Ulcerative colitis: ultrastructure of interstitial cells in myenteric plexus.

Interstitial cells of Cajal (ICC) are key regulatory cells in the gut. In the colon of patients with severe ulcerative colitis (UC), myenteric ICC had myoid ultrastructural features and were in close contact with nerve terminals. In all patients as opposed to controls, some ICC profiles showed degenerative changes, such as lipid droplets and irregular vacuoles. Nerve terminals often appeared swollen and empty. Glial cells, muscle cells, and fibroblast-like cells (FLC) showed no alterations. FLC enclosed macrophages (MLC), which were in close contact with naked axon terminals. The organization and cytological changes may be of pathophysiological significance in patients with UC.

Chenodeoxycholic acid stimulated fibroblast growth factor 19 response - a potential biochemical test for bile acid diarrhoea.

BACKGROUND: Bile acid diarrhoea is underdiagnosed and better diagnostic tests are needed. Fasting serum fibroblast growth factor-19 (FGF19) has insufficient diagnostic value, but this may be improved by stimulation. AIM: To explore if an impaired FGF19 response identifies primary bile acid diarrhoea. METHODS: Eight patients with primary bile acid diarrhoea and eight healthy volunteers ingested (i) a meal plus 1250 mg chenodeoxycholic acid (CDCA), (ii) 1250 mg CDCA or (iii) the meal. Blood was sampled at fasting and repeatedly after stimulation. We analysed FGF19 by enzyme-linked immunosorbent assay and bile acids including 7α-hydroxy-4-cholesten-3-one by liquid chromatography-tandem mass spectrometry. RESULTS: Stimulation with the meal plus CDCA increased median FGF19 in healthy volunteers from fasting 62 pg/mL [interquartile range (IQR): 41-138] to 99 pg/mL (IQR: 67-147; P = 0.012) after 90 min and peaked after 150 min at 313 pg/mL (IQR: 54-512). This response was impaired in primary bile acid diarrhoea patients [fasting 56 pg/mL (IQR: 42-79); 90 min: 48 pg/mL [IQR: 37-63); 150 min: 57 pg/mL (48-198)]. Receiver operating characteristics (ROCAUC ) for fasting FGF19 was 0.55 (P = 0.75) and at 90 min 0.84 (P = 0.02). The difference in FGF19 from fasting to 90 min after the meal plus CDCA separated the groups (ROCAUC 1.0; P = 0.001). 7α-hydroxy-4-cholesten-3-one was elevated in primary bile acid diarrhoea (P = 0.038) and not significantly affected by stimulation. CONCLUSIONS: The FGF19 response following chenodeoxycholic acid plus meal is impaired in primary bile acid diarrhoea. This may provide a biochemical diagnostic test.

Interstitial cells of Cajal as targets for pharmacological intervention in gastrointestinal motor disorders.

Interstitial cells of Cajal (ICCs) have recently been identified as the pacemaker cells for contractile activity of the gastrointestinal tract. These cells generate the electrical 'slow-wave' activity that determines the characteristic frequency of phasic contractions of the stomach, intestine and colon. Slow waves also determine the direction and velocity of propagation of peristaltic activity, in concert with the enteric nervous system. Characterization of receptors and ion channels in the ICC membrane is under way, and manipulation of slow-wave activity markedly alters movement of contents through the gut organs. Here Jan Huizinga, Lars Thuneberg, Jean-Marie Vanderwinden and Jüri Rumessen, suggest that, as ICCs are unique to the gut, they might be ideal targets for pharmacological intervention in gastrointestinal motility disorders, which are very common and costly.

Fructans of chicory: intestinal transport and fermentation of different chain lengths and relation to fructose and sorbitol malabsorption.

Fructans (fructooligosaccharides and inulin) are of increasing interest to clinical nutritionists as functional food additives. The chemically closely related food carbohydrates fructose and sorbitol are implicated in functional bowel disease. Intestinal handling of these carbohydrates is incompletely understood. Intestinal absorption, transit, and fermentation (breath hydrogen and methane, venous acetate, blood glucose, and urine fructans) after ingestion of 10-30 g short- and long-chain fructans from chicory were studied by single-blind, crossover randomization in 10 healthy adults. Responses were compared with responses after ingestion of lactulose, fructose, and sorbitol. Breath hydrogen and venous acetate production increased in proportion to increasing fructan dose and were similar to responses to lactulose. The transit times of long-chain fructans were longer than those of short-chain fructans (75 compared with 30 min, P<0.001). Semiquantitative estimates of unabsorbed carbohydrate were not significantly different with either short-chain fructans or lactulose as nonabsorbable standards. Venous acetate curves were less precise estimates of the magnitude of carbohydrate malabsorption than were breath-hydrogen curves (P<0.01). All subjects showed malabsorption of 50 g fructose, resulting in significantly more symptoms than 20 g fructose (P<0.05). Ingestion of sorbitol with equimolar amounts of glucose did not reduce malabsorption or abdominal distress. Abdominal symptoms after fructans increased with increasing dose and decreasing chain length. The overall gastrointestinal effects of short-chain fructans seem similar to those of lactulose. Fructans with different chain lengths may have different physiologic properties and further studies of fructans in disease states are warranted.

Blood glucose response to pea fiber: comparisons with sugar beet fiber and wheat bran.

Two new fiber types, pea fiber (PF) and sugar beet fiber (BF), were compared with wheat bran (WB) to investigate the effect on postprandial blood glucose and serum insulin responses in normal subjects. The control meal consisted of 150 g ground beef mixed with 50 g glucose and 20 g lactulose. Only addition of PF (15 g pure fiber) reduced the area under the incremental blood glucose curve significantly (by 65%, p less than 0.05). None of the fibers affected the area under the insulin-response curve significantly although it was reduced by all fibers. Mouth-to-cecum transit time, assessed by the hydrogen breath technique, was decreased by WB and BF, (p less than 0.05) but not by PF. PF is palatable and may prove beneficial as a fiber supplement for diabetics.

Fructans of Jerusalem artichokes: intestinal transport, absorption, fermentation, and influence on blood glucose, insulin, and C-peptide responses in healthy subjects.

Fructans are naturally occurring plant oligosaccharides with sweetening properties. Fructans (FAs) isolated from Jerusalem artichokes (Helianthus tuberosus) were studied with respect to intestinal handling and influence on blood glucose (BG), insulin, and C-peptide responses in eight healthy subjects. The responses were compared with those for fructose ingestion. The effect of FAs added to a wheat-starch meal was also studied. Standardized breath-hydrogen excretion indicated that FAs were completely malabsorbed and, after a 20-g dose, traces of FA were detected in 24-h urine collections in one subject only. Orocecal transit times were longer for FAs than for lactulose and fructose. The BG and insulin increments were very low after FA ingestion, lower than after fructose ingestion, whereas hydrogen production was much higher. Areas under BG curves tended to be smaller when 10 g FA was added to a 50-g wheat-starch meal, but there was no apparent interference with starch absorption.

Interstitial cells of Cajal in human gut and gastrointestinal disease.

This paper reviews the distribution of interstitial cells of Cajal (ICC) in the human gastrointestinal (GI) tract, based on ultrastructural and immunohistochemical evidence. The distribution and morphology of ICC at each level of the normal GI tracts is addressed from the perspective of their functional significance. Alterations of ICC reported in achalasia of cardia, infantile hypertrophic pyloric stenosis, chronic intestinal pseudoobstruction, Hirschsprung's disease, inflammatory bowel diseases, slow transit constipation, and some other disorders of GI motility as well as in gastrointestinal stromal tumors are reviewed, with emphasis on the place of ICC in the pathophysiology of disease.

Hydrogen and methane breath tests for evaluation of resistant carbohydrates.

This review considers in detail the background, principles, techniques, limitations and advantages of the hydrogen and methane breath tests. Resistant food carbohydrates, defined as dietary carbohydrates partly or totally escaping small intestinal assimilation, are fermented in the human colon. This results in production of H2, CH4 and volatile fatty acids. Increased colonic H2 production is a sensitive index of increased carbohydrate fermentation, and a rather constant fraction of the colonic H2 production is excreted by the lungs. It is therefore possible to assess mouth-to-caecum transit times as well as to estimate absorption capacities for several types of resistant carbohydrates by means of H2 breath tests. A prerequisite for correct interpretation is that procedures for determination of H2 concentrations and for breath sampling and storage are carefully validated and standardized. Due to the large interindividual variations of hydrogen excretion, unabsorbable standards should be used. The intraindividual variations of H2 production/excretion and differences in fermentability of different carbohydrate substrates only allow for semiquantitative estimates of malabsorbed amounts of some carbohydrates. Methane breath tests may supplement the information gained from hydrogen measurements, but further evaluations are needed. The hydrogen breath technique is rapid, simple and non-invasive as well as non-radioactive. It may be carried out in a large number of intact individuals under physiological circumstances, and it may be used for studies in children and for field studies. Compared to classical tolerance tests the hydrogen breath test is more sensitive. It is concluded that the hydrogen breath test is a useful tool for investigations of dietary carbohydrates.

Intestinal transport and fermentation of resistant starch evaluated by the hydrogen breath test.

OBJECTIVE: To study fermentability of different samples of resistant starch (RS), compared to one another and to lactulose, and to study the effect on gastric emptying of addition of RS to test meal. Finally to study if adaptation to RS results in a measurable change in fermentation pattern, (H2/CH4 production). Sources of RS: Raw potato starch (RPS), 58% RS; corn flakes (CF), 5% RS; hylon VII high amylomaize starch, extrusion cooked and cooled (HAS) 30% RS; highly retrograded hylon VII high amylomaize starch (HRA) 89% RS. DESIGN: (1) Fermentation: seven healthy volunteers ingested in randomized order 50 g RPS, 100 g CF, 75 g HAS, 25 g HRA. End-expiratory H2/CH4 was measured every 30 min for 12 to 22 hours post-ingestion as a measure of fermentation. A dose-response study of RPS, 5, 10, 25, 50, 75 and 100 g was performed. (2) Adaptation: In five 3-week periods seven volunteers added daily to their usual diet 50 g of either RPS, HAS, oat bran, wheat bran or common maize starch. The polysaccharides were administered in randomized order. The test periods were separated by 1 week's wash out. Basic end-expiratory H2/CH4 was measured once a week prior to and during the test periods. (3) Gastric emptying: The rate of increase in blood glucose was measured after test meals consisting of 50 and 100 g of RPS, 50 g HAS and 50 g glucose dissolved in a gel, alone, and mixed with 25 g of RPS. As controls we chose wheat bran and oat bran. RESULTS: (1) We found that RPS is fermentable, although the cumulated excessive H2 production after 50 g RPS corresponding to 29 g RS was clearly less than after 10 g lactulose. The time from ingestion of RPS to a sustained increase in end-expiratory H2 (apparent transit time; 5-11 h) was longer than lactulose (1-4 h), indicating either a slow passage through the small intestine or a slow fermentation rate. 100 g of corn flakes (4.6 g RS) resulted in a measurable increase in H2 production, equivalent to 10-20 g RPS, whereas neither of the two samples of hylon VII high amylomaize resulted in any significant increase in H2 production. The dose-response study with RPS showed that even 5 g of RPS resulted in a measurable increase in end-expiratory H2, and increasing doses from 5 g to 100 g resulted in a seemingly exponential increase in H2 production. (2) 3 weeks' daily administration of HAS resulted in a slightly elevated increase in basic end-expiratory H2, although the increase did not reach statistical significance. RPS resulted in a sustained increase in basic end-expiratory H2. Both RS samples increased measurable end-expiratory CH4 in volunteers with measurable CH4 production after a lactulose load, but 3 weeks' daily challenge with these slowly fermentable substrates did not increase measurable CH4 in volunteers, who prior to the study only produced CH4 intermittently. (3) The rate of increase in blood sugar was unaffected by addition of RS or non-starch-polysaccharides to the test meal, indicating that addition of the polysaccharides does not affect gastric emptying. CONCLUSIONS: A fraction of RPS is resistant to digestion in the small intestine, and it is fermentable by the colonic microbial flora. RS from CF, HAS and RPS give very different H2 responses, either due to differences in digestion patterns or fermentation patterns. Short-term adaptation (3 weeks) to HAS or RPS does not change the H2/CH4 response. RS does not affect gastric emptying of a test meal consisting of glucose dissolved in a gel.

Effect of sustained-release isosorbide dinitrate on post-prandial gastric emptying and gastroduodenal motility in healthy humans.

Nitric oxide (NO) is an inhibitory neurotransmitter released by non-adrenergic and non-cholinergic neurons that innervate the smooth muscles of the gastrointestinal tract. We examined whether NO, derived from a sustained-release preparation of isosorbide dinitrate, influenced gastric emptying and gastroduodenal motility after a meal. Eleven healthy volunteers participated in a double-blind, placebo-controlled, cross-over study. Each subject ingested 40 mg isosorbide dinitrate orally as a sustained-release formulation or oral placebo, in random order. Gastric emptying and gastroduodenal motility were measured using scintigraphic and manometric techniques. Isosorbide dinitrate did not change the area under the curve of gastric retention versus time, and did not influence the frequency of antral contractions as assessed at 15-min intervals or the integrated duodenal motility index, as recorded over consecutive 15-min periods. A 40 mg single dose of sustained-released isosorbide dinitrate does not seem to alter gastric emptying or gastroduodenal motility after a meal.

[Strategies for investigating non-assimilation. A critical status]. / Strategier ved udredning af malassimilation. En kritisk status.

This review reevaluates the rational basis for choice of diagnostic strategies in patients with suspected malassimilation. Prospective evaluation of diagnostic tests must fulfil several requirements for a correct assessment of their clinical value. Very few studies meet such requirements, resulting in unnecessary investigations as well as overlooked cases with a negative impact on patients and society. This problem includes evaluation of assimilation of macronutrients (carbohydrate, fat, protein) as well as micronutrients (e.g. vitamin B12), and it is further complicated by the occurrence of conditions with occult (compensated) malassimilation. Malassimilation of carbohydrates may be physiological (starch, fructose, sugar alcohols etc., in certain ethnic groups lactose) as well as pathological. In both instances chronic gastro-intestinal distress may arise in sensitive individuals. The diagnosis is based on tolerance tests, combined with blood tests or breath tests (hydrogen excretion). The latter is considered the most reliable, but the available evidence for choice of tests is not solid. Similar reservations apply to conditions of bacterial overgrowth of the small intestine, which may lead to diffuse malassimilation. The frequency and clinical importance of this condition is in all probability underestimated. Screening for coeliac disease may be achieved by several serological tests (reticulin-, gliadin-, endomysial antibodies), of which IgA-endomysial antibodies seem superior. Comparative studies are often flawed in design, however, and permeability tests may also eventually find their place in the test battery. There is thus a strong need for more evidence-based diagnostic strategies in patients with suspected malassimilation.

[Dimethicone in lactulose-induced dyspepsia. Effect on H2 production and symptoms]. / Dimetikon ved laktuloseinduceret dyspepsi. Effekt på H2-produktion og symptomer.

The results of studies of the effect of simethicone on abdominal gas-related symptoms have been contradictory. In a randomized, double-blind, cross-over study, ten healthy volunteers were given 30 g lactulose and 600 mg simethicone or placebo. End-expiratory breath samples were collected and analyzed for H2, and gastrointestinal symptoms registered. There were no differences in biochemical parameters or symptom score between simethicone and placebo. In contrast to previous studies, we used a sufficiently large dose of lactulose to produce gastrointestinal symptoms, a higher dose of simethicone and placebo tablets containing the same additives as the simethicone tablets. There was no demonstrable effect of simethicone on symptoms or intestinal gas production caused by carbohydrate malabsorption.

Pacemaker cells in the gastrointestinal tract: interstitial cells of Cajal.

Interstitial cells of Cajal (ICC) were described a century ago as primitive neurons in the intestines. Through the years, ICC have been mistaken for neurons, glial cells, fibroblasts, smooth muscle cells, and macrophages. We identified ICC in the musculature of mouse small intestine by their characteristic morphology and topography, and we analysed the relation between ICC, autonomic nerves, and smooth muscle. Subsequent morphological and electrophysiological evidence has strongly supported our hypotheses that some ICC populations are gut pacemakers and may hold other fundamental regulatory functions (coordinative, mechanoreceptive, mediating nervous input). Recognition of common principles of ICC organization (confinement to specific locations in relation to smooth muscle layers; formation of extensive cellular networks through tight coupling of overlapping thin processes; innervation patterns; characteristic patterns of contact with smooth muscle cells) and ultrastructure (myoid features: basal lamina, caveolae, rich in sER and mitochondria, often prominent filament bundles and dense bands/bodies) has allowed the identification of ICC in the GI musculature of all species investigated. However, variation in organization and ultrastructure is significant, between both species and regions of the GI tract. Our studies of ICC in human intestine permit an extension of the above hypotheses to man and provide a basis for further studies of ICC pathology and pathophysiology. The latter may become a fruitful area of research in the coming decades.

Fructose and related food carbohydrates. Sources, intake, absorption, and clinical implications.

It is possible to point out subjects consuming considerable quantities of fructose and sorbitol, and the intake seems to be increasing both from added and natural sources. Studies of the absorption of fructose in animals are inconsistent, and the mechanisms of fructose uptake seem to vary in accordance with the species. In most species fructose absorption takes place by a specific carrier (facilitated transport), but it may be active in the rat. In vitro studies of human intestine are very scarce; there is no evidence of active intestinal fructose transport in the human intestine. By means of hydrogen breath tests, a very low absorption capacity for fructose given as the free monosaccharide has been found in humans. Fructose given as sucrose or in equimolar combinations with glucose is well absorbed, and only fructose in excess of glucose is malabsorbed. On this basis it is hypothesized that two different uptake mechanisms for fructose are present in the human intestine. One of these may be a disaccharidase-related uptake system. Sorbitol ingestion may aggravate malabsorption of fructose given as the monosaccharide; it is not known whether a specific mechanism is involved. In children and adults with functional bowel distress the absorption capacities for fructose may not differ from those of healthy individuals, but malabsorption of fructose and/or sorbitol may be the cause of or aggravate abdominal symptoms. Fructose polymers (fructans) are also subject to increasing nutritional interest. Fructans are not absorbed in the small intestine but are strongly fermented in the large bowel. Fructans may be of potential benefit for large-bowel function and blood glucose regulation.