Irritable bowel syndrome: is the search for lactose intolerance justified?

OBJECTIVES: To determine if confirmation of hypolactasia offers any benefit to the dietary treatment of patients with irritable bowel syndrome (IBS). METHODS: One hundred and twenty-two consecutive IBS patients (37 male, 85 female) were given lactose hydrogen breath tests (LHBT). Those with positive LHBT followed a low lactose diet for 3 weeks. Those improving on the diet were given double-blind, placebo-controlled challenges (DBPCC) with 5 g, 10 g and 15 g of lactose and a placebo, to confirm lactose intolerance. Those who did not respond to the low lactose diet followed either an exclusion or low fibre diet. Symptoms scores were kept prior to the LHBT, 8 h post-LHBT and daily whilst following any dietary change. Patients with negative LHBT returned to clinic and subsequent dietary interventions were recorded. RESULTS: LHBT was positive in 33/122 (27%) IBS patients. Syrr otom scores prior to LHBT were not significantly different between the two groups, but after LHBT the symptoms in the positive group were significantly worse. Twenty-three patients followed a low-lactose diet of which only nine (39%) improved. Six who did not improve followed an exclusion diet, three improved and all were intolerant of milk. Three tried a low fibre diet with two improving. DBPCC were inconclusive. In the negative LHBT group 35 agreed to try a diet and 24 improved (69%). Eight were intolerant of cow's milk. CONCLUSIONS: Use of a low lactose diet was disappointing in IBS patients with lactose malabsorption. Food intolerance was demonstrated in IBS patients with positive or negative LHBT and milk was identified as a problem in both groups. DBPCC were inconclusive. There appears to be little advantage in trying to separate patients who malabsorb lactose from others with IBS.

A 3-month, double-blind, controlled trial of feeding with sucrose polyester in human volunteers.

Sucrose polyester (SPE) is a tasteless, odourless substance which reduces plasma cholesterol concentrations and may therefore be valuable as a fat substitute in human foodstuffs. It has recently been approved for use in snack foods by the United States Federal Drug Administration. The current study was designed to investigate its effects on gastrointestinal physiology and nutrient absorption in human subjects. A 6-month (2 x 3-month periods) double-blind, placebo-controlled, randomized, cross-over trial of SPE and control fat was performed in healthy free-living volunteers. Subjects consumed 20-40 g of SPE daily (mean 26.8 (SE 6.8) g) which reduced the intake of total and saturated fat but had no effect on energy intake or body weight. Plasma cholesterol and triacylglycerols were reduced. The frequency of bowel movements and their urgency were increased and anal leakage occurred in 7.2% of subjects. Abdominal pain was more frequent in subjects receiving SPE and was significantly greater than in the control group after 8 weeks feeding. The plasma concentrations of vitamin E and six carotenoids were significantly reduced. Routine haematology and biochemistry, other vitamins, intestinal biopsies, bile-salt retention, rectal prostaglandins, fractional Ca absorption and aminopyrine metabolism were unaffected. The ingestion of foods containing 20-40 g SPE daily provoked significant gastrointestinal problems. This intake is greater than that to be expected from the use of SPE in savoury snack foods, for which it has been approved by the United States Federal Drug Administration. However, the favourable effects on lipid profiles must be balanced against the reduction in the concentrations of vitamins and carotenoids, as these compounds may have beneficial effects on health through protection from free-radical oxidative stress.

The effects of aminosalicylic acid derivatives on nitric oxide in a cell-free system.

AIMS AND METHODS: To determine the effect of aminosalicylic acid derivatives on the concentration of nitric oxide produced in a cell-free system, by the use of a sensitive and specific polarographic meter. RESULTS: The aminosalicylic acid derivatives 3-ASA (IC50 100 microM), 4-ASA (IC50 350 microM) and 5-ASA (IC50 5 microM) all decreased the nitric oxide signal. These drugs had a similar inhibitory effect on the formation in vitro of nitrite from sodium nitroprusside (IC50: 200 microM, 500 microM and 100 microM, respectively). Sulphasalazine (31.1 +/- 5% decrease in signal at 1 mM) was less effective than 5-ASA, but sulphapyridine, N-acetyl 5-ASA, indomethacin and hydrocortisone produced no decrease in nitric oxide signal at all. CONCLUSIONS: Nitric oxide binding may be part of the mechanism by which ASA derivatives exert their therapeutic effect, and this work suggests that it may be an important factor in the pathogenesis of ulcerative colitis.

Relaxation of distal colonic circular smooth muscle by nitric oxide derived from human leucocytes.

The role of nitric oxide (NO) as a mediator of colonic circular smooth muscle relaxation by human leucocytes was investigated. Granulocytes and mononuclear cells were obtained by gradient centrifugation of venous blood from healthy volunteers. Both cell types relaxed precontracted distal colonic circular smooth muscle in a concentration dependent manner. Muscle relaxation was inhibited by preincubation of cells with NG-monomethyl-L-arginine (100 microM/l) but not by preincubation with NG-monomethyl-D-arginine (100 microM/l). Muscle relaxation by cells was reduced by 200 nM oxyhaemoglobin and 10 microM methylene blue but was increased by 60 units/ml superoxide dismutase. Non-viable cells did not produce muscle relaxation. Activation of mononuclear cells by incubation with 100 nM/l FMet-Leu-Phe increased muscle relaxation, whereas activation of granulocytes did not. Granulocytes and mononuclear cells relax precontracted distal colonic circular smooth muscle in vitro by the release of NO that may contribute to motility disorders of the gut associated with inflammation.

Nitric oxide affects mammalian distal colonic smooth muscle by tonic neural inhibition.

1 The role of the L-arginine-nitric oxide (NO) pathway in tonic neural inhibition of spontaneous mechanical activity of distal colonic circular smooth muscle (DCCSM) was investigated in male Wistar rats. 2 Muscle strips were mounted in organ baths and spontaneous contractions recorded with isometric force transducers. They were characterized as low frequency (LFCs) 0.41 +/- 0.03 N cm-2 or high frequency contractions (HFCs) 0.22 +/- 0.04 N cm-2. The latter occurred intermittently to produce summation contractions (SCs) range 0.5-12 N cm-2. 3 Tetrodotoxin (100 nM) increased the forces of LFCs and SCs. Increase in force to tetrodotoxin did not occur after incubation of the muscle with NG-monomethyl-L-arginine (L-NMMA) 500 microM, an inhibitor of NO biosynthesis. 4 L-NMMA but not its enantiomer D-NMMA increased the force of LFCs (EC50: 200 microM) and SCS (EC50:175 microM) in a concentration-dependent manner which was reversed by L-arginine but not by D-arginine. 5 Muscle, precontracted by acetylcholine, relaxed to sodium nitroprusside (EC50:1.8 microM) NO gas (EV50:70 microliters) and NO solutions (EC50:4 microM) in a concentration-dependent manner. Guanosine 3':5'-cyclic monophosphate tissue concentrations (pmol mg-1 protein) were elevated in muscle after relaxation by sodium nitroprusside (500 microM) from 0.32 +/- 0.06 to 1.2 +/- 0.37 and by 1 ml of NO gas from 0.49 +/- 0.05 to 1.54 +/- 0.14. 6 These data suggest that DCCSM is under tonic neural inhibition mediated by NO biosynthesis.

Increased nitric oxide synthesis in ulcerative colitis.

Nitric oxide (NO) is produced in tissues by NO synthase with the liberation of equimolar amounts of citrulline. Citrulline concentrations were significantly higher in rectal biopsy specimens from patients with active ulcerative colitis than in those from patients with quiescent disease or with normal histology. Incubation of biopsy samples from patients with ulcerative colitis with NG-monomethyl-L-arginine (L-NMMA) inhibited citrulline production. These findings suggest that mucosal NO biosynthesis is increased in active colitis and that NO may have a pathogenic role in ulcerative colitis.

Food intolerance: a major factor in the pathogenesis of irritable bowel syndrome.

Specific foods were found to provoke symptoms of irritable bowel syndrome (IBS) in 14 of 21 patients. In 6 patients who were challenged double blind the food intolerance was confirmed. No difference was detected in changes in plasma glucose, histamine, immune complexes, haematocrit, eosinophil count, or breath hydrogen excretion produced after challenge or control foods. Rectal prostaglandin E2 (PGE2), however, increased significantly, and in a further 5 patients rectal PGE2 correlated with wet faecal weight. Food intolerance associated with prostaglandin production is an important factor in the pathogenesis of IBS.

Further observations on an ether-O-oxidase, formerly called alkyl etherase, from liver tissue.

1. The microsomal enzyme from liver previously called an "etherase" is now described more accurately as an ether-O-oxidase. It has been investigated further to free it from the membranes in aqueous solution and to try to define its physiological substrate. 2. After a variety of attempts with detergents, etc., the enzyme was obtained in impure solution from precipitation with 35-45% (NH4)2SO4 solution after a short digestion at room temperature. 3. When a suitably reinforced the enzyme in solution forms citrate from added ethyl ether, as it does in membranous form. This indicates the intermediary formation of acetyl CoA. 4. The enzyme in solution is unstable, though some activity remains after standing at 0degrees C for 2-3 days. Activity is lost rapidly by deep freezing, exposure to 2M-NaCl and at a pH more acid than pH 5-0. 5. The enzyme does not appear to be a known oxidase obtainable from liver microsomes; it is not for instance part of the inducible mixed oxygenase system, nor a peroxidase or catalase. 6. Since there were some similarities in stability with enzymes dealing with protozoal plasmalogens, or with lanosterol or cholesterol, we were led to explore these substrates in detail, with negative results. But a specimen of cholesterol oxidase from the branching bacterium Nocardia gave O-oxidation with diethylether. 7. The enzyme is present in the livers of all four animals examined, namely the rat, pig, guinea-pig and pigeon, but not in kidney or brain. 8. The enzyme takes up O2 with some compounds containing O-me groups. 9. The hypothesis is advanced that this normal oxidase in liver membranes exists to deal with some substances from plant sources which might prove toxic upon entering the circulation.

An alkyl etherase in rat liver.

1. Diethyl ether, which is known to be partly metabolized in vivo, has been found to show an O2 uptake with the rat liver microsomal membranes; a similar reaction is given with other short chain aliphatic ethers, isoproply and n-butyl ether. 2. The "etherase" reaction is optimal at pH 7.2-7.4 and is not accompanied by an increased formation of malondialdehyde. 3. When CoA is added to the microsomes together with a source of oxaloacetate and the consensing enzyme synthase, the etherase present forms citrate from diethyl ether, indicating an acetylation of CoA, which then enters the citric acid cycle. 4. Similarly to 3, fluorocitrate is formed from methyl fluoroethyl ether. 5. Differing from plasmalogens, a tetrahydropteridine does not have to be added as a co-factor.