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Effect of Fructooligosaccharides Supplementation on the Gut Microbiota in Human: A Systematic Review and Meta-Analysis.
Dou, Y, Yu, X, Luo, Y, Chen, B, Ma, D, Zhu, J
Nutrients. 2022;14(16)
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Fructooligosaccharide is a prebiotic fibre that undergoes fermentation in the gut, due to which it can cause gas and bloat. Additionally, this prebiotic fibre ferments to produce short-chain fatty acids, which are beneficial for the body. This systematic review and meta-analysis included eight randomised controlled trials investigating the effects of fructooligosaccharide on gut microbial composition. Short-term supplementation with fructooligosaccharide altered the gut’s microbial composition without causing any adverse effects. Bifidobacterium spp. levels were elevated in those who consumed fructooligosaccharide supplements than those who did not. Supplementation with fructooligosaccharide did not significantly change harmful bacteria such as Bacteroides and Enterobacteriaceae levels. In addition, a higher dosage of 7.5–15 g/d of fructooligosaccharide supplementation for a period of more than four weeks was found to be beneficial. Healthcare professionals can use these results to understand better how fructooligosaccharide modulates beneficial gut bacteria such as Bifidobacterium spp. However, there is a need for more robust studies since the number of currently available studies is limited, and the exact health implications of fructooligosaccharide supplementation need to be evaluated further.
Abstract
Background: Numerous studies have investigated the effects of the supplementation of fructooligosaccharides (FOS) on the number of bacteria in the gut that are good for health, but the results have been inconsistent. Additionally, due to its high fermentability, supplementation of FOS may be associated with adverse gastrointestinal symptoms such as bloating and flatulence. Therefore, we assessed the effects of FOS interventions on the composition of gut microbiota and gastrointestinal symptoms in a systematic review and meta-analysis. Design: All randomized controlled trials published before 10 July 2022 that investigated the effects of FOS supplementation on the human gut microbiota composition and gastrointestinal symptoms and met the selection criteria were included in this study. Using fixed or random-effects models, the means and standard deviations of the differences between the two groups before and after the intervention were combined into weighted mean differences using 95% confidence intervals (CIs). Results: Eight studies containing 213 FOS supplements and 175 controls remained in this meta-analysis. Bifidobacterium spp. counts significantly increased during FOS ingestion (0.579, 95% CI: 0.444-0.714) in comparison with that of the control group. Subgroup analysis showed greater variation in Bifidobacterium spp. in adults (0.861, 95% CI: 0.614-1.108) than in infants (0.458, 95% CI: 0.297-0.619). The increase in Bifidobacterium spp. counts were greater in the group with an intervention duration greater than 4 weeks (0.841, 95% CI: 0.436-1.247) than an intervention time less than or equal to four weeks (0.532, 95% CI: 0.370-0.694), and in the group with intervention doses > 5 g (1.116, 95% CI: 0.685-1.546) the counts were higher than those with doses ≤ 5 g (0.521, 95% CI: 0.379-0.663). No differences in effect were found between FOS intervention and comparators in regard to the abundance of other prespecified bacteria or adverse gastrointestinal symptoms. Conclusions: This is the first meta-analysis to explore the effect of FOS on gut microbiota and to evaluate the adverse effects of FOS intake on the gastrointestinal tract. FOS supplementation could increase the number of colonic Bifidobacterium spp. while higher dose (7.5-15 g/d) and longer duration (>4 weeks) showed more distinct effects and was well tolerated.
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A Low-FODMAP Diet Provides Benefits for Functional Gastrointestinal Symptoms but Not for Improving Stool Consistency and Mucosal Inflammation in IBD: A Systematic Review and Meta-Analysis.
Peng, Z, Yi, J, Liu, X
Nutrients. 2022;14(10)
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The low-FODMAP diet eliminates carbohydrates that cannot be easily digested in order to reduce functional gastrointestinal symptoms associated with irritable bowel disease (IBD). The symptoms of irritable bowel disease include abdominal pain and bloating. This systematic review and meta-analysis aimed to evaluate whether a low-FODMAP diet can alleviate functional gastrointestinal symptoms in individuals with inflammatory bowel disease. In comparison with a regular diet, a low-FODMAP diet significantly reduced symptoms of bloating, wind, flatulence, abdominal pain, fatigue, and lethargy in patients with IBD. In addition, patients with Crohn's disease have achieved remission or reduced symptoms after following a low-FODMAP diet. Healthcare professionals can use this study to understand better the effects of a low-FODMAP diet on patients with IBD who have functional gastrointestinal symptoms. Further robust studies are, however, required to evaluate the evidence's robustness and identify the mechanism behind the improvement of symptoms.
Expert Review
Conflicts of interest:
None
Take Home Message:
- LFD use in IBD improved symptoms of bloating, wind or flatulence, borborygmi, abdominal pain, and fatigue or lethargy, but not nausea and vomiting.
Evidence Category:
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A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
Introduction
This meta-analysis assesses the efficacy of a low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols diet (LFD) in inflammatory bowel disease [IBD: ulcerative colitis (UC) and Crohn’s disease (UC)] participants with functional gastrointestinal symptoms (FGSs).
Methods
A search was performed on PubMed, Web of Science, EMBASE, Cochrane Central Register of Controlled Trials, Chinese National Knowledge Infrastructure (CNKI), WanFang (Chinese) Database up to March 2022. Quality assessment of all included studies was performed.
Results
9 studies (4 randomised controlled trials, 5 non-randomised studies) with a total of 351 participants diagnosed with IBD were included, and compared LFD with a placebo diet or normal diet (ND), overall and individual
LFD Effects of FGS:
- Overall 9 studies: an improvement (0.47, 0.33–0.66, p = 0.0000)
- No difference in the subgroup classified by disease type
- CD and UC: no improvement
Individual improvement:
- Bloating (0.37, 0,24-0,57, p=0.0000); wind or flatulence (0.38, 0,28-0,51, p=0.0000); borborygmi (0.48, 0,26-0,89, p=0.0000), abdominal pain (0.5, 0,37-0,68, p=0.0000), fatigue/lethargy (0.71, 0,61-0,82, p=0.0000)
- No difference in nausea and vomiting (0.54, 0,22-1,32, p=018)
IBS Quality of Life Score:
- 2 studies: reduced Short IBD Questionnaire (SIBDQ) score (11.24, 6.61-15.87, p=0.0000)
Bristol Stool Form Chart:
- 2 studies: normal stool consistency (type 3-4); no difference (5.99, 0.17-216.51, p=0.33)
- 2 other studies: no difference (-0.17, 0.48 - 0.15, p=0.30)
Diseases activity (Harvey-Bradshaw index):
- 2 studies using the Mayo score: no difference (-32, -1,09-0.45, p=0.41)
- 3 studies using BHi score: reduction (-1.09, -1,77-0.42, p=0.002)
Faecal calprotectin:
- 2 studies: no change (-16.03, -36,78-4.73, p=0.13)
Limitations
- Comparison diets were not standardised, suggesting the potential of different dietary habits to bias results..
- Heterogeneity of included studies, and the relatively small sample size of the studies can reduce the reliability of the results.
Conclusion
While the study found inconsistent definition standards for FGS, all the nine studies showed that LFD was associated with an improvement in some symptoms.
Clinical practice applications:
- This study suggests that IBD patients with FGSs may benefit from LFD treatment with the assistance of a healthcare professional.
Considerations for future research:
- This study has shown that LFD can improve FGSs in IBD, but further research with a larger sample size and more comprehensive analysis is warranted to replicate the results.
- The description of the findings and Quality of Life data are a little unclear. The impact on Quality of Life warrants further investigation, as clinicians need to consider the impact of following a restrictive diet on Quality of Life.
Abstract
BACKGROUND A low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols diet (LFD) is claimed to improve functional gastrointestinal symptoms (FGSs). However, the role of LFD in inflammatory bowel disease (IBD) patients with FGSs remains unclear. OBJECTIVE To systematically assess the efficacy of LFD in IBD patients with FGSs. METHODS Six databases were searched from inception to 1 January 2022. Data were synthesized as the relative risk of symptoms improvement and normal stool consistency, mean difference of Bristol Stool Form Scale (BSFS), Short IBD Questionnaire (SIBDQ), IBS Quality of Life (IBS-QoL), Harvey-Bradshaw index (HBi), Mayo score, and fecal calprotectin (FC). Risk of bias was assessed based on study types. A funnel plot and Egger's test were used to analyze publication bias. RESULTS This review screened and included nine eligible studies, including four randomized controlled trials (RCTs) and five before-after studies, involving a total of 446 participants (351 patients with LFD vs. 95 controls). LFD alleviated overall FGSs (RR: 0.47, 95% CI: 0.33-0.66, p = 0.0000) and obtained higher SIBDQ scores (MD = 11.24, 95% CI 6.61 to 15.87, p = 0.0000) and lower HBi score of Crohn's disease (MD = -1.09, 95% CI -1.77 to -0.42, p = 0.002). However, there were no statistically significant differences in normal stool consistency, BSFS, IBS-QoL, Mayo score of ulcerative colitis, and FC. No publication bias was found. CONCLUSIONS LFD provides a benefit in FGSs and QoL but not for improving stool consistency and mucosal inflammation in IBD patients. Further well-designed RCTs are needed to develop the optimal LFD strategy for IBD.
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Improvement in Gastrointestinal Quality of Life Index (GIQLI) following meditation: An open-trial pilot study in India.
Kanchibhotla, D, Sharma, P, Subramanian, S
Journal of Ayurveda and integrative medicine. 2021;12(1):107-111
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Gut health is a complex phenomenon, consisting of micro and macro integrity of various gastrointestinal organs from oesophagus to the rectum, allowing us to eat and digest without discomfort. The aim of this study was to investigate the improvement in gut health and gastrointestinal quality of life with the regular practice of a novel meditation called the Vaishvanara Agni meditation (VAM). This study was an open-trial single-arm, pre-post pilot study. Of all the 80 participants enrolled for the study, 54 participants completed the assessments at all three time points, and were considered for data analysis. Results indicate an overall improvement in the quality of life with regular practice of Vaishvanara Agni meditation. In fact, regular practice of VAM not only improved the physical strength and digestion of the individual, but also contributed to their mental, emotional and social health. Authors conclude that meditation practices which focus on improving digestion can be an effective tool for improving gut health.
Abstract
BACKGROUND Medical science is increasingly recognizing the role of gut health in achieving optimal wellbeing. A healthy gut improves digestion. Additionally, it has a positive impact on multiple physiological networks such as immune system, central nervous system and hepato-endocrine system, thus contributing to the overall quality of life. Functional gastrointestinal disorders: also known as disorders of gut-brain interaction, such as irritable bowel syndrome are increasing worldwide. Conditions like stress, anxiety and mental disorders are correlated with these disorders. Mind-body interventions have been shown to ameliorate stress, anxiety and related conditions that may aggravate functional gastrointestinal disorders. OBJECTIVE The present study aims to investigate the benefits of a novel meditation technique called the Vaishvanara Agni meditation (VAM) on the gastrointestinal quality of life. MATERIALS AND METHODS 54 subjects participated in the study and practiced VAM for 50 days. During the Vaishvanara Agni meditation (VAM), attention is directed to the navel region and the digestive system. The effect of the meditation was evaluated using the gastrointestinal quality of life (GI-QoL) questionnaire, which was administered to subjects at three different time points i.e. day 0, day 24 and day 50. RESULTS GI-QoL was significantly improved with the practice of VAM. Additionally, significant improvements were noticed in all sub domains especially core symptoms, physical strength and the psychological domain. CONCLUSION Meditation practices that focus on improving digestion can be an effective tool for improving gut health.
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Exposure to Different Amounts of Dietary Gluten in Patients with Non-Celiac Gluten Sensitivity (NCGS): An Exploratory Study.
Roncoroni, L, Bascuñán, KA, Vecchi, M, Doneda, L, Bardella, MT, Lombardo, V, Scricciolo, A, Branchi, F, Elli, L
Nutrients. 2019;11(1)
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Non-coeliac gluten sensitivity (NCGS) is characterised by adverse gastrointestinal symptoms related to ingestion of gluten-containing foods and amelioration of symptoms when gluten is removed from the diet. It is currently unclear whether gluten sensitivity is a permanent condition. The aim of this exploratory study was to evaluate the effects of gluten re-introduction in 22 NCGS patients who have been on a strict gluten-free diet for three weeks. Working with a qualified nutritionist, participants began incrementally introducing gluten each week for three weeks. Gastrointestinal symptoms and quality of life were assessed at baseline and post-intervention. When adverse symptomology was reported, participants returned to the gluten-level before symptoms started. This study found mixed results with gluten reintroduction. Of the 22 participants, 8 were able to return to a normal gluten-containing diet, and the remaining participants had differing levels of tolerance for gluten consumption. Based on these results, the authors conclude further controlled studies are required to assess the clinical response of reintroducing dietary gluten in patients with NCGS.
Abstract
It is unclear whether patients with non-celiac gluten sensitivity (NCGS) can tolerate gluten. We have evaluated the changes of both gastrointestinal symptoms and quality of life for NCGS patients after the re-introduction of dietary gluten. Twenty-two NCGS patients reporting functional gastroenterological symptoms and on gluten-free diet (GFD) for the previous three weeks were exposed to incremental gluten-containing diets. Three groups were compared at baseline (immediately after 3-weeks on GFD) and immediately after the return of symptomatology: (i) a group tolerating a low-gluten diet (3.5 g gluten/day, week 1, n = 8), (ii) a group tolerating a mid-gluten diet (8 g gluten/day, week 2, n = 6), and (iii) a group tolerating a high-gluten diet (13 g gluten/day, week 3, n = 8). Their gastrointestinal symptoms and quality of life were assessed at baseline and post-intervention. The most common symptoms were: constipation (46%), abdominal pain (50%) and dyspepsia (38%). A decrease in several short form health survey (SF-36) sub-scores (all p < 0.03) after gluten re-introduction was only observed in the group tolerating the low-gluten diet; the same group showed a lower post-intervention role-emotional SF-36 score (p = 0.01). Most gastrointestinal symptoms remained similar after gluten re-introduction. However, a decrease in the general perception of well-being was only found after gluten re-introduction in the group tolerating a low-gluten diet (p = 0.01); the same was true when comparing the post-intervention general well-being perception among the three groups (p = 0.050). In conclusion, dissimilar responses from patients with NCGS were observed after the re-introduction of gluten, with gluten at a low dosage affecting the quality of life and general well-being of a group of patients, whereas others tolerate even higher doses of dietary gluten.
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Systematic review: probiotics in the management of lower gastrointestinal symptoms - an updated evidence-based international consensus.
Hungin, APS, Mitchell, CR, Whorwell, P, Mulligan, C, Cole, O, Agréus, L, Fracasso, P, Lionis, C, Mendive, J, Philippart de Foy, JM, et al
Alimentary pharmacology & therapeutics. 2018;47(8):1054-1070
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The role of the gut microbiota in health and disease is far reaching and there is a growing body of evidence on the therapeutic potential of probiotics in gastrointestinal (GI) disease. Patients with GI disease present with a variety of symptoms and current evidence suggests probiotics may play a role in ameliorating these adverse symptoms. The purpose of this review is to update the previous systematic review and incorporate new findings on the role of probiotics in adult patients presenting with a variety of GI symptoms. Based on the updated evidence, this study confirms the finding that specific probiotics are beneficial for certain lower GI problems. According to this review, the author deems this study useful for clinicians when recommending probiotics to patients.
Abstract
BACKGROUND In 2013, a systematic review and Delphi consensus reported that specific probiotics can benefit adult patients with irritable bowel syndrome (IBS) and other gastrointestinal (GI) problems. AIM: To update the consensus with new evidence. METHODS A systematic review identified randomised, placebo-controlled trials published between January 2012 and June 2017. Evidence was graded, previously developed statements were reassessed by an 8-expert panel, and agreement was reached via Delphi consensus. RESULTS A total of 70 studies were included (IBS, 34; diarrhoea associated with antibiotics, 13; diarrhoea associated with Helicobacter pylori eradication therapy, 7; other conditions, 16). Of 15 studies that examined global IBS symptoms as a primary endpoint, 8 reported significant benefits of probiotics vs placebo. Consensus statements with 100% agreement and "high" evidence level indicated that specific probiotics help reduce overall symptom burden and abdominal pain in some patients with IBS and duration/intensity of diarrhoea in patients prescribed antibiotics or H. pylori eradication therapy, and have favourable safety. Statements with 70%-100% agreement and "moderate" evidence indicated that, in some patients with IBS, specific probiotics help reduce bloating/distension and improve bowel movement frequency/consistency. CONCLUSIONS This updated review indicates that specific probiotics are beneficial in certain lower GI problems, although many of the new publications did not report benefits of probiotics, possibly due to inclusion of new, less efficacious preparations. Specific probiotics can relieve lower GI symptoms in IBS, prevent diarrhoea associated with antibiotics and H. pylori eradication therapy, and show favourable safety. This study will help clinicians recommend/prescribe probiotics for specific symptoms.
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Saccharomyces cerevisiae CNCM I-3856 in irritable bowel syndrome: An individual subject meta-analysis.
Cayzeele-Decherf, A, Pélerin, F, Leuillet, S, Douillard, B, Housez, B, Cazaubiel, M, Jacobson, GK, Jüsten, P, Desreumaux, P
World journal of gastroenterology. 2017;23(2):336-344
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Irritable bowel syndrome (IBS) is a digestive disorder with various symptoms, affecting a significant number of the population. Gut bacteria are known to play a role in triggering the syndrome and research is exploring the manipulation of the gut microbiome in treating and managing symptoms. One yeast strain of interest is Saccharomyces Cerevisiae CNCM-I 3856. This meta-analysis of 2 randomised controlled trial, including 579 patients diagnosed with IBS, aimed to confirm previous conclusions on the effectiveness of supplementation of Saccharomyces Cerevisiae on typical IBS-C (constipation predominant IBS) symptoms. The pooled results showed a statistically significant improvement in abdominal pain, bloating and stool consistency when compared to placebo, after 2 months. It is important to note that positive effects were not reported after 1 month, but required 2 months of supplementation. When compiling nutrition protocols for IBS patients, Nutrition Practitioners need to take account of the length of intervention required to have the desired impact, as well as the choice of protocol itself.
Abstract
AIM: To confirm previous conclusions on Saccharomyces cerevisiae (S. cerevisiae) CNCM I-3856 for irritable bowel syndrome (IBS) management. METHODS An individual patient data meta-analysis was performed on two randomized clinical trials studying the effect of S. cerevisiae CNCM I-3856 supplementation on gastrointestinal (GI) symptoms in IBS subjects. A total of 579 IBS subjects were included. Outcomes were the daily Likert scale scores of abdominal pain/discomfort and bloating [area under the curve (AUC) and weekly means], responder status, and bowel movements (stool frequency and consistency). Statistical analyses were conducted in Intent to Treat (ITT) population, IBS-C subjects and IBS-C subjects with an abdominal pain/discomfort score higher than or equal to 2 at baseline ("IBS-C ≥ 2 subpopulation"). RESULTS S. cerevisiae CNCM I-3856 significantly improved abdominal pain/discomfort and bloating during the second month of supplementation [AUC (W5-W8)] with improvement up to the minimal clinically relevant threshold of 10%: a 12.3% reduction of abdominal pain/discomfort in the ITT population compared to the Placebo group (P = 0.0134) has been observed. In the IBS-C ≥ 2 subpopulation, there were a 13.1% reduction of abdominal pain/discomfort and a 14.9% reduction of bloating compared to the Placebo group (P = 0.0194 and P = 0.0145, respectively). GI symptoms significantly decreased during supplementation but no statistical differences were reported between groups at the end of the supplementation period. Responder status was defined as a subject who experienced a decrease of 1 arbitrary unit (a.u.) or 50% of the abdominal discomfort score from baseline for at least 2 wk out of the last 4 wk of the study. A significant difference between groups was reported in the ITT population, when considering the first definition: subjects in the Active group had 1.510 higher odds to be a responder (reduction of 1 a.u. of abdominal pain/discomfort) compared with subjects in the Placebo group (P = 0.0240). At the end of supplementation period, stool consistency in the Active group of the ITT population was significantly improved and classified as "normal" compared to Placebo (respectively 3.13 ± 1.197 a.u. vs 2.58 ± 1.020 a.u., P = 0.0003). Similar results were seen in the IBS-C ≥ 2 subpopulation (Active group: 3.14 ± 1.219 a.u. vs Placebo group: 2.59 ± 1.017 a.u., P = 0.0009). CONCLUSION This meta-analysis supports previous data linking S. cerevisiae I-3856 and improvement of GI symptoms, in IBS overall population and in the IBS-C and IBS-C ≥ 2 subpopulations.
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Nucleotide supplementation: a randomised double-blind placebo controlled trial of IntestAidIB in people with Irritable Bowel Syndrome [ISRCTN67764449].
Dancey, CP, Attree, EA, Brown, KF
Nutrition journal. 2006;5:16
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Nucleotides are the building blocks of DNA and RNA. Dietary sources of nucleotides are found to varying degrees in many foods – lamb, liver, mushrooms (but not fruit and other vegetables) all are rich in nucleotides. Giving nucleotide supplements to infants has been shown to reduce the incidence and duration of diarrhoea, and animal studies show structural improvements in the intestines when nucleotide supplementation is given. The aim of this study was to test the hypothesis that nucleotide supplements would improve symptoms in people with Irritable Bowel Syndrome (IBS). Thirty-seven people with an IBS diagnosis took part in the study. Participants were asked to rate the severity of their IBS symptoms before and throughout the study period, and psychological measures (anxiety, depression, illness intrusiveness and general health) were also assessed. Participants were assigned to either placebo (56 days) followed by supplement (56 days) or the reverse. The supplement given was IntestAidIB which contained: nucleotides & RNA (concentrated extracts of Saccharomyces cerevisae), hydroxypropyl methylcellulose, FOS (fructo-oligosaccharides), Methionine, Glutamine, Inositol, Lysine, Pantothenic acid (Vitamin B5 as Calcium d-pantothenate), Sodium citrate, Riboflavin (Vitamin B2), Vanillin, Folic acid, and Biotin. The supplement improved the severity of all IBS symptoms, apart from diarrhoea, more than the placebo. Symptom improvement ranged from 4 - 6%. A feeling of incomplete evacuation and abdominal pain showed the most improvement and were statistically significant. The differences between groups for diarrhoea, bloating and flatulence were not significant. Although the improvements in symptoms were consistent, the effects were not strong, and the psychological measures showed no improvement. The authors concluded that dietary nucleotide supplementation improves some of the symptoms of IBS. Further studies need to replicate and extend these results, and clarify the mechanism by which improvements occur.
Abstract
BACKGROUND Dietary nucleotide supplementation has been shown to have important effects on the growth and development of cells which have a rapid turnover such as those in the immune system and the gastrointestinal tract. Work with infants has shown that the incidence and duration of diarrhoea is lower when nucleotide supplementation is given, and animal work shows that villi height and crypt depth in the intestine is increased as a result of dietary nucleotides. Dietary nucleotides may be semi-essential under conditions of ill-health, poor diet or stress. Since people with Irritable Bowel Syndrome tend to fulfil these conditions, we tested the hypothesis that symptoms would be improved with dietary nucleotide supplementation. METHODS Thirty-seven people with a diagnosis of Irritable Bowel gave daily symptom severity ratings for abdominal pain, diarrhoea, urgency to have a bowel movement, incomplete feeling of evacuation after a bowel movement, bloating, flatulence and constipation for 28 days (baseline). They were then assigned to either placebo (56 days) followed by experimental (56 days) or the reverse. There was a four week washout period before crossover. During the placebo and experimental conditions participants took one 500 mg capsule three times a day; in the experimental condition the capsule contained the nutroceutical substances. Symptom severity ratings and psychological measures (anxiety, depression, illness intrusiveness and general health) were obtained and analysed by repeated measures ANOVAs. RESULTS Symptom severity for all symptoms (except constipation) were in the expected direction of baseline>placebo>experimental condition. Symptom improvement was in the range 4 - 6%. A feeling of incomplete evacuation and abdominal pain showed the most improvement. The differences between conditions for diarrhoea, bloating and flatulence were not significant at the p < .05 level. There were no significant differences between the conditions for any of the psychological measures. CONCLUSION Dietary nucleotide supplementation improves some of the symptoms of irritable bowel above baseline and placebo level. As expected, placebo effects were high. Apart from abdominal pain and urgency to have a bowel movement, the improvements, while consistent, are modest, and were not accompanied by improvements in any of the psychological measures. We suggest that the percentage improvement over and above the placebo effect is a physiological effect of the nucleotide supplement on the gut. The mechanisms by which these effects might improve symptoms are discussed.