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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Experimental subjects
  6. Experimental procedures
  7. Scintigraphic colonic transit measurement
  8. Stool collection and stool analysis
  9. Chemical analysis.
  10. Statistical analysis
  11. Results
  12. Effect of lactulose and PEG on stool weight and consistency
  13. Colonic transit during lactulose and PEG: effect of increasing lactulose doses on stool weight and colonic transit
  14. Total colonic transit.
  15. Regional colonic transit.
  16. Correlation between stool weight and transit time
  17. Total colonic transit.
  18. Regional colonic transit.
  19. Comparison of stool weight and transit during PEG (59 g/day) and lactulose (99 g/day) ingestion
  20. Total colonic transit.
  21. Regional colonic transit.
  22. Faecal composition in lactulose induced diarrhoea: relation between faecal composition and stool weight
  23. Relation between faecal composition and transit
  24. Factors influencing stool consistency
  25. Discussion
  26. Acknowledgement
  27. References

Background : The effects of lactulose and polyethylene glycol on colonic transit are poorly established.

Aim: To assess the effects of these laxatives on colonic transit in normal subjects.

Methods : Colonic transit (mean residence time, cumulative counts in stool, counts remaining in the proximal or distal colon) was measured scintigraphically in normal subjects on the second and third day of a 3-day ingestion of 67–134 g/day lactulose, or 59 g/day polyethylene glycol.

Results : At similar stool weight (lactulose: 653 ± 120 g/day; polyethylene glycol: 522 ± 66 g/day), transit was significantly slower during 99 g/day lactulose when compared with 59 g/day polyethylene glycol; this was most pronounced in the distal colon (mean residence time: lactulose – 403 ± 55 min; polyethylene glycol – 160 ± 41.9 min). Short chain fatty acid concentration in 24-h stool correlated significantly with counts remaining in the distal colon at 12 h(r = 0.79, P = 0.001). Increasing lactulose doses were significantly associated with increasing stool weight (r = 0.79) and shorter mean residence time in the total (r = −0.56) and distal colon (r = −0.64). The sum of faecal carbohydrates plus short chain fatty acids was associated with stool weight (r = 0.95, P < 0.001).

Conclusion : Lactulose accelerates colonic transit. However, compared with polyethylene glycol, transit during lactulose is prolonged.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Experimental subjects
  6. Experimental procedures
  7. Scintigraphic colonic transit measurement
  8. Stool collection and stool analysis
  9. Chemical analysis.
  10. Statistical analysis
  11. Results
  12. Effect of lactulose and PEG on stool weight and consistency
  13. Colonic transit during lactulose and PEG: effect of increasing lactulose doses on stool weight and colonic transit
  14. Total colonic transit.
  15. Regional colonic transit.
  16. Correlation between stool weight and transit time
  17. Total colonic transit.
  18. Regional colonic transit.
  19. Comparison of stool weight and transit during PEG (59 g/day) and lactulose (99 g/day) ingestion
  20. Total colonic transit.
  21. Regional colonic transit.
  22. Faecal composition in lactulose induced diarrhoea: relation between faecal composition and stool weight
  23. Relation between faecal composition and transit
  24. Factors influencing stool consistency
  25. Discussion
  26. Acknowledgement
  27. References

Lactulose and polyethylene glycol (PEG) are widely prescribed in the treatment of chronic constipation.1 Lactulose is a synthetic disaccharide that is not absorbed in the small intestine, but is metabolized by colonic bacteria to short chain fatty acids and gases. The laxative effect is related to osmotic binding of water by short chain fatty acids, electrolytes and lactulose, which has escaped bacterial metabolism. However, the osmotic effect of lactulose is greatly reduced by its metabolism, and by absorption of short chain fatty acids by the colonic mucosa.2 PEG 4000 is a mixture of non-absorbable and non-metabolizable polymers which binds water because of its osmotic action and to non-osmotic effects.3

Lactulose has a long history of use in constipation, is licensed for the use in children under the age of 1 year, and is associated with a prebiotic effect on colonic bacterial flora.4 Although bacterial fermentation of lactulose results in production of gases, a study comparing tolerance of lactulose and PEG found only minor differences, with flatus being more common during use of lactulose.5 However, chronic lactulose use may result in bacterial adaptation, necessitating an increase of the lactulose dose, which has not been observed with PEG.5 Because of bacterial metabolism and mucosal absorption the dose–response curve of lactulose is non-linear.2

It is unclear, to what extent the time available for bacterial metabolism and mucosal absorption may influence the laxative effect of lactulose, and it is conceivable that delayed colonic transit, which can be observed in a considerable subset of patients with constipation,6 might reduce the osmotic effect of lactulose, by allowing more time for bacterial metabolism and mucosal absorption. In addition, the short chain fatty acids that retard proximal colonic transit have been identified,7 although this may depend on their concentration and molecular structure, on responsiveness of different colonic segments and on animal species.8 Other studies have shown short chain fatty acids to either accelerate colonic transit9 or to have no effect on colonic contractile activity.10

In contrast to lactulose, PEG is neither metabolized nor absorbed. Therefore, its laxative effect is less likely to be influenced by delayed colonic transit in constipation and, in addition, it is also less likely that PEG has a direct effect on colonic motility which goes beyond the effects secondary to an increase in the intracolonic fluid load. The dose–response curve of PEG is linear.2

The effect of PEG on total and regional colonic transit in normal subjects has been evaluated in the past.12 In contrast, little is known about the effects of lactulose on colonic transit in normal subjects. The aim of our study was to evaluate colonic transit in normal subjects after ingestion of different lactulose doses. Based on previous experience,2 three different doses of lactulose were chosen to result in a wide interindividual range of stool weight and consistency, ranging from stools with normal weight (below 200 g/day) and formed consistency, to diarrhoeal stool. Faecal short chain fatty acid and carbohydrate concentrations were measured in subjects who developed diarrhoea. To separate volume effects of laxatives from specific effects because of lactulose metabolism we also measured transit during ingestion of PEG.

The results of our studies in normal subjects shall improve our understanding of colonic transit during ingestion of lactulose and pave the way for future studies on the effect of lactulose and PEG in patients with constipation because of different pathophysiological mechanisms.

Experimental subjects

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Experimental subjects
  6. Experimental procedures
  7. Scintigraphic colonic transit measurement
  8. Stool collection and stool analysis
  9. Chemical analysis.
  10. Statistical analysis
  11. Results
  12. Effect of lactulose and PEG on stool weight and consistency
  13. Colonic transit during lactulose and PEG: effect of increasing lactulose doses on stool weight and colonic transit
  14. Total colonic transit.
  15. Regional colonic transit.
  16. Correlation between stool weight and transit time
  17. Total colonic transit.
  18. Regional colonic transit.
  19. Comparison of stool weight and transit during PEG (59 g/day) and lactulose (99 g/day) ingestion
  20. Total colonic transit.
  21. Regional colonic transit.
  22. Faecal composition in lactulose induced diarrhoea: relation between faecal composition and stool weight
  23. Relation between faecal composition and transit
  24. Factors influencing stool consistency
  25. Discussion
  26. Acknowledgement
  27. References

Healthy volunteers, aged 20–49, mean age 25.7 ± 1.5 years (15 males, five females) participated in the study. None reported a history of gastrointestinal disease or abdominal surgery, except appendectomy. The subjects were not allowed to drink alcohol or to take any medication known to alter gastrointestinal motility at least 24 h before the start of the study. Written informed consent was obtained from every subject. The study protocol was approved by the ethics committees of the Karl-Franzens University of Graz and of the medical faculty of the University of Vienna.

Experimental procedures

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Experimental subjects
  6. Experimental procedures
  7. Scintigraphic colonic transit measurement
  8. Stool collection and stool analysis
  9. Chemical analysis.
  10. Statistical analysis
  11. Results
  12. Effect of lactulose and PEG on stool weight and consistency
  13. Colonic transit during lactulose and PEG: effect of increasing lactulose doses on stool weight and colonic transit
  14. Total colonic transit.
  15. Regional colonic transit.
  16. Correlation between stool weight and transit time
  17. Total colonic transit.
  18. Regional colonic transit.
  19. Comparison of stool weight and transit during PEG (59 g/day) and lactulose (99 g/day) ingestion
  20. Total colonic transit.
  21. Regional colonic transit.
  22. Faecal composition in lactulose induced diarrhoea: relation between faecal composition and stool weight
  23. Relation between faecal composition and transit
  24. Factors influencing stool consistency
  25. Discussion
  26. Acknowledgement
  27. References

Normal subjects ingested either lactulose or PEG 4000 on 3 consecutive days. Transit measurements and 24-h stool collection was started on day 2, when steady-state conditions were achieved.2

In 20 subjects, a total of 25 experiments with lactulose and six experiments with PEG were performed. Subjects were allowed to participate in more than one study, but an interval between two studies of at least 2 weeks was observed. Lactulose was given at a dose of 67 (n = 10), 99 (n = 12) or 134 g/day (n = 3). PEG was given at a dose of 59 g/day (n = 6). The total daily dose of lactulose and PEG was divided into three equal doses. On 3 consecutive days, the subjects drank their assigned dose with each of three meals, starting at 08:00 am on the first day and finishing at 08:00 pm on the third day. Meals on day 2 were standardized and taken at standardized time intervals, which are described in the section on colonic transit measurement.

The lactulose doses were chosen, based on the results of previous studies,2 to cover a broad range of daily stool output. The dose of PEG was chosen to provide daily stool weight which would be similar to stool weight obtained with the 99 g/day dose of lactulose2 in order to allow comparison of transit data in PEG and lactulose-induced diarrhoea with similar stool weight. Lactulose was given as a commercially available syrup containing 50 g lactulose per 100 g (Laevolac; Fresenius Kabi, Linz, Austria) and PEG was given as a balanced solution containing 125 mm sodium, 10 mm potassium, 35 mm chloride, 80 mm sulphate and 20 mm bicarbonate.

Scintigraphic colonic transit measurement

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Experimental subjects
  6. Experimental procedures
  7. Scintigraphic colonic transit measurement
  8. Stool collection and stool analysis
  9. Chemical analysis.
  10. Statistical analysis
  11. Results
  12. Effect of lactulose and PEG on stool weight and consistency
  13. Colonic transit during lactulose and PEG: effect of increasing lactulose doses on stool weight and colonic transit
  14. Total colonic transit.
  15. Regional colonic transit.
  16. Correlation between stool weight and transit time
  17. Total colonic transit.
  18. Regional colonic transit.
  19. Comparison of stool weight and transit during PEG (59 g/day) and lactulose (99 g/day) ingestion
  20. Total colonic transit.
  21. Regional colonic transit.
  22. Faecal composition in lactulose induced diarrhoea: relation between faecal composition and stool weight
  23. Relation between faecal composition and transit
  24. Factors influencing stool consistency
  25. Discussion
  26. Acknowledgement
  27. References

At 07:00 am on day 2, after an overnight fast, the volunteers swallowed a gelatine capsule containing 1 g of 111InCl3-labelled Amberlite 120 IRP resin pellets (Serva, Heidelberg, Germany) with a total radioactivity of 0.1 mCi. The capsule was coated by one layer of acid-resistant methacrylat. Previous studies have shown that capsules covered by this method release their contents in the distal ileum12 from where a bolus transports the pellets into the caecum. The position of the capsule in the gastrointestinal tract was checked by γ-camera imaging which was performed every 10 min. Imaging was performed with the subject in the upright position using a single-head large-field of view γ-camera (Elscint, Haifa, Israel) equipped with a medium-energy collimator. The time when the radiolabels were detected in the caecum for the first time was designated ‘0 h’. As soon as the capsule had left the stomach subjects ingested a standardized breakfast, consisting of 100 g white bread, 10 g butter and 225 mL orange juice. At 4 and 8 h lunch and dinner were ingested both with a standardized meal with 225 mL of orange juice and water ad libitum. Lunch had a total weight of 350 g and contained 500 kcal, 28 g protein, 39 g carbohydrates and 25 g fat. Dinner (325 g, 140 kcal, 6 g protein, 10 g carbohydrates and 9 g fat) was ingested at 8 h. With each of their meals subjects also ingested the designated amount of lactulose and PEG, respectively. Anterior and posterior images were obtained immediately after finishing breakfast. Thereafter, images were repeated in 30-min intervals until 12 h. Subjects returned to the laboratory for additional images at 24 and 36 h after the start of imaging. 111In counts were obtained at 247 keV ± 20%. Data from the scans were stored on an online computer for later analysis.

For the calculations of colonic transit times, the time when the bolus of 111Indium-labelled resin pellets had reached the caecum was considered as time 0. Data obtained at 12, 24 and 36 h, if applicable, were used for analysis. Counts were decay corrected to time 0. The geometric mean of anterior and posterior images were calculated, thus minimizing errors because of a movement of counts in the antero-posterior dimension. Counts were expressed as percentage of total abdominal counts.

Using a variable region of interest (ROI) programme counts of activity of the radiolabel were determined in four different compartments of the large intestine, i.e. caecum plus ascending colon, transverse colon, descending colon and rectosigmoid colon. Ascending and descending colonic regions were separated from the transverse colon by following the medial border of each region so as to include the hepatic and splenic flexures, respectively. The transverse colon was the sector medial to the flexures. The rectosigmoid region was defined by its junction with the descending colon in the mid-pelvic region.12, 13 Anatomical landmarks were affixed on both sides of the lower thorax. Sequential imaging of the colon provided information about the location of various regions of the colon. The ROI for the different colonic regions were drawn once and copied to the other scintigraphic images by aligning them to the anatomical landmarks (Figure 1).

image

Figure 1. Scintigraphic image of a colon filled with radioactive marker. The regions of the colon are delineated as regions of interest.

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For analysis of regional transit, the ascending colon and transverse colon were considered as ‘proximal colon’, and the descending colon and rectosigmoid colon were considered as ‘distal colon’.

When radiolabels were detected in the stool, total counts in the colon immediately after the bowel movement were subtracted from the colonic counts before the bowel movement, and the difference was considered to be the counts in this stool. ‘Transit through the whole colon’ was expressed as:

  • 1
    ‘Cumulative percentage of isotope counts’ (CC) excreted in stool at different points of time.
  • 2
    ‘Mean residency time’ in the whole colon (MRT). MRT was calculated as the area under the curve after plotting the percentage of counts in the region against time, using the formula:
    • image
    where, ΔnTn+1 is the time interval between the two consecutive images n and n + 1, 1/2 (cntn + cntn+1) is the mean percentage of counts of images n and n + 1 in the colon, and Σ is the sum of all calculations.12, 13 MRT has the advantage over the expression of transit as cumulative percentage of counts at prespecified points of time in that it provides information on transit throughout the whole 36-h observation period and as it integrates intracolonic spread of the markers.

‘Segmental colonic transit in the proximal or distal colon’ was expressed as:

  • 1
    ‘Percentage of counts that remained’ in the respective segments at different points of time.
  • 2
    ‘MRT’ of isotopes in the respective segments.

Stool collection and stool analysis

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Experimental subjects
  6. Experimental procedures
  7. Scintigraphic colonic transit measurement
  8. Stool collection and stool analysis
  9. Chemical analysis.
  10. Statistical analysis
  11. Results
  12. Effect of lactulose and PEG on stool weight and consistency
  13. Colonic transit during lactulose and PEG: effect of increasing lactulose doses on stool weight and colonic transit
  14. Total colonic transit.
  15. Regional colonic transit.
  16. Correlation between stool weight and transit time
  17. Total colonic transit.
  18. Regional colonic transit.
  19. Comparison of stool weight and transit during PEG (59 g/day) and lactulose (99 g/day) ingestion
  20. Total colonic transit.
  21. Regional colonic transit.
  22. Faecal composition in lactulose induced diarrhoea: relation between faecal composition and stool weight
  23. Relation between faecal composition and transit
  24. Factors influencing stool consistency
  25. Discussion
  26. Acknowledgement
  27. References

During lactulose ingestion stool was collected starting at 08:00 am on day 2 of the study until 08:00 am on day 3 of the study. Subjects recorded the time of each bowel movement and scored the consistency of each stool on a scale from 1 to 7 according to a modified stool description scale.13

In this stool descriptor scale ‘score 1’ is used to describe stool that appears as separate, hard lumps-like nuts, ‘score 2’ to describe sausage-shaped and lumpy stools, ‘score 3’ to describe sausage-shaped with cracked surface, ‘score 4’ to describe sausage or snaky with smooth and soft surface, ‘score 5’ to describe soft blobs with clear cut edges, ‘score 6’ to describe fluffy pieces with ragged edges and mushy consistency and ‘score 7’ is used for watery stools with no solids.

Stools which were collected during the first 12 h of the scintigraphic transit measurements were weighed, analysed for radioactivity and frozen immediately thereafter. Stools collected between 12 and 24 h were pooled and kept cooled in an ice chest. These stools were returned to the laboratory at the time of the 24-h transit measurement.

In 10 of the 12 subjects on the 99 g lactulose dose, and in three of the 10 subjects on the 67 g lactulose dose watery supernatant could be obtained by centrifugation from all collected stool samples. No stools were saved for analysis on the 134 g lactulose dose. Therefore, stool from 13 lactulose experiments could be analysed for concentration of lactulose and its monosaccharide components fructose and galactose and for lactate, acetate, butyrate and propionate.

Each individual stool sample collected by a subject was analysed separately. Output of carbohydrates and organic acids in an individual stool sample was calculated by multiplying faecal concentrations by the weight of the individual stool sample. Thereafter, daily faecal output of a subject was calculated by summing outputs in the individual stool samples.

Chemical analysis.

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Experimental subjects
  6. Experimental procedures
  7. Scintigraphic colonic transit measurement
  8. Stool collection and stool analysis
  9. Chemical analysis.
  10. Statistical analysis
  11. Results
  12. Effect of lactulose and PEG on stool weight and consistency
  13. Colonic transit during lactulose and PEG: effect of increasing lactulose doses on stool weight and colonic transit
  14. Total colonic transit.
  15. Regional colonic transit.
  16. Correlation between stool weight and transit time
  17. Total colonic transit.
  18. Regional colonic transit.
  19. Comparison of stool weight and transit during PEG (59 g/day) and lactulose (99 g/day) ingestion
  20. Total colonic transit.
  21. Regional colonic transit.
  22. Faecal composition in lactulose induced diarrhoea: relation between faecal composition and stool weight
  23. Relation between faecal composition and transit
  24. Factors influencing stool consistency
  25. Discussion
  26. Acknowledgement
  27. References

Watery supernatants of stool fluid were obtained by centrifugation after thawing of stool samples. Supernatants were filtered using Millipore filters and diluted 1:10 with high-performance liquid chromatography (HPLC)-grade water. Carbohydrates and short chain fatty acid concentrations were measured by HPLC (Merck-Hitachi, Vienna, Austria) according to previously described methods.14–16 Carbohydrates were separated on a CHO-620 column with water as mobile phase (flow rate, 0.5 mL/min; temperature, 90 °C; detection, refractive index). Short chain fatty acids were determined using an Aminex HPX-87H column (Bio-Rad Laboratories, Hercules, CA, USA) and 0.01 n H2SO4 as mobile phase (flow rate, 0.6 mL/min; temperature, 40 °C; detection, UV at 210 nm). In preliminary studies, the methods were validated in our laboratory for analysis of stool samples by demonstrating that known amounts of individual carbohydrates or short chain fatty acids, which were added, to stool samples could be reliably measured by these methods.

Effect of lactulose and PEG on stool weight and consistency

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Experimental subjects
  6. Experimental procedures
  7. Scintigraphic colonic transit measurement
  8. Stool collection and stool analysis
  9. Chemical analysis.
  10. Statistical analysis
  11. Results
  12. Effect of lactulose and PEG on stool weight and consistency
  13. Colonic transit during lactulose and PEG: effect of increasing lactulose doses on stool weight and colonic transit
  14. Total colonic transit.
  15. Regional colonic transit.
  16. Correlation between stool weight and transit time
  17. Total colonic transit.
  18. Regional colonic transit.
  19. Comparison of stool weight and transit during PEG (59 g/day) and lactulose (99 g/day) ingestion
  20. Total colonic transit.
  21. Regional colonic transit.
  22. Faecal composition in lactulose induced diarrhoea: relation between faecal composition and stool weight
  23. Relation between faecal composition and transit
  24. Factors influencing stool consistency
  25. Discussion
  26. Acknowledgement
  27. References

In six of the 10 subjects on the 67 g/day lactulose dose daily stool weight was below 200 g/day, which is considered to be the upper limit of normal stool weight. In the other 19 subjects, i.e. four subjects on 67 g/day of lactulose, 12 subjects on 99 g/day and three subjects on 134 g/day of lactulose, stool weight during the three different lactulose doses covered a range between 220 and 2150 g/day. The range of stool weights is shown in Figure 2.

image

Figure 2. Correlation between daily stool weight and mean residence time of the total (a), distal (b) or proximal (c) colon during ingestion of lactulose.

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In seven of 10 subjects on 67 g/day of lactulose and two of 12 subjects on 99 g/day stool consistency was three or lower, which is considered to be normal to hardened stool consistency. The range of stool consistency in the 16 patients with consistency of four or higher during ingestion of the three lactulose doses is shown in Figure 5.

image

Figure 5. Correlation between stool consistency and the sum of faecal outputs of carbohydrates (COH) and short chain fatty acids (SCFA) in 20 individual stool samples obtained from 13 subjects.

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All subjects who ingested PEG had stool weight in excess of 200 g/day and stool consistency of four or higher.

Regional colonic transit.

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Experimental subjects
  6. Experimental procedures
  7. Scintigraphic colonic transit measurement
  8. Stool collection and stool analysis
  9. Chemical analysis.
  10. Statistical analysis
  11. Results
  12. Effect of lactulose and PEG on stool weight and consistency
  13. Colonic transit during lactulose and PEG: effect of increasing lactulose doses on stool weight and colonic transit
  14. Total colonic transit.
  15. Regional colonic transit.
  16. Correlation between stool weight and transit time
  17. Total colonic transit.
  18. Regional colonic transit.
  19. Comparison of stool weight and transit during PEG (59 g/day) and lactulose (99 g/day) ingestion
  20. Total colonic transit.
  21. Regional colonic transit.
  22. Faecal composition in lactulose induced diarrhoea: relation between faecal composition and stool weight
  23. Relation between faecal composition and transit
  24. Factors influencing stool consistency
  25. Discussion
  26. Acknowledgement
  27. References

Counts remaining in the ‘proximal’ colon at 12 h were significantly correlated with lactulose dose (r = −0.579, P < 0.002), but counts remaining at 24 and 36 h were not correlated with lactulose dose (P > 0.05). There was no significant correlation between lactulose dose and MRT (r = −0.307, P = 0.136).

Transit time in the ‘distal’ colon was significantly faster when the lactulose dose was increased, as demonstrated by the negative correlations between lactulose dose and MRT in the distal colon (r = −0.636, P < 0.001), and the percentage of counts remaining in the distal colon at 12 (r = −0.620, P < 0.001) and 24 h (r = −0.711, P < 0.001).

Comparison of stool weight and transit during PEG (59 g/day) and lactulose (99 g/day) ingestion

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Experimental subjects
  6. Experimental procedures
  7. Scintigraphic colonic transit measurement
  8. Stool collection and stool analysis
  9. Chemical analysis.
  10. Statistical analysis
  11. Results
  12. Effect of lactulose and PEG on stool weight and consistency
  13. Colonic transit during lactulose and PEG: effect of increasing lactulose doses on stool weight and colonic transit
  14. Total colonic transit.
  15. Regional colonic transit.
  16. Correlation between stool weight and transit time
  17. Total colonic transit.
  18. Regional colonic transit.
  19. Comparison of stool weight and transit during PEG (59 g/day) and lactulose (99 g/day) ingestion
  20. Total colonic transit.
  21. Regional colonic transit.
  22. Faecal composition in lactulose induced diarrhoea: relation between faecal composition and stool weight
  23. Relation between faecal composition and transit
  24. Factors influencing stool consistency
  25. Discussion
  26. Acknowledgement
  27. References

As shown in Table 1, ingestion of 99 g/day lactulose or 59 g/day PEG resulted in similar mean stool weights of 653 ± 120 g/day and 522 ± 66 g/day, respectively. These stool weights were not significantly different.

Table 1.  Stool weight and colonic transit parameters (mean ± S.E.M.)
 Stool weight (g/day)Total colonic transitRegional colonic transit
Mean residence time (min)CC at 24 h (%)CC at 36 h (%)Mean residence time (min)
Proximal colonDistal colon
  1. ns, not significant vs. lactulose; CC, cumulative counts in stool; PEG, polyethylene glycol.

  2. P < 0.05, **P < 0.01.

Lactulose (99 g/day)653 ± 120985 ± 87.648 ± 10.178 ± 7.8582 ± 37.1403 ± 55
PEG (59 g/day)522 ± 66ns651 ± 53**85 ± 6.3*100 ± 0**491 ± 50ns160 ± 41.9**

Regional colonic transit.

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Experimental subjects
  6. Experimental procedures
  7. Scintigraphic colonic transit measurement
  8. Stool collection and stool analysis
  9. Chemical analysis.
  10. Statistical analysis
  11. Results
  12. Effect of lactulose and PEG on stool weight and consistency
  13. Colonic transit during lactulose and PEG: effect of increasing lactulose doses on stool weight and colonic transit
  14. Total colonic transit.
  15. Regional colonic transit.
  16. Correlation between stool weight and transit time
  17. Total colonic transit.
  18. Regional colonic transit.
  19. Comparison of stool weight and transit during PEG (59 g/day) and lactulose (99 g/day) ingestion
  20. Total colonic transit.
  21. Regional colonic transit.
  22. Faecal composition in lactulose induced diarrhoea: relation between faecal composition and stool weight
  23. Relation between faecal composition and transit
  24. Factors influencing stool consistency
  25. Discussion
  26. Acknowledgement
  27. References

As shown in Tables 1 and 2, there were no significant differences in MRT of the ‘proximal’ colon in PEG- and lactulose-induced diarrhoea (Table 1). Only at 36 h counts remaining in the ‘proximal’ colon were higher in lactulose when compared with PEG-induced diarrhoea (Table 2).

Table 2.  Proximal and distal colonic transit during 99 g/day lactulose or 59 g/day PEG (mean ± S.E.M.)
 Counts remaining in proximal colonCounts remaining in distal colon
12 h24 h36 h12 h24 h36 h
  1. ns, not significantly different, PEG, polyethylene glycol.

  2. P < 0.05, **P < 0.01.

Lactulose30 ± 4.217 ± 3.811 ± 3.826 ± 519 ± 4.411 ± 4.1
PEG18 ± 4ns9 ± 4.1ns0 ± 0**9 ± 5.5*4 ± 2.4*0 ± 0*

In contrast, in the ‘distal’ colon there was a marked prolongation of MRT in lactulose-induced diarrhoea when compared with PEG-induced diarrhoea; MRT was 403 ± 55 min in lactulose-induced diarrhoea and 160 ± 41.9 min in PEG-induced diarrhoea (Table 1). Counts remaining in the ‘distal’ colon were higher in lactulose than in PEG-induced diarrhoea at 12, 24 and 36 h of colonic transit measurement (Table 2).

Faecal composition in lactulose induced diarrhoea: relation between faecal composition and stool weight

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Experimental subjects
  6. Experimental procedures
  7. Scintigraphic colonic transit measurement
  8. Stool collection and stool analysis
  9. Chemical analysis.
  10. Statistical analysis
  11. Results
  12. Effect of lactulose and PEG on stool weight and consistency
  13. Colonic transit during lactulose and PEG: effect of increasing lactulose doses on stool weight and colonic transit
  14. Total colonic transit.
  15. Regional colonic transit.
  16. Correlation between stool weight and transit time
  17. Total colonic transit.
  18. Regional colonic transit.
  19. Comparison of stool weight and transit during PEG (59 g/day) and lactulose (99 g/day) ingestion
  20. Total colonic transit.
  21. Regional colonic transit.
  22. Faecal composition in lactulose induced diarrhoea: relation between faecal composition and stool weight
  23. Relation between faecal composition and transit
  24. Factors influencing stool consistency
  25. Discussion
  26. Acknowledgement
  27. References

Figure 3 shows that there was a highly significant correlation between stool weight and the sum of the outputs of carbohydrates plus short chain fatty acids (r = 0.954, P < 0.001). There were less pronounced, although still significant, correlations between 24-h stool weight and either only faecal carbohydrate output (r = 0.87, P < 0.001) or only faecal short chain fatty acid output (r = 0.66, P < 0.014). The correlations between 24-h stool weight and faecal concentrations of carbohydrates (r = 0.642, P < 0.013) or short chain fatty acids (r = 0.665, P < 0.013) were less pronounced, but still highly significant.

image

Figure 3. Correlation between daily stool weight and the sum of faecal outputs of short chain fatty acids (SCFA) and carbohydrates (COH).

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Relation between faecal composition and transit

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Experimental subjects
  6. Experimental procedures
  7. Scintigraphic colonic transit measurement
  8. Stool collection and stool analysis
  9. Chemical analysis.
  10. Statistical analysis
  11. Results
  12. Effect of lactulose and PEG on stool weight and consistency
  13. Colonic transit during lactulose and PEG: effect of increasing lactulose doses on stool weight and colonic transit
  14. Total colonic transit.
  15. Regional colonic transit.
  16. Correlation between stool weight and transit time
  17. Total colonic transit.
  18. Regional colonic transit.
  19. Comparison of stool weight and transit during PEG (59 g/day) and lactulose (99 g/day) ingestion
  20. Total colonic transit.
  21. Regional colonic transit.
  22. Faecal composition in lactulose induced diarrhoea: relation between faecal composition and stool weight
  23. Relation between faecal composition and transit
  24. Factors influencing stool consistency
  25. Discussion
  26. Acknowledgement
  27. References

Twelve hours after ingestion of lactulose there were negative correlations between faecal concentrations of short chain fatty acids and CCs of radioactivity in stool (Figure 4a, r = −0.711, P < 0.006). Short chain fatty acid concentration in 24-h stool correlated significantly with percentage of counts remaining in the distal colon at 12 h (Figure 4b, r = 0.789, P = 0.001), but no such correlation was detectable between short chain fatty acid concentration in stool and percentage of counts remaining in the distal colon at 24 h. There was no correlation between proximal colonic transit and faecal short chain fatty acid concentrations.

image

Figure 4. Correlation between faecal short chain fatty acid concentrations (SCFA) and transit time. Total colonic transit time is expressed as cumulative counts remaining in the colon at 12 h (a) and distal colonic transit time is expressed as counts in the distal colon at 12 h (b).

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There were no correlations between faecal carbohydrate concentration or output and total or regional colonic transit.

Factors influencing stool consistency

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Experimental subjects
  6. Experimental procedures
  7. Scintigraphic colonic transit measurement
  8. Stool collection and stool analysis
  9. Chemical analysis.
  10. Statistical analysis
  11. Results
  12. Effect of lactulose and PEG on stool weight and consistency
  13. Colonic transit during lactulose and PEG: effect of increasing lactulose doses on stool weight and colonic transit
  14. Total colonic transit.
  15. Regional colonic transit.
  16. Correlation between stool weight and transit time
  17. Total colonic transit.
  18. Regional colonic transit.
  19. Comparison of stool weight and transit during PEG (59 g/day) and lactulose (99 g/day) ingestion
  20. Total colonic transit.
  21. Regional colonic transit.
  22. Faecal composition in lactulose induced diarrhoea: relation between faecal composition and stool weight
  23. Relation between faecal composition and transit
  24. Factors influencing stool consistency
  25. Discussion
  26. Acknowledgement
  27. References

In 20 individual stool collections, which were obtained from the 13 subjects in whom stool analysis could be performed, stool consistency was significantly correlated with the sum of faecal carbohydrate and short chain fatty acid output in the respective stool sample (r = 0.690, P = 0.001, Figure 5). Correlations between stool consistency and either only faecal carbohydrate output (r = 0.618, P = 0.003) or only short chain fatty acid output (r = 0.557, P = 0.009) had lower correlation coefficients.

Stool consistency was also correlated significantly to MRT of the distal colon (P = 0.035), although the correlation coefficient was small (r = −0.421). There was no correlation between stool consistency and total (r = −0.369, P = 0.070) or proximal colonic MRT (r = −0.188, P = 0.367).

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Experimental subjects
  6. Experimental procedures
  7. Scintigraphic colonic transit measurement
  8. Stool collection and stool analysis
  9. Chemical analysis.
  10. Statistical analysis
  11. Results
  12. Effect of lactulose and PEG on stool weight and consistency
  13. Colonic transit during lactulose and PEG: effect of increasing lactulose doses on stool weight and colonic transit
  14. Total colonic transit.
  15. Regional colonic transit.
  16. Correlation between stool weight and transit time
  17. Total colonic transit.
  18. Regional colonic transit.
  19. Comparison of stool weight and transit during PEG (59 g/day) and lactulose (99 g/day) ingestion
  20. Total colonic transit.
  21. Regional colonic transit.
  22. Faecal composition in lactulose induced diarrhoea: relation between faecal composition and stool weight
  23. Relation between faecal composition and transit
  24. Factors influencing stool consistency
  25. Discussion
  26. Acknowledgement
  27. References

Our transit measurements in healthy subjects during ingestion of three different lactulose doses cover a wide range of bowel habits, from normal stool weight and consistency to diarrhoea. The results of these experiments allow four major conclusions:

First, lactulose results in a dose-dependent acceleration of colonic transit, both in the proximal and in the distal colon. Secondly, stool weight after ingestion of lactulose is correlated to colonic transit, but it is primarily influenced by the unabsorbed osmotic load of carbohydrates and short chain fatty acids. Thirdly, stool consistency is influenced both by stool composition and transit in the distal colon. Fourthly, at similar stool weight, colonic transit is significantly slower during lactulose when compared with PEG.

Clinical effects of laxatives are defined by stool weight and consistency. In our study, stool weight and consistency correlated both with colonic transit and with faecal composition, which is the sum of faecal carbohydrate and short chain fatty acid output. However, the correlations with output of faecal solutes were considerably better than the correlations with colonic transit. The excellent correlation between stool weight and the sum of faecal carbohydrate and short chain fatty acid output has an r2 of 0.91, which suggests that more than 90% of the variability in stool weight during ingestion of lactulose is accounted for by faecal remains of carbohydrate malabsorption. Our results therefore demonstrate that lactulose acts primarily through its osmotic activity. Acceleration of colonic transit during lactulose ingestion is secondary to increased intracolonic volume. This however is partly counteracted by slowing of transit due to short chain fatty acids.

We were very surprised by the size of the differences in colonic transit during ingestion of lactulose and PEG at doses which resulted in similar effects on stool weight. During ingestion of lactulose there was a delay in MRT of colonic contents in the distal colon by 250% when compared with PEG ingestion. MRT in the total colon after lactulose was also increased, but only by 50% when compared with PEG.

Our data suggest that short chain fatty acids play an important role in delaying distal colonic transit after ingestion of lactulose. During lactulose higher faecal short chain fatty acid concentrations were associated with longer residence time of contents in the total and in the distal colon. We can only speculate on the cause–effect relation of this correlation. Theoretically, slower transit might have allowed more time for bacteria to metabolize carbohydrates to short chain fatty acids, thereby increasing their faecal concentrations. However, we consider this unlikely because Lewis and Heaton have reported that slower colonic transit due to ingestion of loperamide resulted in a decrease of faecal short chain fatty acid concentration,17 presumably because of more efficient absorption of the acids.

The other explanation for the association between longer distal colonic transit time and higher faecal short chain fatty acid concentration is that short chain fatty acids had an inhibitory effect on motility in the distal colon. We consider this explanation more likely because a dose-dependent reduction of colonic activity because of short chain fatty acids has been demonstrated in a rat model.18 In addition, ingestion of PEG, which results in very low faecal short chain fatty acid concentration,2, 4 was associated with considerably faster colonic transit in the current study. We can, however, not exclude the possibility that soluble cations which accompany anionic short chain fatty acids, like calcium2, also may have had a slowing effect on distal colonic transit.

The observation that proximal colonic transit was only marginally influenced by lactulose when compared with PEG, and that short chain fatty acid concentration did not correlate with proximal colonic transit, may not be interpreted as suggesting less of an influence of lactulose and short chain fatty acids in the proximal colon. In contrary, because osmotic load to the proximal colon was up to six times higher after 99 g/day lactulose when compared with 59 g/day PEG we would have expected proximal colonic transit after this lactulose dose to be considerably faster when compared with PEG. Since this was not the case, this suggests that there were pronounced lactulose-specific effects also in the proximal colon. The lack of correlation between proximal colonic transit and faecal short chain fatty acid concentration does not exclude a relation between these two parameters. It is possible that this lack of correlation is due to additional bacterial short chain fatty acid production and mucosal absorption in the more distal parts of the colon, which had obscured correlations between luminal short chain fatty acids and transit in the more proximal parts of the colon. The fact that there was hardly any effect of increasing lactulose doses on transit in the proximal colon may suggest that already at the lowest dose of lactulose storage capacity of the proximal colon was beyond its limits.

The inhibitory effects of short chain fatty acids on colonic transit which are suggested by our data deserve further evaluation for their possible clinical role in the pathogenesis and treatment of slow transit constipation. Short chain fatty acids are metabolic products of bacterial metabolism of dietary fibres, which, because of their bulking effect and the presumed acceleration of colonic transit,19 are a first-line treatment of constipation. Our data raise to hypothesis that treatment failure of dietary fibres could be related to inhibitory effects of short chain fatty acids on transit in some susceptible patients.

Although there was a male preponderance in our study, the main conclusions about the effect of lactulose and PEG on colonic transit should not be affected by this. However, clinical studies in patients with constipation which will further evaluate the effect of these laxatives on colonic transit will have to take into consideration the higher prevalence of constipation in female patients.6

In conclusion, our studies in normal subjects extend what is currently known about the effects of osmotic laxatives. They provide further explanation for the previously described2 non-linear dose–effect curve of lactulose, in that bacterial metabolism of lactulose and absorption of its metabolic products do not only result in a reduction of the osmotic load, but also have slowing effects on colonic transit, which in turn may result in increased time for bacterial metabolism and mucosal absorption. Future studies in patients with different pathophysiological mechanisms of constipation will have to explore whether the effects of lactulose on motility are relevant to its use in some of these patients and whether in clinical practice, the previously described linear dose–response relation of PEG may make treatment effects better predictable.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Experimental subjects
  6. Experimental procedures
  7. Scintigraphic colonic transit measurement
  8. Stool collection and stool analysis
  9. Chemical analysis.
  10. Statistical analysis
  11. Results
  12. Effect of lactulose and PEG on stool weight and consistency
  13. Colonic transit during lactulose and PEG: effect of increasing lactulose doses on stool weight and colonic transit
  14. Total colonic transit.
  15. Regional colonic transit.
  16. Correlation between stool weight and transit time
  17. Total colonic transit.
  18. Regional colonic transit.
  19. Comparison of stool weight and transit during PEG (59 g/day) and lactulose (99 g/day) ingestion
  20. Total colonic transit.
  21. Regional colonic transit.
  22. Faecal composition in lactulose induced diarrhoea: relation between faecal composition and stool weight
  23. Relation between faecal composition and transit
  24. Factors influencing stool consistency
  25. Discussion
  26. Acknowledgement
  27. References
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    Hammer HF, Santa CA, Schiller LR, Fordtran JS. Studies of osmotic diarrhea induced in normal subjects by ingestion of polyethylene glycol and lactulose. J Clin Invest 1989; 84: 105662.
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    Benson JR, Woo DJ. Polymeric columns for liquid chromatography. J Chromatogr Sci 1984; 22: 38699.
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    Delahunty T, Hollander D. Liquid-chromatographic method for estimating urinary sugars: applicability to studies of intestinal permeability. Clin Chem 1986; 32: 15424.
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    Lewis SJ, Heaton KW. Increasing butyrate concentration in the distal colon by accelerating intestinal transit. Gut 1997; 41: 24551.
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    Squires PE, Rumsey RDE, Edwards CA, Read NW. Effect of short chain fatty acids on contractile activity and fluid flow in rat colon in vitro. Am J Physiol 1992; 262: G8137.
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    Ashraf W, Park F, Lof J, Quigley EM. Effects of psyllium therapy on stool characteristics, colon transit and anorectal function in chronic idiopathic constipation. Aliment Pharmacol Ther 1995; 9: 63947.