Michael H. Hart

Essential fatty acid deficiency and postresection mucosal adaptation in the rat

The effect of short-term (biochemical) and long-term (clinical) essential fatty acid (EFA) deficiency on mucosal adaptation was studied in a surgical model of short bowel syndrome. Rats fed an EFA-deficient diet for 4 wk had biochemical evidence of EFA deficiency (hepatic and red blood cell triene to tetraene ratios greater than 0.4). Resected animals (70% proximal jejunoileal resection) receiving an EFA-deficient diet had a significantly impaired intestinal mucosal hyperplasia response in all remaining small bowel segments compared with resected controls. The effect of refeeding a control diet to clinically EFA-deficient resected rats was also evaluated. Short-term refeeding (2 wk) of a control diet resulted in a significant return toward normal tissue triene to tetraene ratios. Concomitantly, refed animals had significantly greater mucosal adaptation in the remaining duodenal/jejunal segment compared with resected animals maintained on an EFA-deficient diet postoperatively. These experiments underscore the dynamic nature of tissue EFA status and the importance of fatty acids in the normal compensatory mechanisms of mucosal adaptation after resection.

Suppression of diamine oxidase activity enhances postresection ileal proliferation in the 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.

Crohn's disease presenting with Henoch-Schönlein purpura.

Henoch-Schönlein purpura (HSP) is a syndrome characterized by cutaneous purpura, arthritis, nephritis, abdominal pain, and gastrointestinal bleeding. The clinical features of HSP are a consequence of widespread leukocytoclastic vasculitis owing to immunoglobulin (Ig)A deposition in vessel walls (1). Gastrointestinal involvement occurs in 50% to 75% of children with HSP. The dominant clinical features are colicky abdominal pain, vomiting, and bleeding (1,2). In 15% to 20% of patients, the gastrointestinal symptoms precede the diagnostic rash by a number of days (1,2). In such patients, inflammatory bowel disease is often a diagnostic consideration. Nevertheless, the coexistence of HSP and inflammatory bowel disease has not been reported. In this report, we describe a child with HSP as the presenting feature of Crohn’s disease.

Augmentation of postresection mucosal hyperplasia by plerocercoid growth factor (PGF)

Postresection villus hyperplasia is a major compensatory mechanism in the short-bowel patient. Substances capable of augmenting postresection mucosal hyperplasia could have therapeutic implications. Human growth hormone (hGH) and human growth hormone releasing factor (hGHRF) stimulate growth of the gastrointestinal tract; however, the diabetogenic actions of growth hormone limit its usefulness in clinical practice. Plerocercoid larvae of the tapewormSpirometra mansonoides produce an analog of hGH void of diabetogenic side effects. We assessed effects of plerocercoid growth factor (PGF) on mucosal adaptation following 70% proximal jejunoileal resection in young rats. Mucosal weight, DNA, protein, and total sucrase activity per centimeter of bowel were increased in resected PGF-treated animals compared to resected controls. We conclude PGF augments intrinsic postresection mucosal hyperplasia following extensive intestinal resection.

Effects of Dietary Linoleic Acid on Mucosal Adaptation after Small Bowel Resection

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.

Failure of blind small bowel biopsy in the diagnosis of intestinal lymphangiectasia.

A case of primary intestinal lymphangiectasia is presented in which multiple blind peroral jejunal biopsies were unable to document any abnormality, despite strongly suggestive clinical history and radiographic findings. Endoscopically directed biopsy was necessary to document the characteristic pathologic lesion. This report documents the importance of endoscopy in the diagnosis of intestinal lymphangiectasia when clinical history is suggestive of intestinal lymphangiectasia but standard small bowel biopsy fails to show any abnormality.

The intestinal absorption of 3-O-methyl-D-glucose in methotrexate-treated rats: an in vivo study of small bowel function.

The in vivo absorption of 3–0-methyl-D-glucose (3MG) as a marker of intestinal function has not been studied in an animal model. We evaluated the use of 3MG as a marker of intestinal absorption when given en-terally to rats recovering from small bowel mucosal injury induced by methotrexate (MTX). Radiolabeled 3MG was administered into the duodenum of control (CON) and MTX-treated rats and blood samples were obtained at specified intervals. Mucosal permeability was also assessed using radiolabeled mannitol and polyethylene glycol 900 (PEG). Concentration time points were plotted, and area under the curve was calculated as an approximation of absorbed dose. Mucosal weight, maltase activity, and protein content were determined on mucosal scrapings. During the acute phase (day 5), 3MG absorption and maltase-specific activity were significantly decreased in the MTX group when compared to the CON group (p < 0.001). The MTX group showed a trend toward greater permeability to mannitol when compared to the CON group; however, this was not statistically significant. Mucosal permeability to PEG was similar in both groups. During a later stage in the recovery process (day 12), the area under the curve calculations for 3MG absorption were the same for both CON and MTX animals, with maltase activity in the MTX group recovering to control values. Changes in 3MG absorption paralleled total maltase activities following severe injury. These results suggest that the combined active and passive transport of 3MG in vivo could be of use as a marker of intestinal absorption in states where the small intestine has sustained major damage resulting in compromised absorption as well as brush border digestion.

Acute self-limited colitis associated with Cryptosporidium in an immunocompetent patient.

A case report of acute self-limiting colitis associated with enteric Cryptosporidium infection in an immunocompetent child is presented. This case broadens the spectrum of symptoms and manifestation of Cryptosporidium infection in a normal human host.

REGULATION OF INTESTINAL SUCRASE EXPRESSION IN SUCKLING MOUSE INTESTINE

Intestinal disaccharidase expression in the developing post-natal animal is under a complex system of regulatory mechanisms involving pre-programmed genetic timing as influenced by circulating humoral factors, paracrine factors, and luminal nutrients. The aim of this study was to examine the relative contribution of circulating glucocorticoids and pre-programmed genetic expression of sucrase and lactase in a suckling mouse between post-natal days 13 and 15. We examined primary jejunal and ileal organ culture explants in serum-free medium at 0-2 hours and 22-24 hours of organ culture, respectively. Animals were studied at days 13, 14, and 15, with an additional group of adrenalectomy animals who underwent adrenalectomy on day 13 with organ culture at day 15. The results of sucrase activity are shown below.In summary, day 14 tissues in organ culture for 24 hours reached the same level of expression in organ culture of scrum-free media as in the intact animal on day 15. In addition, adrenalectomy on day 13 did not abolish the time-dependent expression of sucrase. However, the magnitude of expression in the basal state was diminished. We speculate that normal quantitative expression of intestinal disaccharidase in the 15-day suckling mouse is dependent upon a combination of intrinsic tuning in conjunction with circulating glucocorticoids.

AUGMENTATION OF POST-RESECTION MUCOSAL HYPERPLASIA BY LINOLEIC ACID FEEDING

Previous studies indicate long chain fats have trophic effects on post-resection intestinal mucosal adaptation. We have previously shown that short term essential fatty acid (EFA) deficiency impairs normal post-resection mucosal hyperplasia, while 16, 16 dimethyl-PGE2 administration stimulates hyperplasia. The effect of increased dietary linoleic acid (LA) on promoting mucosal adaptation in resected, non-EFA deficient animals was evaluated. Ten Sprague-Dauley rats (5 w/o males) were pair-fed isocaloric diets containing 1% or 5% (LA) (w/w). After 2 weeks all animals underwent 70% proximal jejunoileal resection. Animals were then pair-fed for 14 days. Following sacrifice mucosal weight, protein, DNA, and sucrase activity were determined:Protein levels were increased in all segments in 5% LA animals (p<.05). Similar results were seen for mucosal weight, DNA, and sucrase activity. Our results indicate 5% LA has “trophic” properties on post-resection mucosal adaptation similar to the effect of 16, 16 dimethyl-PGE2. In view of reports of increased dietary LA stimulating intestinal PGE2 synthesis, LA supplementation may exhibit its stimulatory effect via this mechanism.