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Physical Training and Healthy Diet Improved Bowel Symptoms, Quality of Life, and Fatigue in Children With Inflammatory Bowel Disease.
Scheffers, LE, Vos, IK, Utens, EMWJ, Dieleman, GC, Walet, S, Escher, JC, van den Berg, LEM
Journal of pediatric gastroenterology and nutrition. 2023;77(2):214-221
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Inflammatory bowel disease (IBD), including Crohn disease and ulcerative colitis, are chronic inflammatory diseases of the gastrointestinal tract, characterised by periods of remission and relapse of symptoms. The aim of this study was to assess the effects of a tailored lifestyle intervention on physical fitness (maximal and submaximal exercise capacity, strength, and core stability), the patient-reported outcomes (quality of life, fatigue, and fear), clinical disease activity, and nutritional status. This study was a prospective single-centre randomised semi-crossover-controlled trial. Children were randomized into group A (start exercise) or group B (start control period). Results showed improved physical fitness, quality of life, and parent-reported fatigue. Additionally, a combination of lower clinical disease activity scores accompanied by fewer IBD symptoms suggests positive effects on intestinal inflammation. Authors concluded that based on the findings of their study, children and adolescents with IBD should be motivated and supported to acquire and maintain a healthy lifestyle.
Expert Review
Conflicts of interest:
None
Take Home Message:
- IBD is a chronic inflammatory disease of the gastrointestinal tract, characterised by periods of abdominal pain, severe diarrhoea, and fatigue
- This clinical trial suggests that a 12-week program of physical training plus personalised healthy dietary advice may improve physical fitness, quality of life, and fatigue in children with IBD.
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
A randomised semi-crossover controlled trial was conducted to investigate the impact of a 12-week lifestyle program (3 physical training sessions per week plus personalised healthy dietary advice) in children with Inflammatory Bowel Disease (IBD).
Method
- Sixteen children with a median age of 15 [IQR: 12–16]) that were diagnosed with IBD (CD, UC, or IBD-unclassified) were randomized to group A (start exercise) or group B (start control period). Group A started the intervention immediately after the first assessment and did not have a control period. Group B started after a control period (this was planned to last for 6 weeks but due to the COVID-19 lockdown extended to 6 months)
- The lifestyle intervention lasted 12 weeks and consisted of 3 physiotherapist-supervised training sessions per week, lasting 60 minutes each. In addition, all participants received a recommended caloric intake per day based on measured rest energy expenditure and a brochure regarding healthy diet in children
- Endpoints were physical fitness (maximal and submaximal exercise capacity, strength, and core stability), patient-reported outcomes (quality of life, fatigue, and fears for exercise), clinical disease activity (faecal calprotectin and disease activity scores), and nutritional status (energy balance and body composition)
- A total of 15 out of 16 participants (93%) completed the program, one patient dropped out after one training session due to motivational problems.
Results
The primary findings of this study were as follows:
- While medical treatment remained unchanged, Paediatric Crohn's Disease Activity Index decreased versus the control period (15 [3–25] vs 2.5 [0–5], P = 0.012)
- The number of patients in clinical remission increased from 5 to 12 (P < 0.001), compared to the control period
- Quality of life (IMPACT-III) improved on 4 out of 6 domains and the total score (+13 points) versus the control period including a large improvement in bowel-related symptoms, P= 0.029)
- Fecal calprotectin decreased, but not compared to the control period, mainly due to relatively large intra-patient fluctuations (400 μg/g [57.1–1662.7] vs 128 μg/g [23.8–642.3], P = 0.016)
- Parents reported an improvement in the quality of life versus the control period on the child health questionnaire and total fatigue score (PedsQoL • Multidimensional Fatigue Scale) (+14 points, P = 0.048)
- Walking distance improved after the 12-week program, compared to the control period (P = 0.001).
Conclusion
This study revealed that a 12-week physical training program and personalised dietary advice improved bowel symptoms, quality of life, and fatigue in children with IBD.
Clinical practice applications:
- The mechanism behind the anti-inflammatory effects of exercise has not been clarified
- Multiple theories have been suggested in previously published studies such as a reduced release of adipokines due to less visceral fat, increased secretion of anti-inflammatory cytokines such as interleukin (IL)-6, and reduced transient stool time
- This clinical trial demonstrated that a 12-week program of physical training sessions plus personalised healthy dietary advice resulted in improved physical fitness, quality of life, and parent-reported fatigue.
Considerations for future research:
- A sample size calculation was not provided in the study report and it is therefore assumed that the sample size of 16 children in this trial was too small to draw a definite conclusion. A larger study over a longer period is therefore needed across diverse age and ethnic population groups to draw better conclusions
- This study did not measure mucosal inflammation before and after the intervention due to the invasive nature of the procedure. It would however be useful that future research investigate this to gain more insight into the effect of lifestyle interventions on IBD.
Abstract
OBJECTIVES Physical activity programs have been suggested as adjunctive therapy in adult inflammatory bowel disease (IBD) patients. We assessed the effects of a 12-week lifestyle intervention in children with IBD. METHODS This study was a randomized semi-crossover controlled trial, investigating a 12-week lifestyle program (3 physical training sessions per week plus personalized healthy dietary advice) in children with IBD. Endpoints were physical fitness (maximal and submaximal exercise capacity, strength, and core stability), patient-reported outcomes (quality of life, fatigue, and fears for exercise), clinical disease activity (fecal calprotectin and disease activity scores), and nutritional status (energy balance and body composition). Change in maximal exercise capacity (peak VO 2 ) was the primary endpoint; all others were secondary endpoints. RESULTS Fifteen patients (median age 15 [IQR: 12-16]) completed the program. At baseline, peak VO 2 was reduced (median 73.3% [58.8-100.9] of predicted). After the 12-week program, compared to the control period, peak VO 2 did not change significantly; exercise capacity measured by 6-minute walking test and core-stability did. While medical treatment remained unchanged, Pediatric Crohn's Disease Activity Index decreased significantly versus the control period (15 [3-25] vs 2.5 [0-5], P = 0.012), and fecal calprotectin also decreased significantly but not versus the control period. Quality of life (IMPACT-III) improved on 4 out of 6 domains and total score (+13 points) versus the control period. Parents-reported quality of life on the child health questionnaire and total fatigue score (PedsQoL Multidimensional Fatigue Scale) also improved significantly versus the control period. CONCLUSIONS A 12-week lifestyle intervention improved bowel symptoms, quality of life, and fatigue in pediatric IBD patients.
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The Usefulness of the Low-FODMAP Diet with Limited Tryptophan Intake in the Treatment of Diarrhea-Predominant Irritable Bowel Syndrome.
Chojnacki, C, Poplawski, T, Blonska, A, Konrad, P, Chojnacki, J, Blasiak, J
Nutrients. 2023;15(8)
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Several pathogenic factors are responsible for the occurrence of irritable bowel syndrome (IBS-D), and food products are present among them. The human diet contains various nutrients, which may have beneficial or unfavourable effects. Numerous patients with IBS attribute their abdominal symptoms to food, and in fact, certain foods ingested can cause exaggerated gastrointestinal complaints. The aim of this study was to evaluate the effect of a low-fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (known as the low-FODMAP) diet with a limitation of Tryptophan (TRP) intake on the clinical symptoms of patients with IBS-D in relation to its metabolism along the serotonin and kynurenine pathways. This study enrolled 40 healthy people (controls) and 80 patients with IBS-D. The IBS-D patients were randomly divided into two groups of 40 each (Groups IIA and IIB). In Group IIA, the low-FODMAP diet was recommended, while in Group IIB, the same diet was recommended but with limited TRP intake for 8 weeks. Results showed that: - both groups did not differ in clinical parameters or daily TRP consumption. - all IBS-D patients in both subgroups showed similar severity of abdominal complaints as well as anxiety and depressive symptoms before nutritional intervention. - reducing the amount of TRP content in a low-FODMAP diet improves its effectiveness in the treatment of IBS-D patients. Authors concluded that lowering the tryptophan content of a low-FODMAP diet may be useful in treating diarrhoea-predominant irritable bowel syndrome.
Abstract
(1) Background: A low-FODMAP diet is often recommended in the treatment of irritable bowel syndrome, but it does not improve abdominal symptoms in all patients, and an alternative diet is desirable. The purpose of this study was to evaluate the efficacy of a low-FODMAP diet with a concomitant reduction in tryptophan (TRP) intake in irritable bowel syndrome with diarrhea predominance (IBS-D) in relation to its metabolism via the serotonin and kynurenine pathways. (2) Methods: 40 healthy people (Group I, Controls) and 80 patients with IBS-D were included in the study. IBS-D patients were randomly divided into two groups of 40 each (Groups IIA and IIB). In Group IIA, the low-FODMAP diet was recommended, while in Group IIB, the same diet was recommended but with limited TRP intake for 8 weeks. The TRP intake was analyzed with the use of the nutritional calculator. Abdominal complaints were assessed using the Gastrointestinal Symptom Rating Scale (GSRS-IBS), and psychological status was simultaneously determined using two scales: the Hamilton Anxiety Scale (HAM-A) and the Hamilton Depression Scale (HAM-D). TRP and its metabolites: 5-hydoxyindoleacetic acid (5-HIAA), kynurenine (KYN), kynurenic acid (KYNA), and quinolinic acid (QA) were measured in urine using liquid chromatography tandem mass spectrometry (LC-MS/MS). (3) Results: The consumption of TRP per mg/kg/b.w./24 h has decreased in Group IIA from 20.9 ± 2.39 to 17.45 ± 2.41 (16.5%) and in Group IIB from 21.3 ± 2.33 to 14.32 (34.4%). Significantly greater improvement was found after nutritional treatment in patients in Group IIB as compared to Group IIA (GSRS score: 38.1% vs. 49.8%; HAM-A: 38.7% vs. 49.9%; HAM-D: 13.8% vs. 35.0%; p < 0.01). Reducing TRP intake showed a negative correlation with the degree of improvement in the GSRS score. (4) Conclusions: Lowering the TRP content in a low-FODMAP diet may be useful in treating IBS-D.
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Predictors of Symptom-Specific Treatment Response to Dietary Interventions in Irritable Bowel Syndrome.
Colomier, E, Van Oudenhove, L, Tack, J, Böhn, L, Bennet, S, Nybacka, S, Störsrud, S, Öhman, L, Törnblom, H, Simrén, M
Nutrients. 2022;14(2)
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Irritable bowel syndrome (IBS) is a disorder of gut-brain interaction, formerly known as a functional gastrointestinal (GI) disorder. Apart from abdominal pain, altered stool frequency, diarrhoea, and constipation, a large proportion of patients with IBS also experience other GI symptoms such as abdominal distention, bloating and flatulence. The aim of this study was to investigate predictors of treatment response to the low FODMAP (short-chain carbohydrates, i.e., fermentable oligo-, di-, monosaccharides, and polyols) and the traditional IBS diet while focusing on the four core IBS symptoms (bloating, constipation, diarrhoea, and pain). This study was a post-hoc analysis of a previously published randomised controlled trial. In total, 33 patients on low FODMAP diet and 34 patients on the traditional IBS diet were included in the analysis. Results showed that patterns of psychological, dietary, and microbial factors can predict IBS symptom response to two dietary advice systems—the traditional IBS and the low FODMAP diet. A clinical profile with less severe IBS features appears to predict a better symptom-specific response to both dietary interventions. Authors conclude that larger prospective randomised controlled trials which include different treatment approaches are required as they may help to optimize personalized treatment algorithms in IBS.
Expert Review
Conflicts of interest:
None
Take Home Message:
- Dietary intervention for IBS related symptoms was efficacious for up to 75% of patients in this study
- Recommendation for a traditional IBS dietary intervention should supersede the low-FODMAP diet, with the latter only implemented when symptoms persist.
Evidence Category:
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X
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 randomised controlled intervention study of 67 individuals fulfilling the Rome III criteria for IBS drew comparisons between the efficacy of the traditional IBS diet - as directed by the British Dietetic Association and National Institute for Health and Care Excellence (NICE) - and the low fermentable oligo-, di-, monosaccharides, and polyols (FODMAPs) diet on specific IBS-related symptoms (pain, constipation, diarrhoea, and bloating).
Methods
A 10-day screening period included faecal sample analysis, 4-day food diary (pre-randomisation and last week of intervention), and daily stool diary (Bristol Stool Form scale). After 10 days, patients compiled several GI and non-GI related questionnaires, inclusive of IBS severity scoring system (IBS-SSS). Patients who scored ≥175 for the IBS-SSS were randomly allocated to follow either a low-FODMAP or traditional IBS diet for a period of 4-weeks. Thorough explanations were provided by trained Dietitians. During intervention, patients compiled symptom questionnaires (Gastrointestinal Symptoms Rating Scale-IBS) on a weekly basis.
Results
- Both diets reduced symptoms of pain, diarrhoea and bloating (all p<0.0001), but not constipation (p=0.15)
- There was no difference between following the traditional IBS diet and low-FODMAP diet in terms of pain (p=0.80), constipation (p=0.63), diarrhoea (p=0.96) and bloating (p=0.35)
- Less severe gut dysbiosis was weakly associated with better dietary response and improvement of constipation (p=0.05)
- Higher energy intake at baseline predicted better pain improvement with both dietary types compared to lower energy intake (p=0.03)
- More severe psychological distress predicted worse intervention response for bloating (p=0.03)
- Higher baseline oligosaccharide intake predicted a worse response to the low FODMAP diet (p=0.01) but not the traditional IBS diet (p=0.16).
Conclusion
This study demonstrated that based on 4 distinct IBS-related symptomatology, better treatment response to 2 different dietary strategies was noted in patients with less severe clinical characteristics. Higher energy intake at baseline and gut dysbiosis scores that were similar to healthy controls were associated with better improvements following dietary interventions. Thus patients who already follow a calorie restricted diet and who have more significant gut dysbiosis profiles might need more bespoke intervention. Severe psychological distress patients responded worse to both diets.
Clinical practice applications:
- Even a short 4-week specific dietary intervention (low FODMAP or traditional IBS diet) can result in IBS-related symptomatic improvement for pain, bloating, and diarrhoea, but not constipation
- The preferred starting point for dietary intervention should be the traditional IBS diet given its relative ease to follow
- The more restrictive low FODMAP protocol could be considered if symptoms persist
- More bespoke interventions are required for patients who suffer with severe psychological stress, have tested and found gut dysbiosis, and individuals who already follow a restrictive diet.
Considerations for future research:
- Future studies need to include not only larger but more diverse cultural and socio-economic cohorts to ascertain the efficacy of IBS symptom-related dietary interventions
- Longer periods of intervention are needed to confirm dietary intervention efficacy.
Abstract
(1) Background: Predictors of dietary treatment response in irritable bowel syndrome (IBS) remain understudied. We aimed to investigate predictors of symptom improvement during the low FODMAP and the traditional IBS diet for four weeks. (2) Methods: Baseline measures included faecal Dysbiosis Index, food diaries with daily energy and FODMAP intake, non-gastrointestinal (GI) somatic symptoms, GI-specific anxiety, and psychological distress. Outcomes were bloating, constipation, diarrhea, and pain symptom scores treated as continuous variables in linear mixed models. (3) Results: We included 33 and 34 patients on the low FODMAP and traditional IBS diet, respectively. Less severe dysbiosis and higher energy intake predicted better pain response to both diets. Less severe dysbiosis also predicted better constipation response to both diets. More severe psychological distress predicted worse bloating response to both diets. For the different outcomes, several differential predictors were identified, indicating that baseline factors could predict better improvement in one treatment arm, but worse improvement in the other treatment arm. (4) Conclusions: Psychological, nutritional, and microbial factors predict symptom improvement when following the low FODMAP and traditional IBS diet. Findings may help individualize dietary treatment in IBS.
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Sodium Butyrate Effectiveness in Children and Adolescents with Newly Diagnosed Inflammatory Bowel Diseases-Randomized Placebo-Controlled Multicenter Trial.
Pietrzak, A, Banasiuk, M, Szczepanik, M, Borys-Iwanicka, A, Pytrus, T, Walkowiak, J, Banaszkiewicz, A
Nutrients. 2022;14(16)
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Inflammatory bowel diseases (IBD), such as Crohn’s Disease and ulcerative colitis, are chronic gastrointestinal disorders with periods of exacerbation and remission. The disease develops as a result of an abnormal immune response in the gastrointestinal mucosa in genetically predisposed individuals exposed to certain environmental conditions. The primary aim of this study was to evaluate the effectiveness of oral sodium butyrate as an add-on to standard therapy in children and adolescents with newly diagnosed IBD. This study is a prospective, randomised, and placebo-controlled trial. Patients (n = 80) were randomised and assigned to one of two groups: group A received butyric acid at a dose of 150 mg, and group B received 150 mg placebo. Results show that supplementation with sodium butyrate to be ineffective in the add-on treatment of newly diagnosed children and adolescents with IBD. Furthermore, during the study, none of the participants reported adverse events. Authors conclude that the results of their study will contribute to further studies that will determine which patients with IBD may benefit from sodium butyrate supplementation. Further clinical trials on large groups of patients are needed to establish if IBD patients may benefit from sodium butyrate.
Abstract
BACKGROUND Butyric acid's effectiveness has not yet been assessed in the pediatric inflammatory bowel disease (IBD) population. This study aimed to evaluate the effectiveness of oral sodium butyrate as an add-on to standard therapy in children and adolescents with newly diagnosed IBD. METHODS This was a prospective, randomized, placebo-controlled multicenter study. Patients aged 6-18 years with colonic Crohn's disease or ulcerative colitis, who received standard therapy depending on the disease's severity, were randomized to receive 150 mg sodium butyrate twice a day (group A) or placebo (group B). The primary outcome was the difference in disease activity and fecal calprotectin concentration between the two study groups measured at 12 weeks of the study. RESULTS In total, 72 patients with initially active disease completed the study, 29 patients in group A and 43 in group B. At week 12 of the study, the majority of patients achieved remission. No difference in remission rate or median disease activity was found between the two groups (p = 0.37 and 0.31, respectively). None of the patients reported adverse events. CONCLUSIONS A 12-week supplementation with sodium butyrate, as adjunctive therapy, did not show efficacy in newly diagnosed children and adolescents with IBD.
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Probiotic Lactobacillus casei: Effective for Managing Childhood Diarrhea by Altering Gut Microbiota and Attenuating Fecal Inflammatory Markers.
Lai, HH, Chiu, CH, Kong, MS, Chang, CJ, Chen, CC
Nutrients. 2019;11(5)
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Acute diarrhoea caused by pathogens may induce gastroenteritis (inflammation of the stomach and intestines), bloody stool, or severe intra-abdominal infections that establish disease and increase the economic burden, especially among infantile and childhood populations. The aim of the study was to determine whether probiotics (Lactobacilluscasei) inhibited gastrointestinal infection and reduced the associated inflammatory response. The study is a prospective, randomized, case-controlled study which enrolled 81 children aged between 6 months and 6 years. The participants were divided into 2 groups (Lactobacilluscasei variety rhamnosus treatment and a no probiotic control). Study results indicate that probiotics can reduce the severity and duration of diarrhoea. Furthermore, probiotic colonisation improved bowel habits and reduced abdominal pain or colic and bloating. Authors conclude that the efficacy of probiotic preparations for the treatment of acute childhood diarrhoea is related to individual bacteria strains. Thus, the population and modulation of intestinal gut/probiotic bacteria can be restored through the reduction of intestinal inflammatory reactions.
Abstract
BACKGROUND Acute diarrhea is a major cause of childhood morbidity and an economic burden for families. The aim of this study is to explore the effect of probiotics on clinical symptoms, intestinal microbiota, and inflammatory markers during childhood diarrhea. METHODS Children (n = 81) aged six months to six years (mean age 2.31 years) hospitalized for acute diarrhea were randomized to receive probiotics (Lactobacillus casei variety rhamnosus; n = 42) or no probiotics (n = 39) orally twice daily for seven days. Feces samples were also collected to evaluate microbial content using a traditional agar plate and next-generation sequencing. Immunoglobulin A (IgA), lactoferrin, and calprotectin were determined by enzyme-linked immunosorbent assay (ELISA) and compared in different groups. Other clinical symptoms or signs, including fever, vomiting, diarrhea, abdominal pain, bloated abdomen, daily intake, appetite, and body weight were also assessed. RESULTS Data were collected from 81 individuals across three different time points. Total fecal IgA levels in fecal extracts of the probiotics group were higher than those in the control group, reaching statistical significance (p < 0.05). Concentrations of fecal lactoferrin and calprotectin were significantly downregulated in patients with probiotic Lactobacillus casei variety rhamnosus (Lc) consumption compared to those of the control (p < 0.05). Probiotic Lc administration may be beneficial for gut-microbiota modulation, as shown by the data collected at one week after enrollment. Counts of Bifidobacteria and Lactobacillus species were elevated in stool culture of the probiotic group. Appetite and oral intake, body-weight gain, abdominal pain, bloating, as well as bowel habits (diarrhea) were much better in children receiving probiotics compared with those in the control group. CONCLUSION Fecal IgA increased during acute diarrhea under Lc treatment; in contrast, fecal lactoferrin and calprotectin were downregulated during acute diarrhea under Lc treatment. Probiotic Lc may be a useful supplement for application in children during acute diarrhea to reduce clinical severity and intestinal inflammatory reaction.
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Mixed Spices at Culinary Doses Have Prebiotic Effects in Healthy Adults: A Pilot Study.
Lu, QY, Rasmussen, AM, Yang, J, Lee, RP, Huang, J, Shao, P, Carpenter, CL, Gilbuena, I, Thames, G, Henning, SM, et al
Nutrients. 2019;11(6)
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An increasing body of evidence suggests that the gut microbiota has a profound impact on human health. While the microbiome of a healthy individual is relatively stable, gut microbial dynamics can be influenced by host lifestyle and dietary choices. The aim of this study was to investigate the effects of mixed spices (cinnamon, oregano, ginger, black pepper, and cayenne pepper) at culinary doses consumed over 2 weeks in a standardized 5g capsule on the production of gut microbiota and short-chain fatty acids The study is a randomised, placebo-controlled, double-blind pilot study carried out with a total of 31 healthy women and men aged between 18 and 65. The subjects were randomly allocated to one of the two intervention groups. Results indicate that daily intake of 5g of mixed spices for 2 weeks in healthy subjects resulted in a significant reduction in the relative abundance of the phylum Firmicutes (bacteria), and a trend of increasing in phylum Bacteroidetes (bacteria) as compared with a matched control group. Authors conclude that a mixture of spices at culinary doses affects the composition of gut microbiota.
Abstract
Spices were used as food preservatives prior to the advent of refrigeration, suggesting the possibility of effects on microbiota. Previous studies have shown prebiotic activities in animals and in vitro, but there has not been a demonstration of prebiotic or postbiotic effects at culinary doses in humans. In this randomized placebo-controlled study, we determined in twenty-nine healthy adults the effects on the gut microbiota of the consumption daily of capsules containing 5 g of mixed spices at culinary doses by comparison to a matched control group consuming a maltodextrin placebo capsule. The 16S ribosomal RNA sequencing data were used for microbial characterization. Spice consumption resulted in a significant reduction in Firmicutes abundance (p < 0.033) and a trend of enrichment in Bacteroidetes (p < 0.097) compared to placebo group. Twenty-six operational taxonomic units (OTUs) were different between the spice and placebo groups after intervention. Furthermore, there was a significant negative correlation between fecal short-chain fatty acid propionate concentration and Firmicutes abundance in spice intervention group (p < 0.04). The production of individual fecal short-chain fatty acid was not significantly changed by spice consumption in this study. Mixed spices consumption significantly modified gut microbiota, suggesting a prebiotic effect of spice consumption at culinary doses.
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Long-term outcome of patients with steroid-refractory acute severe UC treated with ciclosporin or infliximab.
Laharie, D, Bourreille, A, Branche, J, Allez, M, Bouhnik, Y, Filippi, J, Zerbib, F, Savoye, G, Vuitton, L, Moreau, J, et al
Gut. 2018;67(2):237-243
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Intravenous steroids are the first-line therapy for ulcerative colitis (UC) patients who are hospitalised during a severe UC flare-up. In the 40% of patients who don’t respond to steroids, the drugs ciclosporin and infliximab have been found to be efficient in preventing surgery to remove part or all of the colon, but there is a lack of data on the long-term outcomes of using these medications in UC patients. The aim of this study was to assess long-term outcome of patients included in a randomised trial comparing ciclosporin and infliximab. Between 2007 and 2010, 115 patients with UC that did not respond to steroids were randomised to receive ciclosporin or infliximab in association with azathioprine. Patients were followed to January 2015 or death. After a median follow-up of 5.4 years, colectomy-free survival rates at 1 and 5 years were, respectively, 70.9% and 61.5% in patients who received ciclosporin and 69.1% and 65.1% in those who received infliximab. Long-term colectomy-free survival was independent from initial treatment. However, a higher proportion of patients initially treated with ciclosporin needed a new treatment compared with those who received infliximab first. The researchers concluded that these results further confirm a similar efficacy and good safety profiles of both drugs.
Abstract
OBJECTIVE Ciclosporin and infliximab have demonstrated short-term similar efficacy as second-line therapies in patients with acute severe UC (ASUC) refractory to intravenous steroids. The aim of this study was to assess long-term outcome of patients included in a randomised trial comparing ciclosporin and infliximab. DESIGN Between 2007 and 2010, 115 patients with steroid-refractory ASUC were randomised in 29 European centres to receive ciclosporin or infliximab in association with azathioprine. Patients were followed until death or last news up to January 2015. Colectomy-free survival rates at 1 and 5 years and changes in therapy were estimated through Kaplan-Meier method and compared between initial treatment groups through log-rank test. RESULTS After a median follow-up of 5.4 years, colectomy-free survival rates (95% CI) at 1 and 5 years were, respectively, 70.9% (59.2% to 82.6%) and 61.5% (48.7% to 74.2%) in patients who received ciclosporin and 69.1% (56.9% to 81.3%) and 65.1% (52.4% to 77.8%) in those who received infliximab (p=0.97). Cumulative incidence of first infliximab use at 1 and 5 years in patients initially treated with ciclosporin was, respectively, 45.7% (32.6% to 57.9%) and 57.1% (43.0% to 69.0%). Only four patients from the infliximab group were subsequently switched to ciclosporin. Three patients died during the follow-up, none directly related to UC or its treatment. CONCLUSIONS In this cohort of patients with steroid-refractory ASUC initially treated by ciclosporin or infliximab, long-term colectomy-free survival was independent from initial treatment. These long-term results further confirm a similar efficacy and good safety profiles of both drugs and do not favour one drug over the other. TRIAL REGISTRATION NUMBER EudraCT: 2006-005299-42; ClinicalTrials.gouv number: NCT00542152; post-results.
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Efficacy of Bifidobacterium breve Fermented Milk in Maintaining Remission of Ulcerative Colitis.
Matsuoka, K, Uemura, Y, Kanai, T, Kunisaki, R, Suzuki, Y, Yokoyama, K, Yoshimura, N, Hibi, T
Digestive diseases and sciences. 2018;63(7):1910-1919
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Fermented milk products may improve symptoms in patients with ulcerative colitis (UC). The aim of this B-FLORA study was to assess the ability of a fermented milk product (‘Mil-Mil’) containing Bifidobacterium breve strain Yakult (BFM) to maintain remission in Japanese patients with UC. The study enrolled 195 patients with UC in remission, who were randomised to receive one pack of fermented milk (containing 10 billion BFM and 1 billion Lactobacillus acidophilus) per day, or a placebo, for 48 weeks. Time to relapse was not significantly different between the BFM and placebo groups, neither was the incidence of relapse. Stool samples from a subgroup of patients revealed no changes in the intestinal microbiota in either group, but there was a significant decrease in Bifidobacterium species before relapse, regardless of treatment group. The authors concluded that BFM had no effect on time to relapse in UC patients compared with placebo. Future studies should compare the effects of different probiotics, doses and delivery modes, and consider specific patient populations and disease severity.
Abstract
BACKGROUND Fermented milk products containing Bifidobacterium breve strain Yakult (BFM) may improve clinical status in ulcerative colitis (UC) patients. AIMS To assess efficacy of BFM in maintaining remission in Japanese patients with quiescent UC. METHODS This double-blind study (B-FLORA) enrolled 195 patients with quiescent UC, randomized to receive one pack of BFM fermented milk per day [Bifidobacterium breve strain Yakult (10 billion bacteria) and Lactobacillus acidophilus (1 billion bacteria)] (n = 98) or matching placebo (n = 97) for 48 weeks. The primary efficacy endpoint was relapse-free survival (relapse: rectal bleeding score ≥ 2 on Sutherland disease activity index scale for 3 consecutive days and/or initiation of remission induction therapy for worsening of UC). RESULTS An interim analysis was conducted after inclusion and follow-up of one-third of patients for the first phase of the study (n = 195). Relapse-free survival was not significantly different between the BFM and placebo groups (P = 0.643; hazard ratio 1.16; 95% CI 0.63-2.14, log-rank test), nor was the incidence of relapse. Therefore, the study was discontinued for lack of efficacy. An exploratory analysis of fecal samples from a subgroup of patients revealed no effects of either study beverage on intestinal microbiota, but there was a significant decrease in Bifidobacterium species before relapse, regardless of treatment group. Three mild adverse events occurred for which a causal relationship with the study beverage could not be ruled out (placebo: abdominal bloating and stress in one patient; BFM: body odor in one patient). CONCLUSIONS BFM had no effect on time to relapse in UC patients compared with placebo. STUDY REGISTRATION UMIN000007593.
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Oral versus intravenous iron replacement therapy distinctly alters the gut microbiota and metabolome in patients with IBD.
Lee, T, Clavel, T, Smirnov, K, Schmidt, A, Lagkouvardos, I, Walker, A, Lucio, M, Michalke, B, Schmitt-Kopplin, P, Fedorak, R, et al
Gut. 2017;66(5):863-871
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Iron deficiency is common in patients with Inflammatory Bowel Disease (IBD) and the standard management is with oral iron replacement therapy. However, this is thought to worsen IBD symptoms, as free iron in the gut can alter the composition of the resident gut bacteria and may contribute to inflammation. This open-labelled clinical trial compared oral iron replacement to intravenous iron replacement in subjects with Crohn’s disease (CD), Ulcerative Colitis and iron-deficient, non-inflamed subjects. The data collected included microbiome sequencing, metabolic profiling, serum iron and inflammation markers. Whilst both interventions alleviated deficiency, the intravenous iron replacement was slightly more effective at raising ferritin levels. The results showed that iron replacement therapy shifted the microbiome diversity and composition depending on free iron availability in the gut. A reduced microbiome diversity already distinguishes IBD from healthy subjects and a further decline in abundance following iron replacement therapy was particularly noticeable with oral iron supplementation and in Crohn's Disease subjects. However, over the short course of three months, this was not linked to disease severity in this study. This study affirms the importance of assessing for iron deficiency in IBD clients whilst supporting IV iron replacement being a favourable alternative to oral supplementation for individuals with unstable microbiota.
Abstract
OBJECTIVE Iron deficiency is a common complication in patients with IBD and oral iron therapy is suggested to exacerbate IBD symptoms. We performed an open-labelled clinical trial to compare the effects of per oral (PO) versus intravenous (IV) iron replacement therapy (IRT). DESIGN The study population included patients with Crohn's disease (CD; N=31), UC (N=22) and control subjects with iron deficiency (non-inflamed, NI=19). After randomisation, participants received iron sulfate (PO) or iron sucrose (IV) over 3 months. Clinical parameters, faecal bacterial communities and metabolomes were assessed before and after intervention. RESULTS Both PO and IV treatments ameliorated iron deficiency, but higher ferritin levels were observed with IV. Changes in disease activity were independent of iron treatment types. Faecal samples in IBD were characterised by marked interindividual differences, lower phylotype richness and proportions of Clostridiales. Metabolite analysis also showed separation of both UC and CD from control anaemic participants. Major shifts in bacterial diversity occurred in approximately half of all participants after IRT, but patients with CD were most susceptible. Despite individual-specific changes in phylotypes due to IRT, PO treatment was associated with decreased abundances of operational taxonomic units assigned to the species Faecalibacterium prausnitzii, Ruminococcus bromii, Dorea sp. and Collinsella aerofaciens. Clear IV-specific and PO-specific fingerprints were evident at the level of metabolomes, with changes affecting cholesterol-derived host substrates. CONCLUSIONS Shifts in gut bacterial diversity and composition associated with iron treatment are pronounced in IBD participants. Despite similar clinical outcome, oral administration differentially affects bacterial phylotypes and faecal metabolites compared with IV therapy. TRIAL REGISTRATION NUMBER clinicaltrial.gov (NCT01067547).
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Effect of a Medicinal Agaricus blazei Murill-Based Mushroom Extract, AndoSan™, on Symptoms, Fatigue and Quality of Life in Patients with Ulcerative Colitis in a Randomized Single-Blinded Placebo Controlled Study.
Therkelsen, SP, Hetland, G, Lyberg, T, Lygren, I, Johnson, E
PloS one. 2016;11(3):e0150191
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Plain language summary
AndoSanTM is a medicinal mushroom supplement based on Agaricus Blazei Murrill (ABM), but also contains Hericium erinaceus (lion’s mane, 14.7%) and Grifola frondosa (Maitake, 2.9), and contains immune modulatory beta-glucans as well as other bioactive compounds. This single-centre randomised two-armed patient-blinded study was designed to determine whether daily oral intake of AndoSanTM could improve clinical symptoms, fatigue and quality of life in patients with mild to moderate ulcerative colitis (UC). Patients received either AndoSanTM 60ml per day or placebo for 21 days and were evaluated before start of treatment and at day 14 and 21. Outcome measures were a modified Clinical Activity Index (CAI)), the self-reported health-related quality of life (HRQoL), a fatigue questionnaire, blood parameters and faecal calprotectin (a marker for intestinal inflammation). 24 patients in the AndoSanTM arm and 26 in the placebo arm completed the trial and were included in study analysis. Compared with baseline only the patients in the AndoSan™ group reported significant reductions of symptoms, fatigue and quality of life which were significantly better than in the placebo group. There were no significant changes in blood parameters in either group. There was no change in calprotectin in the AndoSanTM group but a significant worsening in the placebo group. No adverse effects were reported. A limitation of the study is that it was only blinded to the patients but not to the investigators. The authors conclude that AndoSan™ may be beneficial as a supplement to conventional medication in patients with mild to moderate UC.
Abstract
BACKGROUND Ingestion of AndoSan™, based on the mushroom Agaricus blazei Murill, has previously been shown to exhibit anti-inflammatory effects because of reduction of pro-inflammatory cytokines in healthy individuals and patients with ulcerative colitis. In this randomized single-blinded placebo controlled study we examined whether intake of AndoSan™ also resulted in clinical effects. METHODS AND FINDINGS 50 patients with symptomatic ulcerative colitis were block-randomized and blinded for oral daily intake of AndoSan™ or placebo for the 21 days' experimental period. The patients reported scores for symptoms, fatigue and health related quality of life (HRQoL) at days 0, 14 and 21. Fecal calprotectin and general blood parameters were also analyzed. In the AndoSan™ group (n = 24) symptoms improved from baseline (day 0) to days 14 and 21, with respective mean scores (95% CI) of 5.88 (4.92-6.83), 4.71 (3.90-5.52) (p = 0.002) and 4.50 (3.70-5.30) (p = 0.001). Corresponding improved mean scores (±SD) for total fatigue were 16.6 (5.59), 14.1 (4.50) (p = 0.001) and 15.1 (4.09) (p = 0.023). These scores in the placebo group (n = 26) were not improved. When comparing the two study groups using mixed model statistics, we found significant better scores for the AndoSan™-patients. HRQoL for dimensions bodily pain, vitality, social functioning and mental health improved in the AndoSan™ group. There were no alterations in general blood samples and fecal calprotectin. CONCLUSIONS Beneficiary effects on symptoms, fatigue and HRQoL from AndoSan™ consumption were demonstrated in this per-protocol study, supporting its use as a supplement to conventional medication for patients with mild to moderate symptoms from ulcerative colitis. The patients did not report any harms or unintended effects of AndoSan™ in this study. TRIAL REGISTRATION ClinicalTrials.gov NCT01496053.