Deranged smooth muscle alpha-actin as a biomarker of intestinal pseudo-obstruction: a controlled multinational case series.

BACKGROUND AND AIMS: Chronic idiopathic intestinal pseudo-obstruction (CIIP) is a severe motility disorder associated with significant morbidity. Several histopathological (neuropathic and myopathic) phenotypes have been described but only a single adult with jejunal smooth (circular) muscle alpha-actin deficiency. We present a prospective multinational case series investigating smooth muscle alpha-actin deficiency as a biomarker of this disease. METHODS: A total of 115 fully clinically and physiologically (including prolonged (24 hour) ambulatory jejunal manometry) characterised CIIP patients from three European centres were studied. Immunohistochemical localisation of actins and other cytoskeletal proteins were performed on laparoscopic full thickness jejunal biopsies and compared with adult controls. Distribution of alpha-actin was also characterised in other gut regions and in the developing human alimentary tract. RESULTS: Twenty eight of 115 (24%) CIIP patient biopsies had absent (n = 22) or partial (n = 6) jejunal smooth muscle alpha-actin immunostaining in the circular muscle layer. In contrast, smooth muscle alpha-actin staining was preserved in the longitudinal muscle and in adult jejunal controls (n = 20). Comparative study of other adult alimentary tract regions and fetal small intestine, suggested significant spatial and temporal variations in smooth muscle alpha-actin expression. CONCLUSIONS: The ability to modulate alpha-smooth muscle actin expression, evident in development, is maintained in adult life and may be influenced by disease, rendering it a valuable biomarker even in the absence of other structural abnormalities.

Prolonged ambulatory small intestinal and colonic motility monitoring: potential in irritable bowel syndrome--first report of prolonged ambulatory oesophageal, small intestinal and colonic motility in the same patient.

Irritable bowel syndrome (IBS), which affects up to 25% of the population in western countries and accounts for up to 50% of referrals to gastroenterologist, remains mainly a diagnosis of exclusion. We have studied, for the first time, prolonged ambulatory motility recordings from the oesophagus, small intestine and colon of a patient who was referred to us with a 12-year history of abdominal pain and a presumptive diagnosis of IBS. The results indicated that the diagnosis was pseudo-obstruction syndrome rather than IBS. Wider clinical use of the new techniques of prolonged ambulatory intestinal motility monitoring in IBS would offer considerable potential not only in achieving a greater understanding of its pathophysiology but also in providing a more precise definition of clinical and therapeutic subgroups.

Influence of three different fiber-supplemented enteral diets on bowel function and short-chain fatty acid production.

BACKGROUND: Dietary fiber is known to influence bowel habit and gastrointestinal mucosal cell morphology and function. large-bowel function is particularly influenced by insoluble, poorly fermentable fiber sources, whereas mucosal function is affected by fiber sources that are soluble and highly fermentable. The aim of the present study was to compare bowel function during consumption of a self-selected diet, a fiber-free enteral diet, and three polymeric enteral diets, each supplemented with a fiber with different fermentation characteristics. The fiber sources used were oat, soy oligosaccharide, and soy polysaccharide. METHODS: Seven healthy subjects consumed four diets in random order for 4 to 7 days. These were a self-selected diet, a 2-L polymeric enteral diet, and a 2-L polymeric enteral diet supplemented with 15 g of total dietary fiber per liter derived from either soy oligosaccharide fiber (75 g/L) or oat fiber (15 g/L). An additional six healthy subjects were randomly assigned to three diets (4 to 7 days): a self-selected diet, a 2-L polymeric enteral diet, or the same 2-L polymeric enteral diet supplemented with 20 g of soy polysaccharide fiber per liter (15 g of total dietary fiber per liter). Bowel function was assessed by measuring whole-gut transit time, mean daily stool wet weights, and bowel movement frequency per day. Fermentation characteristics of the different fiber sources were determined quantitatively and qualitatively by measuring short-chain fatty acids produced during in vitro stool culture. RESULTS: Total short-chain fatty acid and butyric acid production with soy oligosaccharide fiber were significantly higher compared with values observed for soy polysaccharide fiber (p < .003), oat fiber (p < .005), and self-selected (control) diet (p < .003). Compared with the fiber-free diet, consumption of the soy polysaccharide, oat, and soy oligosaccharide-fiber-supplemented enteral diets did not significantly (p > .05) alter whole-gut transit time or stool wet weight. However, bowel frequency was significantly improved by consumption of the soy polysaccharide-fiber-supplemented diet but not the oat fiber or soy oligosaccharide-fiber-supplemented diets. CONCLUSION: Compared with a fiber-free polymeric enteral diet, the daily consumption of an enteral diet supplemented with 30 g of total dietary fiber per day derived from a poorly fermentable oat fiber, a highly fermentable soy oligosaccharide fiber, or a moderately fermentable soy polysaccharide fiber has little impact, if any, on bowel function.

Colonic secretory effect in response to enteral feeding in humans.

Diarrhoea complicating enteral feeding is a common clinical problem affecting up to 25% of patients. Its pathogenesis remains unknown. A new technique of human in vivo segmental colonic perfusion was used to investigate colonic water and electrolyte movement in response to enteral feeding. Four groups of studies were performed in which low and high load polymeric enteral diet infusions were undertaken, either intragastrically or intraduodenally (n = 6 each group). Net absorption of sodium, chloride, and water occurred during fasting throughout the colon in all groups. There was a significant net secretion of sodium, chloride, and water in the ascending colon during low load (sodium: -42 mmol/h; 95% confidence limits -52 to -19, Chloride: -18 mmol/h; -50 to +16, water: -174 ml/h; -348 to -30) and high load (sodium: -24 mmol/h; -60 to +8, chloride: -18 mmol/h; -31 to +16, water: -120 ml/h; -246 to +6) gastric feeding, and during high load duodenal feeding (sodium: -12 mmol/h; -22 to -6, chloride; -6 mmol/h; -16 to +3, water: -72 ml/h; -144 to -6). Net secretion persisted in the distal colon only during high load gastric feeding. In the other three groups there was a net absorption in the distal colon. This study identified a significant colonic secretory response to enteral feeding, which is related to the site and load of the diet infusion. This response may play an important part in the pathogenesis of enteral feeding related diarrhoea.

Reversal by short-chain fatty acids of colonic fluid secretion induced by enteral feeding.

Diarrhoea complicates enteral feeding in up to 25% of patients. In-vivo perfusion studies in healthy subjects have shown secretion of salt and water in the ascending colon in response to enteral feeding. This study investigated the effect of short-chain fatty acids (SCFA) on this secretory response. Six healthy volunteers underwent segmental in-vivo colonic perfusion. First, baseline fasting colonic water and electrolyte movement was established, then a standard polymeric enteral diet was infused into the stomach while the colon was perfused with either a control electrolyte solution or a test solution containing SCFA. The electrolyte concentrations and osmolality of the two perfusates were identical. In the fasting state water was absorbed throughout the colon. During the control infusion there was significant (p < 0.05) secretion of water in the ascending colon (median rate 1.0 mL per min [95% CI 2.8 mL per min secretion to 0.8 mL per min absorption]). During the SCFA infusion the secretion was significantly reversed (p < 0.05) and there was net absorption (1.6 [0.8-3.7] mL per min). In the distal colon water absorption was significantly greater during the control infusion than during fasting (3.7 [2.5-4.6] vs 1.3 [0.3-2.2] mL per min); during the test infusion this absorption persisted (2.8 [1.3-3.6] mL per min). Movement of sodium, chloride, and potassium ions was similar to that of water in all stages of the study. Bicarbonate movement did not significantly change at any stage. Infusion of SCFA directly into the caecum reverses the fluid secretion seen in the ascending colon during enteral feeding. This finding could have implications for the management of diarrhoea related to enteral feeding.

The effect of a fibre free and fibre supplemented polymeric enteral diet on normal human bowel function.

Although the effects of dietary fibre in a normal diet on intestinal function are well known, the effects of supplementing enteral diet with fibre on intestinal function are not so clear. The aims of the present study were two fold: firstly to compare intestinal function during ingestion of a self selected diet and fibre free polymeric enteral diet and secondly to investigate the effect of adding the fibre source, soy polysaccharide to the same polymeric diet, on bowel function. Six healthy subjects were randomly assigned to 3 treatment periods (7 days) of a self selected diet (SSD), 2 l polymeric enteral diet (ED), or 2 l of the same polymeric enteral diet supplemented with 20 g/l of soy polysaccharide fibre (SPED). Parameters measured were bowel frequency/day, mean daily wet stool weights and whole gut transit time. Highest stool wet weights (g/24 h +/- SEM) were obtained from subjects consuming a SSD (180.3 +/- 30.6). This was significantly higher (p < 0.02) than those consuming an ED (81.9 +/- 14.5) but not a SPED (123 +/- 22.3). Whole gut transit (h +/- SEM) on a SSD (47 +/- 5.9) was significantly (p < 0.05) quicker than on an ED (73 +/- 4.9), but not significantly different from those ingesting a SPED (54 +/- 5.5). Bowel frequency/day (+/- SEM) in subjects consuming a SPED (1.0 +/- 0.1) was significantly (p < 0.02) higher than in subjects ingesting an ED (0.8 +/- 0.1) but was not significantly different when compared to a SSD (1.0 +/- 0.2). We conclude that ingestion of an ED results in significantly longer whole gut transit time, significantly decreased daily stool wet weights and decreased bowel frequency when compared to a SSD. The ingestion of 30 g of soy polysaccharide in a polymeric enteral diet not only tends to normalise whole gut transit time and daily stool wet weights, but also significantly increases bowel frequency when compared with values seen during the consumption of a fibre free polymeric enteral diet.

Cephalic phase of colonic pressure response to food.

A cephalic phase of colonic pressure response to food was sought in five normal subjects (mean age (22.6) years, 22-24), studied on six separate occasions by recording intraluminal pressures in the unprepared sigmoid colon. Gastric acid secretion was measured simultaneously by continuous aspiration through a nasogastric tube. After a 60 minute basal period, one of five 30 minute food related cephalic stimuli, or a control stimulus was given in random order; records were continued for a further 120 minutes. The cephalic stimuli were: food discussion, sight and smell of food without taste, smell of food without sight or taste, sight of food without smell or taste, and modified sham feeding; the control stimulus was a discussion of neutral topics. Colonic pressures were expressed as study segment activity index (area under curve, mm Hg.min) derived by fully automated computer analysis. Gastric acid output was expressed as mmol/30 min. Food discussion significantly (p < 0.02, Wilcoxon's rank sum test) increased colonic pressure activity compared with control or basal activity. Smell of food without sight or taste also significantly (p < 0.03) increased the colonic pressure activity compared with control and basal periods. Sham feeding and sight and smell of food without taste significantly (p < 0.02 and p < 0.03) increased colonic pressures compared with control but not basal activity. The increase in colonic activity after sight of food without smell or taste was not significantly different from control or basal activity (p = 0.44 and p = 0.34). Food discussion was the strongest colonic stimulus tested. Food discussion and sham feeding significantly (p<0.02) stimulated gastric acid output above control and basal values. Sight and smell of food without taste significantly (p<0.02) increased acid output above basal. Smell of food without sight or taste and sight of food without smell or taste did not significantly (p=0.06, p=0.34) increase acid output. In contrast with the effect on colonic pressures, sham feeding was the best stimulus of acid output. Increased colonic pressure activity after food discussion correlated significantly (r=0.45, p<0.02) with gastric acid output. There was no correlation (r=-0.1, p>0.5) between colonic pressure activity and gastric acid output in the control study. These data show that there is a cephalic phase of the colonic response to food.

Oral or intravenous erythromycin has no effect on human distal colonic motility.

Erythromycin is a prokinetic agent for the lower oesophageal sphincter, the stomach, the gallbladder and the small bowel, acting directly on motilin receptors. Its effect on pressure activity of the human colon has not been investigated. Eight healthy volunteers were studied on 2 occasions and given intravenous or oral erythromycin, or placebo in a single-blind, randomized crossover study. Sigmoid pressure activity was measured using a 4-lumen water perfused system placed sigmoidoscopically at 50, 45, 30 and 15 cm from the anal verge. The pressures were analysed for activity index (mmHg.min) for the 35 cm colonic study segment using dedicated software. No significant difference was found in the activity index following oral erythromycin (500 mg) or placebo, or following intravenous erythromycin 1.8 mg/kg or placebo. A further 8 subjects were studied in a single-blind crossover study to determine the effect of oral erythromycin (500 mg) b.d. on colonic transit, measured with radio-opaque markers and a single abdominal X-ray. Mean or segmental colonic transit times were not statistically significantly different (Student's paired t-test) in the subjects on placebo or erythromycin. This lack of effect of erythromycin on the distal large intestine may indicate the absence of receptors for motilin in that part of the gut.

Effects of olsalazine and sulphasalazine on jejunal and ileal water and electrolyte absorption in normal human subjects.

The effect of sulphasalazine and olsalazine on jejunal and ileal water and electrolyte absorption was investigated in normal subjects by a steady state intestinal perfusion of a physiological glucose bicarbonate electrolyte solution in the absence and presence of increasing concentrations of each drug. (Olsalazine 0.25 g/l, 1.0 g/l, jejunum; 0.5 g/l, 1.0 g/l, ileum; sulphasalazine 0.25 g/l, 0.5 g/l, 2.0 g/l jejunum; 1.0 g/l, 2.0 g/l, ileum.) In the jejunum olsalazine at 1.0 g/l significantly inhibited water, sodium, chloride, and potassium absorption (p less than 0.05). In the ileum olsalazine at 0.5 and 1 g/l significantly inhibited glucose uptake (p less than 0.04) and water absorption (p less than 0.03). In the jejunum sulphasalazine had a dose related and significant inhibitory effect on water, bicarbonate, and sodium absorption and at 2.0 g/l an inhibitory effect on chloride, potassium (p less than 0.005), and glucose (p less than 0.05) absorption. In the ileum sulphasalazine had no significant effect on water and electrolyte absorption. All inhibitory effects were rapidly reversible. These data show that unexplained diarrhoea in patients with ulcerative colitis treated with olsalazine may occur as a consequence of inhibition of water and electrolyte absorption in the small intestine and that the mechanisms of inhibition of sulphasalazine and olsalazine are different.