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It has been shown previously that insulinlike growth factors (IGFs) stimulate the proliferation of intestinal crypt cells in vitro. To examine the in vivo effects of IGF-I on mucosal adaptation, three groups of Sprague-Dawley rats underwent 80% jejunoileal resection. Miniosmotic pumps were then inserted under the skin immediately after resection to deliver vehicle (resected control), 1.5 mg/kg per day of IGF-I, or 1.5 mg/kg per day of des-(1-3)-IGF-I (des-IGF-I). Des-IGF-I is a truncated form of IGF-I that binds as well to type I IGF receptors but less tightly to several forms of IGF-binding proteins (IGFBPs) than IGF-I. Ad libitum food intake did not differ among the three resected groups. Body weight gains were greater in animals receiving des-IGF-I than in those receiving IGF-I, which were greater than resected controls. All animals were killed 7 days postoperatively, and the remaining small intestine was removed and divided at the anastomotic site. Both IGF-I and des-IGF-I induced hyperplasia (increased DNA and protein content) in the duodenojejunum but not in the ileum. IGF-I and des-IGF-I were equally active. In contrast, sucrase, maltase, and leucine aminopeptidase activities were greater only in the ileum of animals receiving IGF-I and des-IGF-I than in resected controls. Although more potent in stimulating overall body weight gain, des-IGF-I was not more potent than IGF-I when duodenal and ileal responses were determined. IGF infusion (IGF-I greater than des-IGF-I) increased the levels of circulating IGFBP-3 and IGFBP-2, which may act to modulate the biological effectiveness of the infused peptides. These results suggest that both IGF-I and des-IGF-I may have potential as therapeutic agents for short bowel patients.

Several recent studies suggest that jejunoileal bypass-induced liver disease results from malabsorption of essential nutrients. However, in experimental animals, resection of the defunctionalized bowel substantially reduces bypass-induced liver injury. Such models are often used to support the theory that bacteria in the defunctionalized bowel produce toxic substances which result in liver damage. We used a rat model to first explore the effects of intestinal bypass vs resection on various parameters of liver injury, and subsequently compared these findings to the effect of both bypass and resection on mucosal adaptation in the remaining intact bowel after each procedure. Bypassed animals had lower levels of hepatic cytochrome P-450, glucose-6-phosphatase, pentobarbital hydroxylase, and serum triglycerides than did animals undergoing resection of defunctionalized bowel. Concurrently, resected animals had much greater increases in mucosal weight, DNA content, and protein content in the intact bowel than did bypassed animals. We speculate that the beneficial effects of resection of bypassed bowel on liver function may be a result of increased mucosal hyperplasia in resected animals, rather than elimination of production of toxic substances in the defunctionalized bowel.

The rat was used as an animal model to explore the mechanism responsible for the development of hepatomegaly and hypoproteinemia which commonly occur after jejunoileal bypass. Sprague-Dawley rats. 300 to 350 g, were divided into three groups of 12 animals. Six of the 12 rats per group served as study animals and six as controls. The first six were subjected to 90% jejunoileal bypass and the six controls were sham-operated and pair-fed. In the second group, six animals were subjected to 90% jejunoileal resection and six controls were sham-operated and pair-fed. Six animals in the third group were underfed so that their weights mimicked that of the bypassed animals and six controls were fed ad libitum. After 8 wk the animals were killed. Liver weights, hepatic protein content, and serum protein and triglycerides were determined. Synthesis and secretion of proteins and glycoproteins were measured using incorporation of 14C-leucine and 14C-glucosamine, respectively, into hepatic and medium proteins by liver slices. Bypassed animals demonstrated hepatomegaly, decreased serum proteins and triglycerides, and increased hepatic protein content. While both protein and glycoprotein synthesis remained normal, the secretion of these proteins into the medium appeared to be impared. Comparable changes did not occur after jejunoileal resection or after underfeeding. This study suggests that the impairment of glycoprotein and protein secretion may be a contributing factor in the increased liver weight and protein content in conjunction with decreased serum protein observed in the bypassed rat.

To assess the influence of diamine oxidase activity on the adaptive process of the small bowel after resection, we administered aminoguanidine, a potent diamine oxidase inhibitor, to rats for 10 days after either small bowel transection (n = 5) or 80% jejunoileal resection (n = 7). Five or more additional animals from each group received saline as controls. Ileal mucosal homogenates from the resection group receiving aminoguanidine, when compared with those from resection controls, showed no diamine oxidase activity with increased putrescine content and ornithine decarboxylase activity. Mucosal proliferation, as measured by mucosal mass, protein content, and deoxyribonucleic acid content, was greater in the resected animals receiving aminoguanidine when compared with that of resection controls. Sucrase activity per gram of mucosa was almost identical in both resection groups. These results show that the suppression of diamine oxidase during the postresection adaptive period results in enhanced mucosal proliferation with no effect on mucosal functional differentiation. Diamine oxidase may play a regulatory role in adaptive intestinal proliferation.

Jejunoileal bypasses were performed in rats to determine the effect of improved absorption on the development of liver dysfunction occurring after this procedure. Several parameters of liver function were measured in rats 7 weeks after both the standard 85% small-bowel bypass and an 80% bypass in which an extra 5 cm of intact bowel was retained. Animals having undergone 80% bypass had a lesser degree of lowering of serum protein and triglyceride levels, hepatic cytochrome P-450 content, and hepatic glucose-6-phosphatase activity than did the animals undergoing 85% bypass. Abnormalities found in 85% bypass animals were only partially reproduced by reducing food intake in another group of 80% bypassed animals. These findings emphasize the importance of nutritional factors in the etiology of bypass-induced liver disease and militate against toxin production in the defunctionalized bowel as the sole cause of liver dysfunction following bypass.

Administration of antibiotics has been reported to prevent or minimize liver dysfunction in experimental animals having been subjected to jejunoileal bypass, suggesting that jejunoileal bypass-induced liver dysfunction results from production of toxic substances by bacteria in the defunctionalized bowel. However, improved absorption will also prevent bypass-induced liver injury. We studied the effects of tetracycline on the development of bypass-induced liver dysfunction and compared it to the mucosal adaptation of the intact bowel after bypass. After 6 weeks, rats subjected to bypass but not given antibiotics had decreased levels of serum triglycerides, hepatic cytochrome P-450, and hepatic pentobarbital hydroxylase. Evaluation of intestinal mucosal hyperplasia after bypass indicated that animals given antibiotics after bypass developed greater increases in mucosal DNA content, mucosal protein, and mucosal weight than bypassed animals not receiving antibiotics. We speculate that the beneficial effects of antibiotic administration on liver function after bypass may be a result of improved absorption.

We have shown that dietary long-chain triglycerides and 16,16-dimethyl prostaglandin E2 enhance and aspirin impairs postresection mucosal adaptation in rats. The present studies examined the hypothesis that supplemental linoleic acid (LA) above the minimum requirement may enhance postresection mucosal adaptation through altered prostaglandin (PG) synthesis. Forty male Sprague-Dawley rats (105 +/- 5 g) were fed purified diet containing either 5% LA or 4% palmitic acid and 1% LA. After 2 weeks, 12 rats from each dietary group underwent 70% proximal jejunoileal resection and the remainder were sham-operated. Dietary regimens were continued for an additional 13 days. Mucosal fatty acid analysis of 1% LA group revealed a ratio of 20:3 n-9/20:4 n-6 lower than 0.2, indicating normal essential fatty acid status. Mucosal protein per centimeter bowel was higher in the 5% LA group compared to the 1% group, but mucosal DNA, maltase, and ex vivo PG synthesis were not affected. These results indicate that LA stimulates postresection mucosal hypertrophy, which does not appear to be related to PG synthesis.

The pathogenesis of jejunoileal bypass-induced liver disease was investigated in the rat model. Male Sprague-Dawley rats were subjected to 90% jejunoileal bypass and compared to rats having undergone 90% jejunoileal resection, to ad libitum and pair-fed controls and to weight-matched (underfed) controls. After 8 weeks the animals were killed and selected analyses performed. Several indications of liver dysfunction were observed in the bypass rats including hepatomegaly, hypotriglyceridemia, hypoproteinemia, elevated SGOT levels, and markedly decreased levels of cytochrome P-450. All of these abnormalities with the exception of elevated SGOT levels and decreased serum proteins were not observed to the same degree in animals in which the defunctionalized bowel was resected. Rats which were underfed (weight matched) did not develop any of the abnormalities of liver injury demonstrated in the bypass rats. Multiple factors appear to be responsible for the production of bypass-induced liver disease, but the defunctionalized bowel plays an important role.

Intestinal tapering and lengthening were performed in a child with short bowel syndrome to prevent the need for home parenteral nutrition. The intestinal lengthening was not successful, presumably because the vascular anatomy was not favorable. Significant clinical improvement and avoidance of home parenteral nutrition resulted from the tapering procedure. These procedures have a role in the treatment of selected patients with short bowel syndrome.