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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Study design
  6. Patients
  7. Study drugs
  8. Dietary restrictions
  9. Clinical efficacy and tolerance
  10. Faecal studies
  11. Sample size and randomization
  12. Statistical analysis
  13. Results
  14. Bowel habits and symptoms
  15. Bacteriological analyses
  16. Faecal characteristics
  17. Discussion
  18. Acknowledgement
  19. References

Background : Although lactulose and polyethylene glycol are osmotic laxatives widely used in the treatment of chronic constipation, no study has been conducted to compare their actions on the colonic bacterial ecosystem, which has an important influence on host health.

Aim : To assess the effects of lactulose and polyethylene glycol on the composition and metabolic indices of the faecal flora in patients with chronic idiopathic constipation.

Methods : Sixty-five patients with chronic idiopathic constipation were included in this controlled, multi-centre, randomized, parallel-group study. Participants received lactulose (Duphalac) or polyethylene glycol-4000 (Forlax) powders for the first week at a fixed dosage at night (20 g/day); in the second week, patients were given the option to vary the dose according to efficacy and tolerance (10–30 g/day); for the last 2 weeks, treatment was administered at a fixed dosage based on the results of the second week (10–30 g/day). Stools were recovered for bacteriological analysis at days − 1, 21 and 28.

Results : Clinical efficacy and tolerance were similar with both treatments. In the lactulose group, an increase in faecal bifidobacteria counts (P = 0.04) and β-galactosidase activity (P < 0.001) was observed from day − 1 to day 28, whereas, in the polyethylene glycol group, there was a decrease in total short-chain fatty acids (P = 0.02), butyrate (P = 0.04), acetate (P = 0.02) and faecal bacterial mass (P = 0.001). No differences were observed in stools with regard to the following parameters: counts of Lactobacillus, clostridial spores, Bacteroides and enterobacteria, pH, biliary acids and neutral sterol concentrations.

Conclusions : Both lactulose and polyethylene glycol are efficacious and well tolerated. However, although lactulose can be considered as a pre-biotic in constipated patients, polyethylene glycol produces signs of decreased colonic fermentation in the stool.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Study design
  6. Patients
  7. Study drugs
  8. Dietary restrictions
  9. Clinical efficacy and tolerance
  10. Faecal studies
  11. Sample size and randomization
  12. Statistical analysis
  13. Results
  14. Bowel habits and symptoms
  15. Bacteriological analyses
  16. Faecal characteristics
  17. Discussion
  18. Acknowledgement
  19. References

Chronic idiopathic constipation is a common symptom in gastroenterology and general practice. Standard treatment includes increasing the oral intake of fibre, such as wheat bran or bulk-forming agents. Although there is some evidence from controlled trials confirming the efficacy of this treatment, high-fibre diets fail to normalize bowel habit in up to 40% of patients.1–3 In patients unresponsive or intolerant to fibre, osmotic laxatives are effective.4 Osmotic and fermentable laxatives may induce changes in colonic bacterial metabolism, which may have a beneficial influence on host health.5, 6

Lactulose is a synthetic disaccharide, not absorbed by the small intestine but readily metabolized by colonic bacteria.6 Known as an effective laxative, lactulose is prescribed in chronic constipation.7–9 In experimental studies in healthy humans, the ingestion of lactulose has been shown to lead to an increase in bifidobacterial counts10, 11 and to an inhibition of bacterial degradation of primary to secondary bile acids.12 Lactulose ingestion results in an acidification of the colonic contents,13, 14 a protective factor against colonic cancer.12 For these reasons, lactulose can also be perceived as a pre-biotic, defined as a non-digestible food ingredient that beneficially affects the host by selectively stimulating the growth and/or activity of one or a limited number of colonic bacteria; thus, a pre-biotic may improve host health.15

Polyethylene glycol (PEG)-4000 is a mixture of non-absorbable, non-metabolized polymers with a mean molecular weight of 4000 g/mol (± 10%) that acts as a pure osmotic agent. Recent data have indicated that small volumes of PEG electrolyte solution are effective for the treatment of constipation.16, 17

Lactulose and PEG are extensively prescribed in the treatment of chronic constipation, but no study has been conducted in general clinical practice to compare their actions on the faecal flora. Thus, the aim of this study was to assess the effects of lactulose and PEG on faecal flora composition and selected metabolic parameters in patients with chronic idiopathic constipation.

Study design

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Study design
  6. Patients
  7. Study drugs
  8. Dietary restrictions
  9. Clinical efficacy and tolerance
  10. Faecal studies
  11. Sample size and randomization
  12. Statistical analysis
  13. Results
  14. Bowel habits and symptoms
  15. Bacteriological analyses
  16. Faecal characteristics
  17. Discussion
  18. Acknowledgement
  19. References

The study was randomized into two parallel groups, and was carried out in three co-ordinating centres in France (Lille, Nantes and Paris). As the two treatments differed in appearance and taste, the study was blind only for the bacteriologists and biochemists, but not for the physicians and patients. Patients were treated with either PEG electrolyte solution or lactulose for 4 weeks. The trial was performed in accordance with the principles stated in the Declaration of Helsinki and was approved by the local ethics committee (Paris-Saint Louis, France). All patients gave written informed consent.

As shown in Figure 1, after the selection visit (visit 1: V1; day − 7: d−7), patients underwent a week of diet and laxative restrictions (see below), i.e. a ‘wash-out’ period (W−1), prior to randomization, in order to obtain baseline assessments. Following randomization (d0), the allocated treatment was administered for 1 week (W1) at a fixed single dose of two sachets of medication per day. In the second week (V2; d7), patients were given an option to change the dosage (variable dose), and to take one to three sachets per day, depending on the efficacy of and tolerance to the drug (W2). At visit 3 (V3; d14), the investigator changed the treatment to a fixed dosage, based on the results of the second week, for the last 2 weeks (W3 and W4). This last treatment period was terminated by the end-of-study visit (V4; d28). Stools were collected at days − 1, 21 and 28.

image

Figure 1. Design of the study.

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Patients

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Study design
  6. Patients
  7. Study drugs
  8. Dietary restrictions
  9. Clinical efficacy and tolerance
  10. Faecal studies
  11. Sample size and randomization
  12. Statistical analysis
  13. Results
  14. Bowel habits and symptoms
  15. Bacteriological analyses
  16. Faecal characteristics
  17. Discussion
  18. Acknowledgement
  19. References

Seventeen French general practitioners enrolled patients with chronic idiopathic constipation. The diagnosis was based on the Rome I diagnostic criteria of constipation, i.e. the presence for at least 6 months of less than three stools per week and/or difficulty in defecation and/or straining on passage of stool.18 Patients taking concomitant medications which may modify bowel habit were excluded, as were those suffering from severe liver, renal or cardiac diseases, and pregnant or breast-feeding women. An organic cause of constipation was excluded by the practitioner.

Study drugs

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Study design
  6. Patients
  7. Study drugs
  8. Dietary restrictions
  9. Clinical efficacy and tolerance
  10. Faecal studies
  11. Sample size and randomization
  12. Statistical analysis
  13. Results
  14. Bowel habits and symptoms
  15. Bacteriological analyses
  16. Faecal characteristics
  17. Discussion
  18. Acknowledgement
  19. References

The investigational drugs were lactulose (1-β4-galactosido-fructose) and PEG-4000 [CH2OH-(CH2-O-CH2)n-CH2OH (n is about 80)]. Both treatments were given as a soluble powder packed in 10-g sachets. Lactulose was provided by Solvay Duphar B.V. (The Netherlands) and PEG-4000 was bought from Solvay-Pharma (France). The compliance to study treatment was considered to be good if less than 20% of the prescribed study treatment sachets were returned unused.

After randomization, study treatments were taken as described above (‘Study design’ section, Figure 1). Local treatments for constipation (enema, suppositories) were allowed during the wash-out period, but patients were asked to stop these treatments 48 h before the first stool collection.

Dietary restrictions

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Study design
  6. Patients
  7. Study drugs
  8. Dietary restrictions
  9. Clinical efficacy and tolerance
  10. Faecal studies
  11. Sample size and randomization
  12. Statistical analysis
  13. Results
  14. Bowel habits and symptoms
  15. Bacteriological analyses
  16. Faecal characteristics
  17. Discussion
  18. Acknowledgement
  19. References

Throughout the study, subjects were instructed to follow their usual diet, with the exception of fermented dairy products containing viable bifidobacteria, as they have been shown to lead to an increase in faecal bifidobacteria within a few days of consumption.19 Food compliance was evaluated individually on a patient food record form.

Clinical efficacy and tolerance

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Study design
  6. Patients
  7. Study drugs
  8. Dietary restrictions
  9. Clinical efficacy and tolerance
  10. Faecal studies
  11. Sample size and randomization
  12. Statistical analysis
  13. Results
  14. Bowel habits and symptoms
  15. Bacteriological analyses
  16. Faecal characteristics
  17. Discussion
  18. Acknowledgement
  19. References

Clinical efficacy and tolerance were assessed using a daily diary card in which the patient reported the number of stools and the severity of the following symptoms: flatus, bloating, borborygmi and abdominal pain. For each symptom, a score ranging from zero (absence) to three (severe) was used.

At visits V1, V3 and V4, the investigator assessed constipation in terms of frequency, consistency and number of stools per week, straining to defecate and tolerance to treatment.

Fresh stool analysis. Stool samples from one defecation were collected the day before visits V1, V3 and V4 (days − 1, 21 and 28, respectively). They were collected in plastic containers under anaerobic conditions (Anaerocult A; Merck, Darmstadt, Germany), and immediately transferred to the laboratory using special motor-bike transporters. An aliquot was prepared and analysed within 4 h of defecation. The remaining stool samples were frozen at − 20 °C for later analysis. The fresh stool aliquot was diluted 10-fold (w/v) in an anaerobic solution (1/4 strength cysteinated Ringer diluents). After homogenization, the faecal slurry was diluted at 10 : 10 up to 10−9 in the anaerobic solution. According to the chosen genera, selective media were inoculated: total anaerobic count (Wilkins–Chalgren agar), bifidobacteria (Beerens' medium), Lactobacillus (MRS agar), enterobacteria (McConkey agar), Bacteroides (BBE agar) and clostridial spores (Wilkins–Chalgren agar inoculated with aliquots heated for 10 min at 80 °C). Plates were incubated aerobically or anaerobically as appropriate.

The pH was measured by a pH meter on a fresh stool aliquot (Bioblock, Illkirch, France).

Frozen stool analysis. Stools were thawed and blended, diluted to 1 : 3 and lyophilized. The dry weight was measured. After extraction with formylsaline (0.9% w/v NaCl and 1% v/v formalin) and sodium lauryl sulphate 10%, and after several centrifugations and filtrations, the bacterial mass was assessed.20

Bacterial enzyme activities. From the frozen aliquots, faecal enzyme activities were measured in a thermo-regulated anaerobic chamber (H2/CO2/N2 =10 : 10 : 80). Faecal samples were diluted 1 : 20 in pre-reduced phosphate-buffered saline (pH 6.7). β-Galactosidase and β-glucuronidase activities were measured by determining the rate of p-nitrophenol release from the chromogenic substrates p-nitrophenyl-β-d-galactopyranoside and p-nitro-β-d-glucuronide. A diluted faecal sample (0.2 mL) was incubated with 0.2 mL of substrate solution (5 mm). The reaction was stopped between 1 and 30 min by the addition of 1.6 mL of 0.25 mm Na2CO3. The absorbance was measured at 400 nm after centrifugation. Enzyme activities were expressed as the number of micromoles of metabolized substrate per minute and per gram of protein.

The protein concentration was determined in triplicate by the method of Lowry et al.21 on a 1 : 500 faecal dilution in Na2CO3 (2%) and NaOH (0.1 n). Bovine serum albumin was used as the standard.

Bile acids, neutral sterols and short-chain fatty acids. For the analysis of bile acids and neutral sterols, frozen stools were lyophilized and lipids were extracted with ethanol for 24 h in a Soxhlet apparatus. Lipid fractions were saponified in boiling ethanolic 2 m potassium hydroxide for 1 h. The sterols were extracted with hexane, and bile acids were deconjugated.22 Total bile acids were measured by 3-hydroxy-steroid-dehydrogenase, according to a slight modification of the technique of Stempfel and Sidbury.23 Prior to enzyme determination, bile acids were dissolved in 2-propanol. Free bile acids were methylated with diazomethane, silylated with Deriva-sil (Chrompack, Middelburg, The Netherlands) and assayed on a Carlo Erba (Milan, Italy) HGRC 5160 gas chromatograph equipped with a standard fused silica WCOT capillary column cross-linked with OV 1701 (Spiral, Dijon, France) (length, 25 m; film thickness, 0.2 µm; oven temperature, 240 °C; flow rate of hydrogen carrier gas, 2 mL/min). Faecal sterols were silylated with bis(trimethylsilyl)trifluoroacetamide (BSTFA) + 1% trimethylchlorosilane (TMCS) (Pierce, Rockford, IL, USA) and quantified using gas chromatography described above, with the following modifications: fused silica WCOT OV 101 capillary column (Spiral, Dijon, France) (length, 25 m; film thickness, 0.2 µm; oven temperature, 220 °C).

For the analysis of short-chain fatty acids, the remaining fraction was acidified (pH 2) and 5 mL was pre-treated by steam distillation, as described by Zijlstra et al.,24 before high performance liquid chromatography. The chromatography sample was injected into a pre-column (Microguard, 30 × 4.6 mm, Bio-Rads, Ivry sur Seine, France), prior to the ion exchange column (Aminex HPX-87H, 300 × 7.8 mm, Bio-Rads, Ivry sur Seine, France), with a Shimadzu LC-10AS pump (Touzard Matignon, Vitry sur Seine, France). The liquid phase was sulphuric acid (0.0025 m) with a flow rate of 0.6 mL/min. The temperature was kept at 65 °C and the UV detector (Shimadzu SPD-10A, Touzard Matignon, Vitry sur Seine, France) was calibrated for short-chain fatty acids at 210 nm.25, 26 The chromatographic data were treated by a Borwin peak integration system (EG&G Instruments, Evry, France).

Sample size and randomization

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Study design
  6. Patients
  7. Study drugs
  8. Dietary restrictions
  9. Clinical efficacy and tolerance
  10. Faecal studies
  11. Sample size and randomization
  12. Statistical analysis
  13. Results
  14. Bowel habits and symptoms
  15. Bacteriological analyses
  16. Faecal characteristics
  17. Discussion
  18. Acknowledgement
  19. References

Sample size estimation was based on a two-sided test of size α = 0.05 with power (1 − β) = 0.95. Assuming a difference between the two treatments of Δ = 2 log colony-forming units (CFU) of resistant acid flora (mainly composed of bifidobacteria and lactobacilli), and a standard deviation of σ = 2.14 units, 30 patients per treatment group would be required. Therefore, a total of 60 assessable patients was needed. Assuming that 10% of patients would have missing data, a total of 65 patients, undergoing all visits and stool collection, needed to be randomized into the study.

Treatments were assigned by randomization. The investigator gave Duphalac or Forlax 10 g to the patient after telephone contact with an operator. The operator opened a sealed envelope containing the individual randomization code. Randomization was performed within each centre with balanced blocks of patients. The randomization list was provided by Solvay Duphar B.V.

Statistical analysis

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Study design
  6. Patients
  7. Study drugs
  8. Dietary restrictions
  9. Clinical efficacy and tolerance
  10. Faecal studies
  11. Sample size and randomization
  12. Statistical analysis
  13. Results
  14. Bowel habits and symptoms
  15. Bacteriological analyses
  16. Faecal characteristics
  17. Discussion
  18. Acknowledgement
  19. References

Data quality control and statistical analysis were carried out using SAS Software, release 6.12 (SAS Institute, Cary, NC, USA). The faecal bacterial population shows a large inter-subject variation.15 Therefore, a pragmatic study in a large population of patients, selected only on the basis of constipation criteria, will tend to show an even more important inter-patient variation. Therefore, it is best to describe bacterial count changes in terms of the median, minimum and maximum, even though they were expressed in log CFU/g wet weight. The other data were expressed as means ± standard deviation (s.d.).

The nominal qualitative variables were compared using the chi-squared test, or Fisher's exact test if the validity conditions of the chi-squared test were not met. The ordinal qualitative variables were compared using the Wilcoxon rank test. The quantitative variables were compared using Student's t-test when their distribution within two groups was normal; otherwise, the Wilcoxon rank test was carried out. Repeated analysis of variance (anova) measures were performed on the treatment group, according to whether or not the data approximated to a normal distribution. The intra-group change in data was analysed using the non-parametric Friedman test in each treatment group. If the results of the Friedman test were significant, the Dunnett test was used to study the significantly different period. The symptoms reported in the patients' diary cards were described, but not analysed statistically.

All analyses were performed as intention-to-treat procedures. All statistical comparisons were made using two-sided tests with an α risk of 0.05.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Study design
  6. Patients
  7. Study drugs
  8. Dietary restrictions
  9. Clinical efficacy and tolerance
  10. Faecal studies
  11. Sample size and randomization
  12. Statistical analysis
  13. Results
  14. Bowel habits and symptoms
  15. Bacteriological analyses
  16. Faecal characteristics
  17. Discussion
  18. Acknowledgement
  19. References

From March to December 1998, 65 patients were allocated to treatment with either PEG (n = 32) or lactulose (n = 33). The numbers of patients included at the Lille, Nantes and Paris co-ordinating centres were 32, 22 and 11, respectively. The two treatment groups were well matched with regard to the clinical characteristics of constipation (Table 1).

Table 1.  Patient characteristics at selection visit (V1)
 LactulosePEGTotalP
  1. PEG, polyethylene glycol.

Number of patients333265 
Sex (male/female)4/295/279/56N.S.
Age (years), mean (s.d.)59 (18)57 (19)57 (18)N.S.
Inclusion criteria
 Mean weekly stool frequency < 3, n (%)26 (79)29 (91)55 (85)N.S.
 Difficulty in defecation (often/always), n (%)29 (88)28 (88)57 (88)N.S.
 Straining on passage of stool (often/always), n (%)21 (64)22 (69)43 (66)N.S.

The mean treatment doses after the adaptation period were 1.9 ± 0.7 and 1.9 ± 0.5 sachets/day (i.e. 19 ± 7 and 19 ± 5 g/day) for the lactulose and PEG groups, respectively (P = 0.92). Patients were compliant with the dietary instructions, as shown by their answers to questions about dietary use. Only six patients (9%) were taking concomitant treatment on entry into the study and this was stopped. At the inclusion visit, concomitant treatment was prescribed to two-thirds of patients. There was no difference between the groups with regard to concomitant treatment.

Bowel habits and symptoms

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Study design
  6. Patients
  7. Study drugs
  8. Dietary restrictions
  9. Clinical efficacy and tolerance
  10. Faecal studies
  11. Sample size and randomization
  12. Statistical analysis
  13. Results
  14. Bowel habits and symptoms
  15. Bacteriological analyses
  16. Faecal characteristics
  17. Discussion
  18. Acknowledgement
  19. References

The stool and constipation characteristics reported by the investigators from the patient interviews were not significantly different between the treatment groups at either day 14 or day 28 (Table 2). After 28 days, both treatments demonstrated laxative effects, although patients reporting fewer than or equal to three stools per week were twice as numerous in the PEG group as in the lactulose group (29% and 13%, respectively). In the last week of the study, patients reported a slight increase in daily frequency of stools in the lactulose group (from 1.06 ± 0.37 to 1.12 ± 0.33 stools per day) and in the PEG group (from 0.98 ± 0.56 to 1.26 ± 0.65 stools per day). The proportion of patients reporting at least one day with difficult/very difficult straining to defecate evolved in parallel in both groups (from 77% to 46% and from 91% to 35% in the lactulose and PEG groups, respectively). In the last week of treatment, patients in the PEG group presented mostly soft/liquid stools (60 ± 42%), whereas those in the lactulose group reported principally normal stools (42 ± 46%).

Table 2.  Changes in constipation (investigators' assessments) (mean number of patients reporting symptoms)
 Lactulose (n = 33)PEG (n = 32)P
V3 (d14) n (%)V4 (d28) n (%)V3 (d14) n (%)V4 (d28) n (%)
  1. PEG, polyethylene glycol.

Mean weekly stool frequency ≤ 37 (22)4 (13)8 (25)9 (29)N.S.
Difficulty in defecation (often/always)14 (44)6 (20)8 (25)6 (19)N.S.
Straining on passage of stool (often/always)13 (41)10 (33)14 (44)10 (32)N.S.

Patients assessed their digestive symptoms daily (Table 3). The proportion of patients reporting at least one day of moderate to severe intensity of borborygmi and bloating decreased in a similar manner in both groups. From the adverse events reported by the investigators, eight patients in the lactulose group and five in the PEG group experienced a total of 17 adverse events (P = 0.39). No serious adverse event was reported during the study. The number of premature study terminations was similar in both groups (three in the PEG group and four in the lactulose group). They all resulted from adverse events, such as abdominal pain or abdominal distension.

Table 3.  Mean number of patients reporting at least 1 day of moderate to severe intensity of digestive symptoms during the wash-out period (W−1) and the last week of treatment (W4)
 Lactulose (n = 33)PEG (n = 32)
W−1n (%)W4n (%)W−1n (%)W4n (%)
  1. PEG, polyethylene glycol.

Borborygmi17 (65)12 (46)12 (52)9 (39)
Bloating15 (58)11 (42)17 (74)10 (43)
Abdominal pain10 (38)9 (35)14 (61)6 (26)
Flatus in excess18 (69)16 (62)17 (74)15 (65)

Bacteriological analyses

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Study design
  6. Patients
  7. Study drugs
  8. Dietary restrictions
  9. Clinical efficacy and tolerance
  10. Faecal studies
  11. Sample size and randomization
  12. Statistical analysis
  13. Results
  14. Bowel habits and symptoms
  15. Bacteriological analyses
  16. Faecal characteristics
  17. Discussion
  18. Acknowledgement
  19. References

Faecal bifidobacterial counts were higher in the lactulose group than in the PEG group (P = 0.04) (Figure 2, Table 4). There was a significant increase in bifidobacteria and anaerobe counts in the lactulose group, but not in the PEG group, between days − 1 and 28 (P < 0.02). Lactobacillus, clostridia spores, Bacteroides and enterobacteria counts did not change throughout the study in either group.

image

Figure 2. Effect of lactulose and polyethylene glycol (PEG)-4000 ingestion on faecal bifidobacteria in constipated humans (n = 65, median values). CFU, colony-forming units.

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Table 4.  Faecal bacterial counts [log CFU/g wet weight: median (minimum, maximum)] in 65 constipated patients treated with lactulose or PEG (10–30 g/day) for 28 days
 Lactulose (n = 33)PEG (n = 32)P
d−1d21d28d−1d21d28
  1. CFU, colony-forming units; PEG, polyethylene glycol.

  2. a  ≠b: P < 0.02.

Anaerobes10.6 (9.3, 11.7)a11.1 (8.2, 11.7)10.9 (9.6, 11.9)b10.7 (8.6, 11.8)10.8 (8.0, 11.8)10.7 (7.5, 11.7)
Bifidobacteria8.4 (3.6, 11.2)a8.1 (4.0, 11.4)9.1 (3.9, 11.6)b8.1 (3.9, 10.8)8.1 (3.9, 10.5)7.0 (3.9, 11.0)0.04
Lactobacilli7.5 (4.7, 10.1)6.9 (3.9, 11.0)7.4 (5.1, 10.5)7.4 (4.0, 10.0)7.4 (3.8, 10.2)7.0 (4.4, 9.8)
Bacteroides9.1 (3.7, 10.2)7.7 (4.0, 10.5)9.1 (4.9, 10.7)9.4 (3.8, 10.3)9.1 (3.8, 11.3)9.1 (4.1, 10.6)
Clostridia6.0 (3.7, 8.6)5.6 (3.6, 8.9)5.7 (4.8, 8.9)5.8 (4.0, 11.0)5.8 (4.6, 8.3)5.4 (3.9, 8.3)
Enterobacteria7.7 (3.6, 10.2)7.6 (3.8, 11.1)8.0 (3.8, 10.6)7.9 (6.2, 9.6)7.4 (4.7, 10.0)7.6 (4.6, 10.2)

Proteins and enzymes. Protein concentrations (Table 5) were different between the two groups (P = 0.02), with a decrease in the PEG group (P = 0.006). β-Galactosidase activity was different between the groups (P = 0.0001), with a significant increase in the lactulose group (P < 0.0001). These changes were significant between days − 1 and 21 and days − 1 and 28 (P < 0.05). β-Glucuronidase activity did not change between the two groups throughout the study.

Table 5.  Protein concentrations (mg/g dry faeces) and enzyme activities (µmol/min per gram of protein) in 65 constipated patients treated with lactulose or PEG (10–30 g/day) for 28 days (mean ± s.d.)
 Lactulose (n = 33)PEG (n = 32)P
d−1d21d28d−1d21d28
  1. PEG, polyethylene glycol.

  2. a  ≠b: P < 0.02.

Proteins113 ± 49105 ± 41114 ± 36124 ± 50101 ± 4598 ± 360.006
β-Galactosidase activity92 ± 48a152 ± 80b154 ± 59b117 ± 76107 ± 88106 ± 760.0001
β-Glucuronidase activity5.0 ± 3.24.8 ± 2.55.1 ± 2.64.2 ± 3.04.9 ± 3.04.7 ± 2.7

Short-chain fatty acids. Total short-chain fatty acids were different between the groups (P = 0.02) (Table 6). In the PEG group, they decreased from day − 1 to 21 (P = 0.08) and from day − 1 to 28 (P = 0.02); acetate concentration decreased from day − 1 to 28 (P = 0.02) and tended to decrease from day − 1 to 21 (P = 0.06); butyrate concentration decreased from day − 1 to 28 (P = 0.04). In the lactulose group, no significant differences were noted.

Table 6.  Faecal short-chain fatty acids (SCFAs) (mmol/L) in 65 constipated patients treated with lactulose or PEG (10–30 g/day) for 28 days (mean ± s.d.)
 Lactulose (n = 33)PEG (n = 32)P
d−1d21d28d−1d21d28
  1. PEG, polyethylene glycol.

  2. a  ≠b: P = 0.02.

  3. c  ≠d: P = 0.04.

Total SCFAs58 ± 3162 ± 3458 ± 3357 ± 44a40 ± 2835 ± 25b0.02
Acetate30 ± 1732 ± 1530 ± 1631 ± 25a20 ± 1418 ± 11b
Propionate12 ± 1012 ± 911 ± 713 ± 169 ± 88 ± 7
Butyrate11 ± 612 ± 1011 ± 910 ± 9c7 ± 66 ± 5d

Biliary acids and neutral sterols. No differences were observed between the two groups throughout the study (Table 7).

Table 7.  Biliary acids and neutral sterols (mg/g dry matter) in 65 constipated patients treated with lactulose or PEG (10–30 g/day) for 28 days (mean ± s.d.)
 Lactulose (n = 33)PEG (n = 32)
d−1d21d28d−1d21d28
  1. PEG, polyethylene glycol.

Primary biliary acids2.6 ± 3.13.1 ± 3.33.7 ± 5.63.3 ± 6.53.1 ± 2. 92.8 ± 2.4
Secondary biliary acids97 ± 396 ± 396 ± 697 ± 697 ± 397 ± 2
Coprosterol74 ± 2368 ± 3277 ± 2169 ± 2965 ± 2967 ± 29
Epicoprosterol1.9 ± 1.42.0 ± 1. 81.9 ± 1.42.1 ± 2.12.6 ± 2.81.8 ± 1.7
Cholestanol1.8 ± 2.12.2 ± 2.42.3 ± 2.51.7 ± 1. 91.6 ± 1.31.4 ± 1.5
Microbial sterols78 ± 2472 ± 3381 ± 2173 ± 3069 ± 3170 ± 31
Cholesterol22 ± 2427 ± 3319 ± 2127 ± 3031 ± 3129 ± 31
Microbial sterols/cholesterol17 ± 2414 ± 3014 ± 1816 ± 2010 ± 1410 ± 14

PH, moisture content and bacterial mass. pH and moisture content did not change between the two groups throughout the study (Table 8). The bacterial mass decreased from day − 1 to 21 (P = 0.002) and from day − 1 to 28 (P = 0.001) in the PEG group.

Table 8.  pH, moisture content and bacterial mass in 65 constipated patients treated with lactulose or PEG (10–30 g/day) for 28 days (mean ± s.d.)
 Lactulose (n = 33)PEG (n = 32)
d−1d21d28d−1d21d28
  1. PEG, polyethylene glycol.

  2. a  ≠b: P < 0.01.

pH6.9 ± 0.56.8 ± 0.66.8 ± 0.66.6 ± 0.86.7 ± 0.56.9 ± 0.5
Moisture content (%)75 ± 776 ± 874 ± 671 ± 1173 ± 674 ± 7
Bacterial mass (dry wt %)56 ± 1358 ± 1362 ± 1351 ± 14a44 ± 15b43 ± 13b

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Study design
  6. Patients
  7. Study drugs
  8. Dietary restrictions
  9. Clinical efficacy and tolerance
  10. Faecal studies
  11. Sample size and randomization
  12. Statistical analysis
  13. Results
  14. Bowel habits and symptoms
  15. Bacteriological analyses
  16. Faecal characteristics
  17. Discussion
  18. Acknowledgement
  19. References

Lactulose and PEG appear to be of comparable efficacy and tolerance for the treatment of chronic idiopathic constipation in adults. The optimal doses used to obtain a clinical effect were approximately 20 g/day for both, as demonstrated previously in other studies.27, 28 Our results also showed that lactulose induced significant changes in the composition of the faecal flora, whereas PEG inhibited most of the metabolic activities of the faecal flora.

With regard to the composition of the faecal flora, we observed a significant increase in faecal bifidobacterial counts and β-galactosidase activity in the lactulose group. A bifidogenic effect of lactulose has been demonstrated previously in healthy volunteers,10, 11, 29, 30 and we can conclude that this bifidogenic effect is also expressed during constipation, where lower bifidobacterial counts have been observed (C. Neut, personal communication, 2003), such as in the elderly where constipation is more common.31–33 As extracellular β-galactosidase activity is expressed specifically by the genus Bifidobacterium, its increase observed in the lactulose group has the same significance.34, 35

With regard to the metabolic activities of the faecal flora, they remained stable in the lactulose group, and were strongly inhibited in the PEG group, as demonstrated by the significant decrease in total short-chain fatty acids, acetate, butyrate and faecal bacterial mass. As all these metabolic activities are sustained by the fermentation process,13, 36 our results corroborate that PEG does not act on constipation via intestinal flora fermentation, but through mechanical cleansing.

The maintenance of the fermentation process is probably an important determinant for health, as these reactions lead to the acidification of colonic contents. Acidification interferes with bacterial metabolism in a way that tends to be beneficial for the host, especially for the prevention of colonic cancer.37, 38 We did not find any differences in faecal pH in the two groups during treatment, but faecal pH may not accurately reflect the pH in the colon, which depends on short-chain fatty acid absorption and bicarbonate secretion.13, 14

Short-chain fatty acids are implicated in colonic physiology and, of these, butyrate arising from microbial fermentation is important for the energy metabolism and normal development of colonic epithelial cells and has mainly a protective role in relation to colonic disease.39 The long-term consequences of a decrease in production, as observed with PEG for total short-chain fatty acids, butyrate and acetate, are still unknown.

Other metabolic parameters have been studied with the aim to demonstrate a potentially beneficial effect of colonic microflora modifications. A previous study has shown that faecal bacterial β-glucuronidase activity is increased in patients on a high-meat diet, and that this enzyme can increase the amount of toxic substances, such as carcinogens, within the colonic lumen.40 This pro-carcinogenic enzyme may play a role in the metabolic activation of pro-carcinogens and in deconjugation processes in the colonic lumen.41 We failed to show an effect of lactulose or PEG on this enzyme activity, but two previous studies using lactulose at different doses have shown a decrease in this faecal bacterial enzymatic activity in healthy volunteers.10, 30 Another study using a fermentable substrate (i.e. fructo-oligosaccharides) failed to show a decrease in this enzyme activity in constipated patients.32 Thus, a specific study must be designed to assess this enzyme activity and evolution in such patients.

The percentages of biliary acids and neutral sterols did not change over the treatment period. Endogenous or exogenous bile acids and dietary cholesterol are carcinogenic factors involved in colon cancer in laboratory animals.40, 42 Various epidemiological studies have suggested that these steroids may also be involved in colon cancer in humans.43 Microbial metabolites of bile acids (secondary bile acids), mainly lithocholic and deoxycholic acids, and of cholesterol, mainly coprostanol, are particularly involved in colon cancer.44, 45 The absence of any effect on these parameters in our study could be due to the high inter- and intra-individual variations of these metabolites or to the relatively low doses of study drug used.

This study has several strengths and limitations. It is relevant in that we have addressed a practical question, i.e. the colonic functional changes that occur during the administration of two common therapies for constipation, as used in clinical general practice. We evaluated the most pertinent bacteriological and metabolic parameters in optimal, i.e. anaerobic, conditions within a very short time after defecation; special motor-bike transporters were used to transport samples to the laboratory. The issues and outcomes studied are also appropriate and of potential application in decision making for the long-term management of chronic constipation. Two limitations should be noted: (i) even though dietary restrictions were provided, fibre, lactose, fructose and other intakes were not fully controlled, which may induce bias; however, the study was randomized, and this risk was equally divided between the two groups; we also asked volunteers not to deviate dramatically from their usual diet and to exclude probiotics; moreover, many studies have shown that normal diets do not lead to significant modifications of intestinal microflora;46 (ii) some observations in stools (a decrease in short-chain fatty acids and faecal bacterial mass in the PEG group and not in lactulose group) could be due to stool dilution induced by PEG; such an interpretation is questionable, however, as the percentage moisture content did not change in the two groups.

In conclusion, this study confirms that, after 28 days of treatment of constipated patients, both lactulose and PEG are efficient and well tolerated. However, they induce different changes in the colonic microbiota, especially bifidobacteria concentrations. Although lactulose fulfils the necessary criteria to be considered as a pre-biotic in constipated patients, as well as in healthy volunteers, PEG inhibits the colonic fermentation process usually considered to be beneficial to the host. The long-term consequences of such effects are unknown and require further study.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Study design
  6. Patients
  7. Study drugs
  8. Dietary restrictions
  9. Clinical efficacy and tolerance
  10. Faecal studies
  11. Sample size and randomization
  12. Statistical analysis
  13. Results
  14. Bowel habits and symptoms
  15. Bacteriological analyses
  16. Faecal characteristics
  17. Discussion
  18. Acknowledgement
  19. References
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