A conscious mouse model of gastric ileus using clinically relevant endpoints
© Firpo et al; licensee BioMed Central Ltd. 2005
Received: 08 September 2004
Accepted: 06 June 2005
Published: 06 June 2005
Gastric ileus is an unsolved clinical problem and current treatment is limited to supportive measures. Models of ileus using anesthetized animals, muscle strips or isolated smooth muscle cells do not adequately reproduce the clinical situation. Thus, previous studies using these techniques have not led to a clear understanding of the pathophysiology of ileus. The feasibility of using food intake and fecal output as simple, clinically relevant endpoints for monitoring ileus in a conscious mouse model was evaluated by assessing the severity and time course of various insults known to cause ileus.
Delayed food intake and fecal output associated with ileus was monitored after intraperitoneal injection of endotoxin, laparotomy with bowel manipulation, thermal injury or cerulein induced acute pancreatitis. The correlation of decreased food intake after endotoxin injection with gastric ileus was validated by measuring gastric emptying. The effect of endotoxin on general activity level and feeding behavior was also determined. Small bowel transit was measured using a phenol red marker.
Each insult resulted in a transient and comparable decrease in food intake and fecal output consistent with the clinical picture of ileus. The endpoints were highly sensitive to small changes in low doses of endotoxin, the extent of bowel manipulation, and cerulein dose. The delay in food intake directly correlated with delayed gastric emptying. Changes in general activity and feeding behavior were insufficient to explain decreased food intake. Intestinal transit remained unchanged at the times measured.
Food intake and fecal output are sensitive markers of gastric dysfunction in four experimental models of ileus. In the mouse, delayed gastric emptying appears to be the major cause of the anorexic effect associated with ileus. Gastric dysfunction is more important than small bowel dysfunction in this model. Recovery of stomach function appears to be simultaneous to colonic recovery.
Ileus is a common post-surgical occurrence characterized by transient impairment of gastrointestinal function. In addition to abdominal surgery, sepsis, trauma, pancreatitis, anesthetic agents, and opioid analgesics are also associated with ileus. The mechanisms of ileus involve neural inhibitory signals and humoral factors including paracrine agents and gut hormones [1–3]. No single event or factor has been clearly implicated as being responsible; it is more likely that multiple mediators act at various times throughout the course of the condition. These mediators communicate throughout the gastrointestinal tract. For example, surgical manipulation of the distal bowel can induce gastric dysfunction [4–8]. Once established, ileus is thought to resolve at different rates in humans with functional inhibition lasting a few hours within the small intestine, 1–2 days within the stomach and 2–3 days within the colon [9, 10].
Many recent studies of ileus have focused attention on small bowel smooth muscle dysfunction in isolated muscle strips [11–14]. The weakness of the muscle strip method, however, is the inability to examine complex interactions including brain-gut interactions or organ specific neural reflexes. Similarly, in vitro preparations require tissue harvest to assay the condition and do not allow a systems approach to the problem of ileus. The availability of complete genomic sequence information in the mouse has made the application of a systems approach feasible using global gene expression analysis. However, phenotypic characterizations of ileus in animal models that provide system wide information are lacking. Development of such a model in the mouse would be useful.
In the clinical setting, resolution of ileus is determined by the resumption of normal eating behavior and the passage of flatus or stool. Despite the fact that food intake and fecal output are simple measurements of gastrointestinal function they have not been rigorously analyzed in animal models of ileus. Here we describe a conscious mouse model that uses food intake and fecal output to monitor the time course of ileus, allowing measurement of both the magnitude and duration of the condition in the same animal. This integrative approach to defining the phenotype of ileus may facilitate investigations of potential clinically relevant interventions or preventive strategies. In addition, this conscious mouse model offers the opportunity to study molecular events associated with ileus.
Male C3H mice, 8–12 weeks old, were used throughout the study. Mice were maintained on a 12-hour light/dark cycle and given free access to standard rodent chow and water. For the continuous food intake monitoring study, mice were given 20 mg dustless food pellets (Bio-Serv, Frenchtown, NJ). All procedures were approved and monitored by the University of Utah Institutional Animal Care and Use Committee.
Food intake and fecal output measurement
Mice were separated into individual cages with free access to water and a tared amount of food. Food, fecal and mouse mass were measured every 12 hours at the beginning of each scotophase and photophase (7 AM and 7 PM). The amount of food consumed over the 12-hour period was calculated as the difference between the mass of food at the end of the period and the amount of food at the beginning of the period. Fecal output was determined from the mass of fecal pellets collected and measured at the end of the 12-hour period. The potential effect of fecal pellet dehydration over the 12 hour period was addressed in pilot studies in which ileus was induced using either 0.1 mg/kg LPS or laparotomy followed by 4 minute bowel manipulation as well as the corresponding controls. Fecal pellets were collected every 12 hours and fecal output was determined in three ways: 1) mass determination immediately upon collection (as reported in this study), 2) mass determination after a further 24 hour dehydration period, and 3) by counting fecal pellets. The decrease in fecal output relative to controls after ileus induction was similar and not significantly different among the three methods of measurement (data not shown). We concluded that the potential effect of dehydration was inconsequential. After a three-day acclimation period, the mice were randomized into experimental groups and a sham group. Data collection started 24 hours before the induction of ileus and continued after induction until a normal (baseline) circadian pattern of feeding and fecal output returned. For continuous food intake monitoring, mice were placed into individual metabolic chambers with free access to water. Single 20 mg dustless food pellets were delivered on demand using a Coulbourn Instruments Habitest system (Allentown, PA) equipped with a pellet feeder and food trough. The presence of a food pellet within the trough blocked light emitted from a light emitting diode reaching a photodetector. When the mouse removed the pellet, a new pellet was delivered. This exchange was automatically monitored and recorded by the Graphic State Notation 2 software program (Coulbourn Instruments, Allentown, PA). Mice were acclimated to the cage for 4 days prior to data collection.
Induction of ileus
After acclimation and baseline data collection periods, ileus was induced 30 minutes before scotophase unless otherwise noted. To mimic sepsis, lipopolysaccharide (E. coli O111:B4, List Biological Laboratories, Campbell, CA) was administered by intraperitoneal injection. The dose-dependent relationship of endotoxin on food intake and fecal output was investigated by determining the time courses for each endpoint after administration of 0.005, 0.01, 0.02, 0.04, 0.1, 0.2, and 0.4 mg/kg mouse mass of endotoxin. Control mice received a similar volume of saline carrier. Post-surgical ileus was induced in mice anesthetized with isoflurane either by laparotomy followed by manipulation of the cecum for 1 minute or laparotomy, evisceration onto a saline moistened sponge and manipulation of the small bowel, cecum and colon for a total manipulation time of 4 minutes. Manipulation was carried out using cotton tipped swabs. After closure of the incision with sutures, the mouse was removed from anesthesia and allowed to recover under a warming lamp for 30 minutes before data collection resumed. To assess the effects of thermal injury, a 20% total body surface area (TBSA) scald burn was induced on mice from which truncal hair was removed. The scald burn was induced by immersion of the exposed dorsal skin in 70°C water for 7 seconds. Immediately following burn injury, the mice were administered 1 ml of intraperitoneal (IP) lactated Ringer's solution. Mice were given 0.5 ml of LR IP every 12 hours for 72 hours post-burn injury. Control animals had truncal hair removed and received a similar time course of anesthesia and resuscitation with LR. Acute pancreatitis was induced in mice after an eighteen hour fasting period using 3 or 7 hourly IP injections of cerulein (50 μg/kg/dose). Sham treated control mice were given similar volumes of carrier (0.1% BSA in PBS). The timing of the injections was coordinated such that the last injection occurred at the beginning of scotophase.
Gastric emptying and intestinal transit
After a 2-hour fast to empty stomach content, mice were given 200 μl of a 1.5% (w/v) methylcellulose, 0.5% (w/v) phenol red solution in normal saline by gavage. Thirty minutes after gavage, the mice were sacrificed by cervical dislocation, a laparotomy performed and the stomach isolated by clamping the duodenum near the pylorus and the esophagus at the cardia. The entire procedure from sacrifice to clamping was performed in less than one minute. The GIT was removed, separating the stomach from the intestine. The small bowel was dissected from the cecum/colon and divided into four equal length segments by sequential bisection. The amount of phenol red in the stomach and intestinal segments was determined spectrophotometrically after homogenization as described . Gastric emptying was evaluated as the percentage of dye remaining in the stomach relative to the total amount of dye recovered in a standardization group of mice that were sacrificed immediately after gavage. Intestinal transit was determined by measuring the partitioning of dye within the small bowel segments and colon numbered 1–5, proximal to distal. The geometric center of dye transit was calculated for each animal as (∑(% dye per segment X segment number)/100) as described .
Mean arterial blood pressure
Mice were anesthetized with isoflurane and placed on a 37°C heating pad. A polyethylene cannula (PE 10), connected to a pressure transducer, was inserted approximately 5 mm into the femoral artery. Mean arterial pressure and respiratory rate (counted over 1 minute) was recorded every five minutes. After 10 minutes of monitoring to ensure stability of pressure and respiratory rate, LPS (25 μg/ml, in doses of 0.1 and 0.4 mg/kg) or carrier was injected IP. Blood pressure and respiratory rate was recorded every five minutes for a total of 1 hour.
Digital video images were recorded using a personal computer based system consisting of a WebCam (PC-Cam 300, Creative Labs, Milpitas, CA) and WebCam Control Center version 5.6 software http://www.webcam-control-center.com. The camera was placed above four standard mouse cages with wire tops. In lieu of litter, a single shredded paper towel was placed in each cage for bedding. A darkroom light equipped with a single 15-watt bulb and a Kodak GBX-2 Safelight filter (Eastman Kodak, Rochester, NY) provided illumination. Individual mice were placed in each cage with free access to water and a tared amount of food. In order to maintain an unobstructed view, water was provided in a glass bottle and food was limited to 4 standard rodent chow pellets (approximately 5 g each). Mice were acclimated to the cages for 5 days prior to data collection. Mice were administered saline, 0.1 mg/kg LPS or 2 mg/kg LPS in a blinded manner 30 minutes before scotophase. Images were recorded at 1 image per second for 10 seconds every 10 minutes for 36 hours. Investigators blinded to the treatment scored the recorded images for mouse activity and mouse induced movement of the food pellets. Activity was scored if gross movement of the mouse body was evident within any of the 10-second images. Likewise, food pellet movement was scored if the position of any of the food pellets were different when the 10 images were compared. New food pellets were placed and food mass recorded at 12-hour intervals corresponding to scotophase and photophase.
Statistical comparisons were made using factorial ANOVA or repeated measures ANOVA (for time course analyses) and Fisher's protected least significant difference (PLSD) post-hoc tests. Comparisons were considered statistically significant at the P < 0.05 level. Values are expressed as mean ± SEM unless data from individual mice are shown.
In order to determine the median-effect dose of LPS on food intake and fecal output, the 12-hour (first night) data was fitted to a dose-response curve. The model had an inverse proportionality form with offsets:
Food intake = A + (B-A)*D m / (Dose + D m ) + error
where Dose is the dose of the drug, A is the minimum food intake at arbitrary large doses (horizontal asymptote), B is the baseline food intake (when Dose = 0) and D m is the median-effect dose, that is the dose at which the food intake is halfway between the baseline B and minimum A. The error term reflects the between-animal variability of food intake, it is assumed to have normal distribution with mean 0 and variance proportional to the response: error~ N(0,s 2 (Food Intake)). The adjustment of the variability depending on the response was necessary as the between-animal variability decreased as the food intake decreased. Since each data point corresponds to a different mouse, the observations are independent. The above model was extended to all time points by modeling the median-effect dose D m as a function of time:
D m (T) = D m (1) c T , where T is time in "nights"
that is for each night the dose required to produce a median effect is increased c-fold. We also added two random effect terms: between-mouse variability of the median-effect dose D m (1) (on log-scale) and of the baseline food intake B. These mouse-specific terms allow us to accommodate the within-mouse dependence of the observations.
Endotoxin transiently decreased food intake and fecal output in a dose dependent manner
Parameters of the 12-hour endotoxin dose-response curve. Results of the fitted model examining the effect of various doses of endotoxin on food intake and fecal output during the first scotophase are shown.
95% Confidence Interval
A – minimum, grams
B – baseline, grams
D m – median effect dose, mg/kg
s – standard deviation, grams
A – minimum, grams
B – baseline, grams
D m – median effect dose, mg/kg
s – standard deviation, grams
Parameters of the endotoxin dose-response curves for food intake over time. Results of the fitted model examining the effect of various doses of endotoxin on nocturnal food intake extended to include the four nights after LPS injection.
95% Confidence Interval
A – minimum, grams
B – baseline, grams
D m (1) – median effect dose for the first night, mg/kg
c – multiplier of the median effect dose for each additional night
s B – standard deviation of B, g
s D – standard deviation of logD m (1), g
s – residual standard deviation, grams
Decreased food intake and fecal output effects were common to other insults
Decreased food intake correlated with delayed gastric emptying
Effect of LPS administration on blood pressure
Effect of LPS administration on intestinal transit
Intestinal transit of methyl cellulose/phenol red dye after endotoxin injection. The 30-minute transit of dye was measured in each of five intestinal segments and the mean geometric center calculated. (n = 6 for each group, P = 0.3 by two-way ANOVA)
Time Post-LPS Injection
2.28 ± 0.17
2.58 ± 0.16
2.36 ± 0.19
0.1 mg/kg LPS
2.59 ± 0.10
2.71 ± 0.09
2.50 ± 0.12
Changes in activity were insufficient to explain decreased food intake
We have evaluated the feasibility of using food intake and fecal output as markers for ileus in a conscious mouse model by comparing the effect of various insults resulting in ileus on these endpoints. Low doses of LPS, laparotomy/bowel manipulation, 20% TBSA scald burn, and acute pancreatitis comparably produced a transient anorexic effect and delayed defecation consistent with a clinical picture of ileus. The data indicate that both magnitude and duration of the effects were dose dependent establishing a causal link between the initiating insults and the changes in food intake and fecal output. Each insult was self-limiting and mice appeared to have normal grooming habits, vocalizations, and interactions with cage mates within minutes of treatment or recovery from anesthetic. LPS administration in mice has been shown to increase watery secretions in the bowel and induce diarrhea [17, 18], either of which would potentially confound our fecal output measurements. However, in our study, we saw no evidence of increased watery secretion and diarrhea was not evident at any LPS dose in which fecal output was measured. A recent study showed that a minimum dose of 10 mg/kg was required to produce a significant increase in watery secretion, as measured by intestinal content mass , whereas the highest dose of LPS used in our study was more than an order of magnitude lower (0.4 mg/kg). It might be argued that the inhibition of food intake was caused by the pain and discomfort associated with the various insults. For endotoxin treatment, the delay in food intake directly correlated with delayed gastric emptying suggesting gastric dysfunction was responsible, at least in part, for decreased food intake. Peripheral administration of low doses of LPS is a well established model for sepsis and is associated with the inhibition of food intake in rodents . In rats, the anorexic effect of LPS appears to be mediated centrally through the activity of serotonin [20, 21], melanocortins , cytokines [23–26], and prostaglandins [25, 27]. In mice, the anorexigenic effect of peripheral LPS is attenuated by vagotomy  suggesting a brain-gut interaction. There is also evidence that LPS-induced inhibition of food intake in mice is correlated with the inhibition of the orexigenic and motility promoting peptide ghrelin  which is synthesized mainly in gastric tissue and acts centrally. Previous studies have shown that low doses of LPS inhibited gastric emptying [29–32]. Here we show that the time course of the LPS induced anorexic effect directly correlated with delayed gastric emptying (Figure 9C). The parallel recoveries of gastric emptying and food intake suggest that the anorexic effect of LPS was in large part due to gastric dysfunction. Furthermore, although administration of LPS resulted in a significant reduction in movement during the first scotophase, reduced activity alone was not sufficient to explain the anorexic effect (Figure 11) as the decrease in the amount of food taken was significantly higher than the decrease in activity. Delayed gastric emptying has also been demonstrated in rodent models of post-operative ileus [1, 4], thermal injury  and cerulein induced pancreatitis .
The common effects suggest, at some level, a common mechanism is shared by the multiple insults. One likely candidate is the inflammatory response since endotoxemia [13, 14, 35], intestinal manipulation [12, 36–38], and ischemia/reperfusion injury  have all been shown to promote cellular inflammation within the small bowel and colon in rats. Recently it has been shown in mice that post-operative ileus was associated with inflammatory cell infiltration within the manipulated small intestine, but not the untouched stomach or colon . In the same study, gastric emptying, measured by scintigraphic imaging, was delayed for 24 hours after insult, recovering within 48 hours. This delay was prevented by inhibition of leukocyte recruitment indicating that the inflammatory cells were responsible for delayed gastric emptying, apparently via inhibitory neural signals since hexamethonium and guanethidine normalized gastric emptying. Inflammatory cell infiltration within the pancreas during cerulein induced acute pancreatitis has been well established, however, it is unclear if similar infiltration within the small bowel muscularis also occurs. Such an event would be confirmatory for the model mentioned above. Our data suggests that inflammatory cell infiltration would be delayed relative to other insults since the effect of higher doses of cerulein did not reach its maximum until the second scotophase. Establishment of inhibitory neural signals is also likely to be sequelae common to the various insults. The role of corticotropin releasing factor (CRF) in both appetite regulation and gastrocolonic motor function has been well established . CRF receptors are widely expressed in the brain, notably within brain centers that control appetite, the gastrointestinal tract, and on vagal afferent neurons. The known effects of central and peripheral CRF receptors and ligands makes them intriguing investigative targets for systemic control of the different organ systems involved with ileus.
Ileus is most commonly associated with a transient decrease in gastrointestinal motility. In humans, motility resolves differentially within the gastrointestinal tract with the small bowel recovering most rapidly, followed by the stomach and then colon [9, 10] although it is possible that complete recovery of the entire GI tract is not required for clinical resolution. Food intake and fecal output are the most common clinical markers for resolution of ileus and are more generalized indicators of GI function than measurement of motility, MMC or contractility. As shown in this study, delayed food intake is likely to be modified by behavioral effects and thus provides a more integrated description of gastrointestinal function. In our mouse model, fecal output directly tracked food intake for all insults and doses examined in this study. The fitted models for the 12-hour dose-response curves yielded identical median effective LPS doses for food intake and fecal output providing mathematical verification of this correlation. Since data was collected every 12 hours, it is possible that decreased fecal output lagged food intake by a few hours. Therefore it is difficult to distinguish if this tracking was a function of the initiating insult on colonic activity or normal loss of colonic function due to the fasting caused by the anorexic effects of the insults. The fact that the two endpoints tracked demonstrates the functional coordination of the two organs during ileus and illustrates the necessity for endpoints that examine system wide function in order to develop a complete understanding of the mechanisms of ileus. In the small intestine, 30 minute transit of dye remained unchanged between mice administered endotoxin and control mice 12, 36 and 60 hours after injection. This result indicated that if small bowel transit was compromised by LPS, the effect resolved within 12 hours.
The use of food intake and fecal output as endpoints for ileus in mice revealed dissimilarities from more traditional measures of ileus. In the conscious mouse model described here, food intake and fecal output directly correlated with the extent of bowel manipulation. This result is consistent with at least one other study which showed that, in rats, small bowel smooth muscle impairment and inflammation was directly proportional to the extent of bowel manipulation . However, several groups have concluded that inhibition of bowel motility was independent of the degree of manipulation or the duration of surgery [9, 41–43]. It is probable that the discrepancy in outcomes is due to the different endpoints measured. A large body of research into the mechanisms of ileus focuses on changes in intestinal smooth muscle contractility. In rats, changes in small bowel smooth muscle contractility after endotoxin administration were seen only above the threshold dose of 5 mg/kg . In our study, food intake and fecal output were responsive to small changes in LPS dose with the lowest dose of LPS tested (0.005 mg/kg) resulting in a significant reduction in both endpoints indicating that they are highly sensitive measures of gastrointestinal function. These data, along with the lack of change in intestinal transit, suggest that low doses of endotoxin produce limited intestinal ileus.
The ability to conveniently monitor the full time course of ileus in the same animal was lacking in most previous models of ileus (although see ). The use of food intake/fecal output as simple, clinically relevant endpoints in un-anesthetized mice should facilitate examination of potential treatment strategies. Improvements in either magnitude or duration of ileus are desirable and treatment strategies would be considered effective if they improved either or both. The fitted model described in this study provides a method for quantitative assessment of both magnitude and duration. Changes in magnitude due to a treatment are most easily assessed by measuring the 12 hour food intake/fecal output in LPS challenged mice. Improvement in treated mice relative to untreated LPS challenged mice would quantitatively assess effectiveness. The specific challenge is not limited to LPS. The 12 hour food intake/fecal output measurements for other insults can be expressed in terms of LPS dose by substituting the amount into the formula for the fitted curves. Thus, in our study, a 20% TBSA burn was comparable to a 0.04 mg/kg LPS dose. Although a more involved assay, duration can be quantitatively monitored by the c-multiplier which will be altered as duration changes. In this scenario, an intervention is used to treat mice challenged with several doses of LPS. An increased c-multiplier, then, would indicate a decrease in the duration of ileus and, thus, indicate an effective intervention. Finally, the ability to monitor ileus without the necessity of harvesting tissue will facilitate gene expression studies which require the same tissue for RNA isolation.
We have demonstrated in conscious mice that a transient decrease in food intake and fecal output are common to multiple insults that result in ileus. Examination of ileus using these endpoints revealed that restoration of gastric emptying preceded recovery of food intake and that gastric and colonic function recovered nearly simultaneously. The easily monitored, clinically relevant endpoints provide a convenient means for examining ileus in a mouse model and should prove useful for analysis of potential intervention strategies and mechanistic investigations of ileus.
The authors acknowledge the enthusiastic contribution of John Bade, MD (deceased) to this study.
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