The intestine has an inherent ability to adapt morphologically and functionally in response to internal and external environmental changes. The functional adaptations encompass modifications of the brush border membrane fluidity and permeability, as well as up- or down-regulation of carrier-mediated transport. Intestinal adaptation improves the nutritional status following the loss of a major portion of the small intestine, following chronic ingestion of ethanol, following sublethal doses of abdominal irradiation, in diabetes, in pregnancy and lactation, with ageing, and with fasting and malnutrition. Following intestinal resection, morphological and functional changes occur depending upon the extent of the intestine removed, the site studied, and the lipid content of the diet. Therefore, intestinal adaptation has important implications in the survival potential and welfare of the host. An understanding of the mechanisms of, and signals for, intestinal adaptation in the experimental setting forms the basis for the use of management strategies in humans with the short-bowel syndrome.

Segmental small intestinal transplantation (SIT) using living related donors (LRD) is being evaluated as a therapy, clinically. Advantages of this technique include an increase in the donor pool, optimization of the timing of transplants, and potential immunologic benefits. However, the ability of a short segment of intestine to function after transplantation has not been investigated in large animal models. This study evaluates the impact of immunosuppression on the adaptive process and the ability of a transplanted segment of intestine to adapt. A pig model of segmental SIT was used. Animals were resected, leaving 150 cm of distal ileum (n = 5), resected and treated with FK506 (n = 4), or steroids (n = 4), or with FK506 + steroids (n = 7), or transplanted using a similar segment of ileum and treated with FK506 + steroid immunosuppression (n = 9). Animals undergoing resection, or resection plus steroid treatment, did well, gaining weight post-operatively (37% and 15% of preoperative weight, respectively). However, animals undergoing resection and treated with FK506 or FK506 + steroids did poorly, losing weight (-14% and -22% of preoperative weight, respectively) and showing significant impairment of intestinal adaptation, morphologically and functionally. Furthermore, FK506-treated animals developed inflammatory changes in the intestinal mucosa, mimicking rejection. Segmental SIT animals had a high rate of rejection (66%) and showed a similar impairment in adaptation. Hence, segmental SIT is a stringent physiological test of intestinal adaptation. FK506 appears to impair gut function after resection, either directly, or by interfering with the adaptive process. In this model of segmental SIT, FK506 and steroids at the doses tested did not provide adequate immunosuppression to prevent rejection and the graft did not function adequately to allow growth. Further studies are required to evaluate the mechanisms underlying these findings, and to determine if similar effects occur in humans.

The adaptational changes of epithelial ion transport in the short bowel syndrome were studied. Ileal remnants of rats were investigated 8 weeks after 70% proximal small intestinal resection. Pure epithelial resistance measured by impedance analysis decreased from 27 +/- 1 to 21 +/- 1 omega.cm2, and polyethylene glycol 4000 fluxes increased from 2.5 +/- 0.3 to 3.6 +/- 0.3 nmol.h-1.cm-2, indicating increased permeability of the short bowel. Unidirectional flux measurements in control ileum showed absorptive net fluxes of Na+ and Cl- that were assigned to electroneutral NaCl absorption and a short-circuit current that was accounted for by the residual flux (HCO3- secretion). Neither NaCl absorption nor HCO3- secretion were altered in the short bowel. Also, electrogenic Cl- secretion, defined after maximal stimulation by theophylline and prostaglandin E1 was not changed in the short bowel. In contrast, electrogenic Na+/glucose cotransport increased in Vmax from 2.0 +/- 0.3 in controls to 5.0 +/- 1.0 mumol.h-1.cm-2 in the short bowel. Tight junction structure was studied by freeze-fracture electron microscopy. The number of horizontal strands was unchanged, whereas tight junction depth was slightly increased in the short bowel. Microvillus area of short bowels was increased by 20% in villus regions. Under the light microscope, villus height was increased by 30%. In conclusion, the short bowel mucosa undergoes adaptive responses to reduced overall absorptive area by increasing glucose-dependent electrogenic Na+ absorption to 250%, which is partly caused by increased villus and microvillus surface area. Electrogenic Cl- and HCO3- secretion and electroneutral NaCl absorption remained unchanged. The decreased epithelial resistance is caused by mucosal surface amplification.

This study examined the adaptive response to extensive small intestinal resection in the juvenile domestic pig. Control animals underwent an ileal transection with end-to-end anastomosis, whereas resected pigs had a resection of the mid-75% of the total small bowel length. Animals were followed for 16 weeks. Resected animals gained less weight than controls, with no significant difference in feed intake per unit animal weight. In vivo fat, protein, carbohydrate, and total energy absorption were reduced in resected animals. Resected pigs had increased in vitro passive ileal uptake of fatty acids, cholesterol, and L-glucose, but no change in active D-glucose uptake. Microscopic morphology was altered, with an increase in the size of villi, a decrease in villous density, and no net change in mucosal surface area per unit of serosal surface area. Gross bowel length and diameter increased proportionately more in the resected than the control groups. This study demonstrated that massive resection results in a significant change in nutritional status in the growing pig. Functional and morphological changes occur, demonstrating intestinal adaptation. These findings suggest that this model would be suitable for the study of therapeutic modalities for the short-bowel syndrome in humans.

The ability of adapting ileal enterocytes to express different digestive enzymes in their brush border membranes was tested in young female Wistar rats (n = 72) receiving 60% proximal small bowel resection. In control rats with intestinal transection both neutral aminopeptidase and alpha-glucosidase activities were shown, by quantitative cytochemistry, to increase during enterocyte migration over the lower part of the villus; thereafter enzyme activities declined or remained approximately constant. Proximal enterectomy increased the amount of alpha-glucosidase but not neutral aminopeptidase activity appearing during early enterocyte development. Thymidine labelled autoradiography showed that the rate of enterocyte migration along the ileal villus nearly doubled after jejunal resection (19.3 v 11.1 microns/h). Nevertheless, the time taken for both peptidase and saccharidase activities to appear at maximal rates in the brush border membrane was diminished by about five hours. Thus ileal enterocytes adapt to proximal small bowel resection by selective increments in enzyme expression, findings that contradict the previous hypothesis of simple metabolic immaturity.

The kinetics of L-phenylalanine absorption across rat small intestine in sham and 50% distal resected animals, in vivo, have been studied by perfusing jejunal loops and monitoring the disappearance of the substrate from the perfusate. After 5 months postresection the total phenylalanine absorption was increased. The relationship between total absorption of substrate and its concentration in the bulk phase shows a non-saturable component and a saturable one that can be inhibited by methionine, both in control and remnant jejunum. The slope of the line that represents the non-saturable component is greater in remnant jejunum, indicating that the apparent mass-transfer coefficient, K'D, was increased by distal resection. The kinetic analysis of the saturable component shows that Jmax was unaltered and the apparent semisaturation constant, K'M, was slightly decreased by distal small intestine resection. Correction of the kinetic constant for the unstirred water layer effects shows that the differences between 'real' KD values of the two experimental groups increase whereas 'real' KM values do not change significantly. This indicates that the observed increase in total intestinal absorption in resected animals appears to result from an increase in the intestinal passive permeability.

The aim of the present study was to evaluate in terms of quantitative measurements whether the well-known histomorphological and functional adaptive changes in the intestinal mucosa after small bowel resection are accompanied by alterations on the ultrastructural level. Therefore, samples of the ileal remnants after a 60% proximal resection were processed for ultrastructural evaluation and analyzed employing point counting planimetry and direct measurements. Microvillus surface area increased from the bottom of the crypts to the villus tips in both resected and sham-operated animals. This increase in microvillus surface area from the crypt to the villus was significantly less pronounced after proximal resection, while there were no changes in the crypt compartment. No significant differences of the relative areas of the nuclei, mitochondria, and the rough endoplasmic reticulum were observed when comparing the different positions along the villus crypt axis in normal and hyperplastic mucosa. In agreement with functional and enzyme histochemical results, these ultrastructural findings provide further evidence for an altered pattern of enterocyte maturation after proximal resection, which is most probably due to an increase in the migration rate of the enterocytes.

In this study the early phase of the morphological adaptation of rat ileum after a proximal resection of 60% has been studied using microdissection and cell labelling techniques. Resected rats and sham-operated controls were killed 2, 4, 6, 10 and 12 days after surgery. Intraperitoneal injections of 3H-thymidine were carried out 24 or 12 h prior to sacrifice. In the latter groups mitotic arrest was achieved by vincristine. A stereo-microscope was used to measure and calculate the following parameters: intestinal diameter; villus: height, width, breadth at base and apex, surface, enterocytes per 100 micrometers length, cell pool, number of villi and absorptive surface per mm2 serosal area; crypt: length, enteroblasts per 100 micrometers length and per column, cell columns and mitoses per crypt, cell pool, crypts, and mitoses per unit serosal area; cell kinetics: migration rate, villus transit time. To test the influence of treatments, postoperative time course and the location of the intestinal segment and their possible interactions, factorial analyses of variance were carried out on the parameters investigated. The main findings, demonstrated for the first time, were: 1. An increase in the villus surface which was achieved by proportional enlargement of villus geometry; 2. This increase in the villus surface led to an enlarged absorptive surface per unit serosal area; 3. A reduction of villus transit time of the individual enterocyte; 4. A most pronounced magnitude of adaptative response in the proximal remnants which was gradually diminished in aboral direction, and 5. A sequential course of adaptative response of the various crypt parameters investigated.