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Optimal absorption of fat requires adequate time of contact with the absorptive sites of the small intestine. In order to prevent steatorrhea, intestinal transit must be slowed in response to the fat that has emptied into the small intestine. Intestinal transit is known to be inhibited by fat in the ileum via the ileal brake. This response has suggested that the regulation of intestinal transit is a function of the distal small intestine. However, clinical observations suggest that the ileal brake is not the only control mechanism for intestinal transit. In short bowel patients with resection of the ileum, the proportion of fecal fat recovery remained constant even after the fat intake was increased threefold. In these patients, optimal fat absorption based on the slowing of intestinal transit must have been triggered by an inhibitory mechanism located outside of the distal small intestine. To test the hypothesis that fat in the proximal small intestine inhibited intestinal transit, we compared intestinal transit during perfusion of the proximal half of the small intestine with 0 (buffer only), 15, 30, or 60 mM oleate in dogs equipped with duodenal and mid-intestinal fistula. Intestinal transit across a 150-cm test segment (between fistulas) was measured by counting for the recovery of a radioactive marker in the output of the mid-intestinal fistula during the last 30 min of a 90-min perfusion. We found that oleate inhibited intestinal transit in a load-dependent fashion (P < 0.005). Specifically, while the mean cumulative recovery of the transit marker was 95.5% during buffer perfusion, the recovery decreased when 15 mM (64.3%), 30 mM o(54.7%), or 60 mM oleate (38.7%) was perfused into the proximal half of the small intestine. We conclude that fat in the proximal small intestine inhibits intestinal transit as the jejunal brake.
BACKGROUND & AIMS: Injury to the intestinal mucosa is frequently a dose-limiting complication of radiotherapy and chemotherapy. Approaches to limit the damage to the intestine during radiation and chemotherapy have been largely ineffective. Trefoil factors are produced throughout the gastrointestinal tract and regulate cell migration, restitution, and repair. Studies were undertaken to define the role of intestinal trefoil factor in modulating the intestinal response to chemotherapy and radiation. METHODS: The effect of intestinal trefoil factor on migration and cell survival in intestinal epithelial monolayer exposed to methotrexate was studied in vitro. Chemotherapy and radiation damage was assessed in wild-type and intestinal trefoil factor-null mice in the presence or absence of supplemental intestinal trefoil factor administered in drinking water. RESULTS: Radiation and chemotherapy induced a marked reduction in goblet cell number and intestinal trefoil factor messenger RNA, as well as intestinal trefoil factor promoter activity. Intestinal trefoil factor improved intestinal epithelial cell viability and wound repair after chemotherapy exposure in vitro. Intestinal trefoil factor-deficient mice (intestinal trefoil factor(-/-)) were more susceptible to chemotherapy- and radiation-induced mucositis. Oral recombinant intestinal trefoil factor reduced the severity of both chemotherapy-induced and chemotherapy/radiotherapy-induced intestinal mucositis. CONCLUSIONS: These studies suggest that intestinal trefoil factor is involved in protection against and recovery from intestinal mucositis induced by radiation and chemotherapy.
The present study aimed to evaluate the absorption of D-xylose, a passively absorbed five-carbon monosaccharide, from the large intestine compared with the small intestine, in order to explore the absorption potential of the large intestine. D-Xylose absorption was evaluated in the intestinal loop and everted sacs in rats and comparisons were made between small intestine (mid-gut) and large intestine (colon). The absorption of D-xylose was smaller, by an order of magnitude or more, after administration into the loop of large intestine than after administration into that of small intestine, based on appearance in plasma and disappearance from the intestinal loop. D-Xylose absorption was practically insignificant (nominal 4.9%) in 60 min in the large intestine, whereas it was moderate (57.0%) in the small intestine. Consistently, the uptake of D-xylose in everted sacs was about 20 times larger in the small intestine than in the large intestine. Thus the passive membrane permeability of D-xylose was demonstrated to be negligible in the large intestine, even though the small intestine was fairly permeable. This result helps rationalize kinetic modelling strategies assuming the small intestine as the sole absorption site for gastrointestinal absorption in-vivo. It also suggests that hydrophilic drugs with molecular size similar to or larger than D-xylose may not be good candidates for colonic drug delivery by controlled release.
The ultrastructure of the rat intestinal interstitium was analyzed from the viewpoint of mechanical dynamics to stabilize the intestinal villi, crypts and mucosal folds. In the rat, the small intestine lacks circular folds, but the large intestine possesses spiral folds. The intestinal villi, the largest in the duodenum, decreased in size in the jejunum and ileum successively, and were absent in the large intestine. The intestinal interstitium consisted of lamina propria mucosae (LPM) and tela submucosa (TSM) separated by muscularis mucosae (MM), the LPM was subdivided into an upper part within the villi and a lower part among the crypts in the small intestine. The light microscopic density of interstitium in the intestinal wall was lowest in the upper LPM, moderately dense in the lower LPM and highest in the TSM, and that among the intestinal region was highest in the duodenum and decreased successively in the jejunum and ileum. In the large intestine, the TSM bulged to form spiral folds with very low density. The intestinal epithelium in the villi possessed wide intercellular spaces and that in the crypts had closed intercellular spaces. At electron microscopic level, the upper and lower LPM contained subepithelial supportive meshwork that consisted of collagen fibrils and myofibroblast processes. The lower LPM and TSM contained conspicuous bundles of collagen fibrils and, in addition, TSM contained minor populations of scattered collagen fibrils near the smooth muscle layer (SML). The diameter of collagen fibrils was the largest in the bundles of TSM, and decreased from the duodenum through the jejunum and ileum to the large intestine. On the basis of these observations, we hypothesize that the intestinal villi are mechanically stabilized by the balance between the expansive interstitial pressure and inward pull by the subepithelial supportive meshwork. This hypothesis explains the hitherto neglected fact that the intestinal epithelium possesses wide intercellular spaces only in the villi, and accounts for the counterforce against the perpendicular smooth muscle cells, which are supposed to contract the intestinal villi.
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Whole gut irrigation is a now a well-established method of preoperative bowel preparation. Additional reduction of bacterial content is desirable. The influence of neomycin/bacitracin and clindamycin as well as the combination, as admixture to the whole gut irrigation, on the flora of the large intestine, was therefore investigated in a prospective controlled study. While neomycin/bacitracin caused only a reduction of aerobic, and clindamycin of the anaerobic bacteriae, the combination resulted in a nearly total eradication of detectable bacterial content at the time of operation.
Immune responses to Haemonchus contortus intestinal antigens were evaluated using abomasal lymph node (ALN) lymphocytes from kid goats protected against challenge infection by immunization with parasite intestinal antigen, and from kids that were challenged after immunization with ovalbumin. ALN lymphocytes from the intestinal antigen-immunized group produced significantly higher antibody levels against intestinal antigens than the ovalbumin group, supporting the theory that immunization contributed to that ALN response. In contrast, intestinal lysates and membrane enriched preparations from intestinal cells stimulated significant proliferation of ALN lymphocytes in both groups. The proliferation was antigen-dependent, since intestinal antigens failed to stimulate proliferation in ALN lymphocytes from unimmunized and uninfected kids. For both the intestinal antigen and ovalbumin immunized groups, CD4+ T lymphocytes predominated in ALN lymphocytes that were stimulated to proliferate by intestinal antigens. The results indicate that H. contortus infection alone can induce ALN lymphocyte responses to intestinal antigens. In contrast to ALN lymphocyte responses, serum antibody against intestinal antigens was generally low to undetectable in ovalbumin-immunized kids following infection. Abomasal mucus from an H. contortus infected lamb was probed with a monoclonal antibody that binds to a periodate sensitive determinant on numerous H. contortus intestinal membrane and secreted proteins. Numerous bands of reactivity were detected, indicating that multiple parasite intestinal antigens were released into abomasal mucus during infection. The results, challenge the general concept that H. contortus intestinal antigens are 'hidden' from the host immune system during an infection. On the contrary, parasite intestinal proteins may be relatively abundant antigens presented to the host during infection. In addition, ALN T lymphocytes appear to provide a more sensitive measure than serum antibody to detect presentation of these antigens to the host immune system.
Intestinal cytochromes P450 (P450) may function in the "first pass" metabolism of drugs, the detoxification of xenobiotics, or the activation of carcinogens. However, little is known about the expression of specific P450 genes in intestinal mucosa. We have previously shown that a P450 mRNA that is homologous to rat liver P450IIB1 (P450b) is expressed in rat small intestine and is inducible by phenobarbital, polyhalogenated biphenyls, and organochlorine pesticides. However, there are multiple highly homologous genes in the IIB subfamily and, therefore, studies using liver-derived cDNAs or oligonucleotides based on those cDNAs cannot definitively establish the identity of the intestinal mRNA(s). The polymerase chain reaction was used to enzymatically amplify cDNA synthesized from intestinal and hepatic RNA, and the amplified segments were identified by Southern blot analysis. These studies demonstrated that the amplified segment of the phenobarbital-inducible P450 mRNA in intestine was identical to this same segment of the hepatic P450b mRNA; furthermore, this analysis showed that P450e was not expressed in intestine. To definitively establish the identity of the intestinal mRNA, the full coding sequence of the P450b mRNA was cloned from intestinal and hepatic RNA and sequenced. The sequences of the intestinal and hepatic cDNA were identical and coded for P450b; the deduced protein sequence in the F344 rat differed in one amino acid from the reported sequence in Sprague-Dawley rats and, thus, represents a different allele of the same gene. An increment in intestinal P450b mRNA was detected as early as 1 hr following a single intraperitoneal injection of phenobarbital; this prompt rise in mRNA suggested that transcriptional activation may be the primary mechanism for induction. Nuclear run-on experiments were performed using nuclei isolated from intestinal mucosa 3 and 6 hr following treatment with phenobarbital. The rate of transcription of the P450IIB1 gene was increased approximately 6-fold 6 hr following phenobarbital; this was very similar to the increment in P450b mRNA as measured by quantitative dot blot analysis. Therefore, the predominant mechanism for the induction of P450b mRNA in intestine in response to phenobarbital was an increase in gene transcription. These studies indicate that the same member of the P450IIB subfamily, P450IIB1 or P450b, is expressed and inducible by similar mechanisms in small intestine and liver. Although putative P450b mRNA and apoprotein have been identified in lung and testes, the capacity for induction by phenobarbital, and presumably other xenobiotics, is unique to liver and intestine.(ABSTRACT TRUNCATED AT 400 WORDS)
Mesenteric defects can lead to intestinal volvulus even when the midgut is normally rotated. There are two types of mesenteric defects: basilar, in which the entire base of the mesentery is involved, and segmental, in which only an isolated portion of the mesentery is affected. These defects can present at any age, and the clinical symptoms depend on the extent of the disease and the amount of intestine involved in the volvulus. In the newborn, the basilar defects have clinical signs and symptoms similar to those of midgut volvulus secondary to malrotation. Similar to midgut volvulus secondary to malrotation, this is a surgical emergency. In older patients, basilar defects can be misdiagnosed because of the normal placement of the ligament of Treitz and because of failure to consider mesenteric defects as a possible cause. The treatment for basilar mesenteric defects is intestinal fixation. Intestinal volvulus secondary to segmental defects always presents as intestinal obstruction. In the newborn, these lesions may be indistinguishable from intestinal atresia. Older children present with intestinal obstruction of an unknown cause. Resection of the affected intestine is the treatment for segmental mesenteric defects. Intestinal mesenteric abnormalities as a cause of intestinal atresia unifies under one etiology all the lesions observed in intestinal atresia. Although this theory does not rule out other causes of intestinal atresia, intestinal mesenteric defects may be the primary condition under which intestinal atresia occurs.
BACKGROUND AND AIM: We recently reported that cyclooxygenase (COX)-2 is upregulated in the rat small intestine after administration of indomethacin, and this may be the key to non-steroidal anti-inflammatory drug (NSAID)-induced intestinal damage. The present study investigated the mechanism for COX-2 expression induced in the rat small intestine by indomethacin, in relation with ulcerogenic processes. METHODS: Animals were given indomethacin or SC-560 p.o., and the intestinal mucosa was examined 24 h later. RESULTS: Indomethacin caused hemorrhagic lesions in the small intestine, accompanied with an increase in intestinal motility, bacterial invasion and inducible nitric oxide synthase (iNOS) activity, as well as the expression of COX-2 mRNA in the mucosa. Although SC-560 did not cause any damage, this agent caused intestinal hypermotility, the bacterial invasion and the upregulation of COX-2 expression. The mucosal PGE2 content was decreased by SC-560 at 3 h but recovered 12 h later, and this recovery of PGE2 was attenuated by both atropine and ampicillin, in addition to rofecoxib. The intestinal hypermotility response to indomethacin was prevented by both 16,16-dimethyl PGE2 and atropine, but not ampicillin. Yet all these agents inhibited not only the bacterial invasion but also the expression of COX-2 and iNOS activity in the intestinal mucosa following indomethacin treatment, resulting in the prevention of intestinal lesions. CONCLUSION: These results suggest that COX-2 expression in the intestinal mucosa following the administration of indomethacin is associated with intestinal hypermotility and bacterial invasion. The intestinal hypermotility caused by COX-1 inhibition may be a key to COX-2 expression after administration of NSAIDs and their intestinal ulcerogenic properties.
We previously demonstrated that the large intestine compensated for decreased calcium (Ca) absorption caused by renal failure in rats fed a highly fermentable dietary fiber. In this study, we examined whether the large intestine compensated for insufficient Ca absorption in the rat small intestine without ingestion of a fermentable dietary fiber. Rats were fed one of four test diets containing either insoluble (carbonate) or soluble (gluconate, lactate, or citrate) Ca sources. The dietary Ca level was 2.0 g/kg, which is lower than the minimum requirement for rats (3.0 g/kg), to conduct the present study under a condition in which rats can maximally absorb Ca. To prevent Ca absorption in the small intestine, we replaced a primary phosphate (KH2PO4) with secondary phosphates (K2HPO4 and Na2HPO4) in diets. The apparent Ca absorption in the small intestine was estimated by adding chromic oxide (Cr2O3) as an insoluble and an unabsorbed marker to test diets and by measuring the ratio of Ca:Cr in the cecal content. The apparent Ca absorption in the whole intestine was estimated by the intake and fecal excretion of Ca. The apparent Ca absorption in the small intestine was significantly lower from the Ca carbonate diet than from the Ca gluconate, lactate, or citrate diets. The apparent Ca absorption in the whole intestine was not significantly different among the four groups, and the values were similar to the absorption rates in the small intestines of rats fed diets containing soluble Ca sources. These results show the following: (a) In rats fed 0.2% Ca diets containing soluble Ca salts, Ca is mostly absorbed in the small intestine, even in secondary phosphate intakes; (b) In contrast, in rats fed a 0.2% Ca diet containing an insoluble Ca salt (carbonate), Ca is not sufficiently absorbed in the small intestine. However, the large intestine compensates for the small intestinal Ca absorption decreased by dietary secondary phosphates.
BACKGROUND/AIM: Nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin produce damage in the small intestine as a major adverse reaction. We examined the effect of various NSAIDs on intestinal motility and investigated the pathogenic importance of motility changes in the intestinal ulcerogenic response to indomethacin in rats. METHODS: Animals without fasting were given various NSAIDs (indomethacin 10 mg/kg, diclofenac 40 mg/kg, flurbiprofen 20 mg/kg, naproxen 40 mg/kg) s.c., and in the case of indomethacin, the following parameters were examined in the small intestine 24 h later; the lesion score, the number of enterobacteria and myeloperoxidase (MPO) as well as inducible nitric oxide (iNOS) activity. Intestinal motility was monitored as intraluminal pressure recordings using a balloon under anesthesia. RESULTS: All NSAIDs tested decreased mucosal PGE(2) levels and produced hemorrhagic lesions in the small intestine, accompanied by intestinal hypermotility. As representative of NSAIDs, indomethacin also increased the extent of enterobacterial invasion and MPO as well as iNOS activity before the occurrence of intestinal damage, and the hypermotility response was observed earlier than the onset of any other event caused by this agent. The intestinal lesions induced by indomethacin were prevented by either supplementation with dmPGE(2), inhibition of bacterial invasion with ampicillin or inhibition of iNOS activity with aminoguanidine, while the hypermotility response was prevented by dmPGE(2) only. In addition, the observed effects of dmPGE(2) were all mimicked by atropine when the intestinal hypermotility was suppressed by this agent. CONCLUSION: These results suggest the pathogenic importance of intestinal hypermotility in the intestinal ulcerogenic response to NSAIDs in rats and show that this event is critical for the occurrence of enterobacterial invasion under PG deficiency, followed by various inflammatory changes and damage in the mucosa. This study also suggests that the antispasmodic drug is protective against NSAID-induced intestinal lesions.
Changes in the functional and biochemical characteristics of membrane receptors for vasoactive intestinal peptide (VIP) were evaluated in vitro, using epithelial intestinal cells isolated during rat development, from day 17 of gestation to adulthood. These characteristics included cell cAMP generation, adenylate cyclase and cAMP-dependent phosphodiesterase cAMP-PDE activities, [125I]VIP-binding capacity, and the molecular components of [125I]VIP-binding sites. In 19-day-old fetuses, VIP induced a significant and persistent increase in cAMP production, which lasted for 10 min in intestinal cells. This effect, measured at 37 C in the absence of cAMP-PDE inhibitor, only lasted for 3 min in 5-day-old rats and was undetectable in adult intestine. Addition of the cAMP-PDE inhibitor 3-isobutyl-1-methylxanthine with VIP caused, potentiated, and maintained elevated cAMP levels at the three stages considered. Intestinal cells were more sensitive to VIP in 17- and 19-day-old fetuses (ED50 = 5 and 17 X 10(-11) M VIP, respectively, at 15 and 37 C) than in adult rats (EC50 = 2.7 and 1.6 X 10(-9) M VIP). Adenylate cyclase activity rose 4-fold in fetal intestine and had an apparent Ka of 4 X 10(-10) M VIP. These changes in VIP receptor activity were not observed for PGE2 receptors in developing rat intestinal cells or in the VIP-sensitive adenylate cyclase system prepared from liver of fetuses and adults. They might be due to differences between the molecular components of the intestinal VIP receptor, which were identified here as autoradiographic bands of 64,800 daltons in 19-day-old rat fetuses and 74,600 daltons in adults (P less than 0.01). Alternatively, the changes in VIP receptor activity in 5-day-old rats may result from decreases in the number and affinity of the [125I]VIP-binding sites and increases in the velocity of cAMP-PDE activity. The release of VIP from intestinal nerve endings during fetal and postnatal development and the absorption of VIP from milk might, therefore, modulate the intestinal VIP receptor and its effector systems. Because specific VIP receptors were expressed before the morphological and functional differentiation of intestinal and liver cells, we conclude that their activity is an indicator of their development, and suggest that in rats, this neuropeptide may regulate the maturation and functions of intestine and liver during fetal life.