the effect of EGF on the expression of these bcl-2 family members during adaptation. Mice (C57Bl/6; n = 38) underwent a 50% SBR or sham operation and then were randomized to receive twice-daily orogastric saline or EGF (50 microg/kg/day). After 3 days, the remnant ileum was removed, apoptotic index (No. apoptotic bodies/crypt) calculated, and expression of mRNA and protein for bax and bcl-w quantified. EGF prevented the expected increase in the apoptotic index after SBR and altered the ratio of bax to bcl-w in favor of cell survival. Following massive small bowel resection, EGF retards rates of enterocyte apoptosis and modifies the expression of bcl-2 family members. By decreasing bax and increasing bcl-w expression, the balance between pro- and anti-apoptotic genes is shifted in favor of cell survival. Alteration of bcl-2 family member expression may be an important mechanism by which EGF reduces the increased enterocyte apoptosis that occurs after massive small bowel resection.

Plant phenolics decrease intestinal tumors in an animal model of familial adenomatous polyposis.

Epidemiological studies consistently indicate that consumption of fruits and vegetables lowers cancer risk in humans and suggest that certain dietary constituents may be effective in preventing colon cancer. Plant-derived phenolic compounds manifest many beneficial effects and can potentially inhibit several stages of carcinogenesis in vivo. In this study, we investigated the efficacy of several plant-derived phenolics, including caffeic acid phenethyl ester (CAPE), curcumin, quercetin and rutin, for the prevention of tumors in C57BL/6J-Min/+ (Min/+) mice. These animals bear a germline mutation in the Apc gene and spontaneously develop numerous intestinal adenomas by 15 weeks of age. At a dietary level of 0.15%, CAPE decreased tumor formation in Min/+ mice by 63%. Curcumin induced a similar tumor inhibition. Quercetin and rutin, however, both failed to alter tumor formation at dietary levels of 2%. Examination of intestinal tissue from the treated animals showed that tumor prevention by CAPE and curcumin was associated with increased enterocyte apoptosis and proliferation. CAPE and curcumin also decreased expression of the oncoprotein beta-catenin in the enterocytes of the Min/+ mouse, an observation previously associated with an antitumor effect. These data place the plant phenolics CAPE and curcumin among a growing list of anti-inflammatory agents that suppress Apc-associated intestinal carcinogenesis.

Effect of massive small bowel resection on the Bax/Bcl-w ratio and enterocyte apoptosis

Following small bowel resection (SBR), the remnant intestine undergoes adaptation. Enterocyte proliferation is increased and counterbalanced by increased rates of apoptosis. To elucidate a mechanism for increased enterocyte apoptosis, this study tested the hypothesis that the ratio between pro-apoptotic Bax and pro-survival Bcl-w correlates with the apoptosis that occurs following SBR. Mice (C57Bl/6; n = 76) underwent a 50% proximal SBR or sham operation. After 12 hours and 1, 2, 3, and 7 days, the ileum was removed, the apoptotic index (apoptotic bodies/crypt) was recorded, and the messenger RNA and protein for Bax and Bcl-w were quantified. The apoptotic index was equivalent in the sham and SBR mice at 12 hours; however, it was significantly elevated following SBR at every other day measured. The ratio of Bax to Bcl-w messenger RNA relative to sham operation increased after SBR at 24 hours, decreased by day 3, and returned to baseline levels by 1 week. The protein ratio showed an increase by day 1, which remained elevated through day 7. An augmented ratio of Bax to Bcl-w messenger RNA and protein corresponded with the increase in enterocyte apoptosis. Alterations in the expression ratio of these genes may play a role in establishing a new homeostatic set point between proliferation and apoptosis during adaptation.

Intestinal adaptation and enterocyte apoptosis following small bowel resection is p53 independent.

Adaptation following small bowel resection (SBR) signals enterocyte proliferation and apoptosis. Because p53-induced p21(waf1/cip1) may be important for apoptosis in many cells, we hypothesized that these genes are required for increased enterocyte apoptosis during adaptation. Male C57BL/6 (wild-type) or p53-null mice underwent 50% proximal SBR or sham operation (bowel transection-reanastomosis). Adaptation (DNA-protein content, villus height-crypt depth, enterocyte proliferation), appearance of apoptotic bodies, and p53 and p21(waf1/cip1) protein expression were measured in the ileum after 5 days. Adaptation was equivalent after SBR in both wild-type and p53-null mice as monitored by significantly increased ileal DNA-protein content, villus height, and enterocyte proliferation. The number of crypt apoptotic bodies increased significantly after SBR evenly in both wild-type and p53-null mice. In the p53-null mice, SBR substantially induced the expression of p21(waf1/cip1) protein in villus enterocytes. The p53-independent induction of p21(waf1/cip1) may account for the similar intestinal response to SBR between wild-type and p53-null mice. Intestinal adaptation and increased enterocyte apoptosis following intestinal resection occur via a p53-independent mechanism.