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Gut microbiota modulate distal symmetric polyneuropathy in patients with diabetes.
Yang, J, Yang, X, Wu, G, Huang, F, Shi, X, Wei, W, Zhang, Y, Zhang, H, Cheng, L, Yu, L, et al
Cell metabolism. 2023;35(9):1548-1562.e7
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Distal symmetric polyneuropathy (DSPN) is the most common complication associated with diabetes, which can lead to pain, numbness, and weakness or tingling in the limbs or parts of the body. There are no cures for DSPN only drugs to manage symptoms, highlighting a need for further research. Recently it has been shown that the gut microbiota of individuals with DSPN differs to that of healthy individuals, but it is unclear as to the significance of this. This randomised control trial aimed to determine the effect of transplanting faecal microbiota from healthy individuals into those with DSPN. The results showed that DSPN was associated with a decreased abundance of beneficial gut bacteria and an increased abundance of pathogenic bacteria. Furthermore, compared to placebo, DSPN was alleviated in all 22 patients who received a faecal microbiota transplant from healthy subjects. There was an increase in gut microbiota associated with the production of beneficial short chain fatty acids and a decrease in toxin production. It was concluded that dysbiosis in the gut microbiota contributes to DSPN, which can be alleviated by faecal microbial transplant from healthy individuals. This study could be used by healthcare professionals to understand that the gut microbiota has an important role in DSPN. Further larger studies would be warranted before recommending faecal microbial transplant to individuals with this disorder.
Abstract
The pathogenic mechanisms underlying distal symmetric polyneuropathy (DSPN), a common neuropathy in patients with diabetes mellitus (DM), are not fully understood. Here, we discover that the gut microbiota from patients with DSPN can induce a phenotype exhibiting more severe peripheral neuropathy in db/db mice. In a randomized, double-blind, and placebo-controlled trial (ChiCTR1800017257), compared to 10 patients who received placebo, DSPN was significantly alleviated in the 22 patients who received fecal microbiota transplants from healthy donors, independent of glycemic control. The gut bacterial genomes that correlated with the Toronto Clinical Scoring System (TCSS) score were organized in two competing guilds. Increased guild 1, which had higher capacity in butyrate production, and decreased guild 2, which harbored more genes in synthetic pathway of endotoxin, were associated with improved gut barrier integrity and decreased proinflammatory cytokine levels. Moreover, matched enterotype between transplants and recipients showed better therapeutic efficacy with more enriched guild 1 and suppressed guild 2. Thus, changes in these two competing guilds may play a causative role in DSPN and have the potential for therapeutic targeting.
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Sustained Diet-Induced Remission in Pediatric Crohn's Disease Is Associated With Kynurenine and Serotonin Pathways.
Ghiboub, M, Boneh, RS, Sovran, B, Wine, E, Lefèvre, A, Emond, P, Verburgt, CM, Benninga, MA, de Jonge, WJ, Van Limbergen, JE
Inflammatory bowel diseases. 2023;29(5):684-694
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Crohn’s disease (CD) is an inflammatory bowel disease associated with alterations in intestinal tryptophan metabolism, in particular with increases in metabolites of the kynurenine pathway and decreased metabolites of the serotonin pathway. The aim of this 12-week randomised clinical study was to evaluate the effect of CD exclusion diet with partial enteral nutrition (CDED+PEN) and exclusive enteral nutrition (EEN) on intestinal tryptophan metabolism (as measured in faeces) in 43 children with mild-to-moderate CD. 13 of 15 patients on CDED+PEN and 9/13 on EEN achieved remission at week 6, and 8/9 and 6/9 patients, respectively, maintained remission at 12 weeks. Some kynurenine pathway metabolites decreased and some serotonin metabolites increased, in patients who achieved induction and maintenance of remission. These changes were similar in both intervention groups. On the other hand, in patients on EEN who did not go into remission, these changes were not observed. The authors concluded that further studies are warranted to inform whether there is a causal link and to refine nutritional interventions.
Abstract
BACKGROUND Both the Crohn's disease exclusion diet combined with partial enteral nutrition (CDED+PEN) and exclusive enteral nutrition (EEN) can induce remission in mild-to-moderate pediatric Crohn's disease and are associated with a marked decrease in fecal kynurenine levels. This suggests a link between clinical outcome of dietary therapy and changes in tryptophan metabolism pathways. Here, we characterize the changes in several fecal tryptophan metabolites induced by CDED+PEN or EEN and their association with remission. METHODS A total of 21 tryptophan metabolites were quantified in fecal samples from a 12-week prospective randomized trial with CDED+PEN or EEN for induction of remission in mild to moderate pediatric Crohn's disease. Tryptophan metabolites at week 0 (W0), W6, and W12 of 73 samples were quantitatively measured by liquid chromatography coupled with triple quadrupole mass spectrometry, and data were analyzed according to clinical groups of baselines (W0), induced remission at W6, no remission, sustained remission at W12, and nonsustained remission. RESULTS Reduction in components of the kynurenine pathway, such as kynurenine and quinolinic acid, were strongly associated with induced remission with both CDED+PEN and EEN, which were maintained in sustained remission. Specific serotonin pathway metabolites, such as melatonin, N-acetylserotonin, and 5-OH-tryptophan, were significantly increased in fecal samples from patients maintaining remission at W12 with both CDED+PEN and EEN. Importantly, in samples from patients failing to sustain remission, no changes were observed. Remission induction with EEN differs from CDED+PEN, particularly the moderate effects on indole pathway metabolites. The ratios of kynurenine and melatonin and quinolinic acid and melatonin perform well as markers for sustained remission. CONCLUSIONS The reduction in specific kynurenine pathway compounds and the increase in serotonin pathway compounds are associated with diet-induced and sustained remission. Further studies are warranted to assess causality and the association of these metabolites with specific diet and lifestyle factors, affecting sustained clinical remission. We show that fecal tryptophan metabolites are associated with remission following dietary therapy in a prospective clinical trial of pediatric Crohn’s disease patients. Our study shows that reduction in some kynurenine pathway metabolites and the increase in serotonin pathway compounds are associated with diet-induced and sustained remission. These compounds may play a role in mediating the mechanism of action of dietary therapy.
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Fecal microbiota composition is related to brown adipose tissue 18F-fluorodeoxyglucose uptake in young adults.
Ortiz-Alvarez, L, Acosta, FM, Xu, H, Sanchez-Delgado, G, Vilchez-Vargas, R, Link, A, Plaza-Díaz, J, Llamas, JM, Gil, A, Labayen, I, et al
Journal of endocrinological investigation. 2023;46(3):567-576
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Brown adipose tissue (BAT) is a tissue that dissipates energy through the action of the uncoupling protein-1. Moreover, BAT takes up and oxidises glucose and lipids, as such working as a nutrient sink, and through its endocrine function may have cardiometabolic benefits. The aim of this study was to investigate the association of fecal microbiota composition with BAT volume and activity in young adults. This study was a cross-sectional study of 92 young healthy adults (27 men and 65 women, age: 18–25 years old). Results showed that the relative abundance of: - specific genera (Akkermansia, Lachnospiraceae sp., and Ruminococcus) were negatively correlated with BAT volume and activity. - Bifdobacterium genus was positively correlated with BAT activity. Authors concluded faecal microbiota is involved in the regulation of glucose uptake by human BAT and other metabolic tissues including white adipose tissue and skeletal muscles in young adults.
Abstract
OBJECTIVE Human brown adipose tissue (BAT) has gained considerable attention as a potential therapeutic target for obesity and its related cardiometabolic diseases; however, whether the gut microbiota might be an efficient stimulus to activate BAT metabolism remains to be ascertained. We aimed to investigate the association of fecal microbiota composition with BAT volume and activity and mean radiodensity in young adults. METHODS 82 young adults (58 women, 21.8 ± 2.2 years old) participated in this cross-sectional study. DNA was extracted from fecal samples and 16S rRNA sequencing was performed to analyse the fecal microbiota composition. BAT was determined via a static 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography-computed tomography scan (PET/CT) after a 2 h personalized cooling protocol. 18F-FDG uptake was also quantified in white adipose tissue (WAT) and skeletal muscles. RESULTS The relative abundance of Akkermansia, Lachnospiraceae sp. and Ruminococcus genera was negatively correlated with BAT volume, BAT SUVmean and BAT SUVpeak (all rho ≤ - 0.232, P ≤ 0.027), whereas the relative abundance of Bifidobacterium genus was positively correlated with BAT SUVmean and BAT SUVpeak (all rho ≥ 0.262, P ≤ 0.012). On the other hand, the relative abundance of Sutterellaceae and Bifidobacteriaceae families was positively correlated with 18F-FDG uptake by WAT and skeletal muscles (all rho ≥ 0.213, P ≤ 0.042). All the analyses were adjusted for the PET/CT scan date as a proxy of seasonality. CONCLUSION Our results suggest that fecal microbiota composition is involved in the regulation of BAT and glucose uptake by other tissues in young adults. Further studies are needed to confirm these findings. CLINICAL TRIAL INFORMATION ClinicalTrials.gov no. NCT02365129 (registered 18 February 2015).
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Are probiotics, prebiotics, and synbiotics beneficial in primary thyroid diseases? A systematic review with meta-analysis.
Zawadzka, K, Kałuzińska, K, Świerz, MJ, Sawiec, Z, Antonowicz, E, Leończyk-Spórna, M, Abadi, AK, Trofimiuk-Müldner, M, Bała, MM
Annals of agricultural and environmental medicine : AAEM. 2023;30(2):217-223
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Irregularities in intestinal microbial composition are thought to be correlated with thyroid dysfunction. Supplementation of prebiotics, probiotics and synbiotics are gaining momentum in recent times in improving health in general. This systematic review of randomised controlled trials was conducted to summarise the up-to-date evidence on the therapeutic potential of prebiotics, probiotics and synbiotics in the treatment of thyroid disease. The meta-analysis did not show beneficial effects on thyroid hormone balance, BMI or levothyroxine dosage reduction. Supplementation with Lactobacillus and Bifidobacterium resulted in improvement in constipation and a statistically non-significant reduction in thyroid-stimulating hormone in adult participants with hypothyroidism. Further robust long-term studies are required to evaluate the efficacy of prebiotics, probiotics and synbiotics in thyroid disease treatment as the availability of the number of studies included in this systematic review was limited. However, healthcare professionals can use the review to understand the current evidence in this area and the correlation between gut microbial alterations and thyroid disease.
Abstract
INTRODUCTION AND OBJECTIVE A number of studies indicate the presence of a thyroid-gut axis and the important influence of the gut microbiota on thyroid function. As prebiotics, probiotics and synbiotics show therapeutic potential in the treatment of intestinal dysbiosis, the aim of this review is to evaluate the efficacy of their supplementation in primary thyroid diseases. REVIEW METHODS Electronic databases (Ovid MEDLINE, Embase, CENTRAL), registers of clinical trials, and grey literature up to 6 October 2022 were searched for randomised controlled trials (RCTs) meeting pre-specified inclusion criteria. The protocol was registered in PROSPERO (CRD42021235054). BRIEF DESCRIPTION OF THE STATE OF KNOWLEDGE After screening 1,721 references, two RCTs were identified, which included 136 hypothyroid participants in total. Meta-analysis of the results after eight weeks of supplementation with predominantly Lactobacillus and Bifidobacterium strains indicated a clinically and statistically nonsignificant decrease in TSH (MD -0.19 mIU/L; 95% CI -0.43 to 0.06; I2= 0%), and no effect on fT3 levels (MD 0.01 pg/mL; 95% CI-0.16 to 0.18; I2= 0%). Data from single studies indicated no significant change in the levels of fT4, thyroid auto-antibodies, BMI, levothyroxine doses, and severity of symptoms measured with validated scales. Only constipation scores showed significant improvement (MD -8.71 points in the Faecal Incontinence Questionnaire; 95% CI -15.85 to -1.57; I2= 0%). SUMMARY Low-certainty evidence from two randomised trials, suggests that routine administration of probiotics, prebiotics or synbiotics may result in little to no benefit in patients with primary hypothyroidism.
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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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Modulating the Gut Microbiome in Multiple Sclerosis Management: A Systematic Review of Current Interventions.
Tsogka, A, Kitsos, DK, Stavrogianni, K, Giannopapas, V, Chasiotis, A, Christouli, N, Tsivgoulis, G, Tzartos, JS, Giannopoulos, S
Journal of clinical medicine. 2023;12(24)
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Multiple sclerosis (MS) is an autoimmune disease caused by the altered immune system mistakenly attacking the central nervous system. While genetics play a leading causative role in the manifestation of this disease, other contributing environmental factors can also exist, such as a disruption in the intestinal microbial composition. Previous research has shown that the bidirectional communication between the brain's and gut's health, also known as the gut-brain axis, may contribute to the prognosis of MS. Modulating gut microbial composition can be a therapeutic strategy in MS patients to manage symptoms and prevent disease progression. This systematic review assessed different protocols for modulating gut microbial composition, including dietary modifications, probiotic use, intermittent fasting, and faecal microbial transplantation. The review included thirteen studies that compared the effects of the above gut microbial modulation intervention protocols in MS patients with healthy participants. While different dietary modification strategies improved MS symptoms, probiotic supplementations and intermittent fasting reduced inflammation, and faecal microbial transplantation showed promising positive effects in a few reports. Due to the methodological limitations of the included studies, further robust studies are required to evaluate the beneficial effects of gut microbial modulation strategies in reducing the symptoms of MS patients. However, healthcare professionals can use the results of this study to understand the benefits of gut microbial modulation in MS patients.
Abstract
This review attempted to explore all recent clinical studies that have investigated the clinical and autoimmune impact of gut microbiota interventions in multiple sclerosis (MS), including dietary protocols, probiotics, fecal microbiota transplantation (FMT), and intermittent fasting (IF). Methods: Thirteen studies were held between 2011 and 2023 this demonstrated interventions in gut microbiome among patients with MS and their impact the clinical parameters of the disease. These included specialized dietary interventions, the supply of probiotic mixtures, FMT, and IF. Results: Dietary interventions positively affected various aspects of MS, including relapse rates, EDSS disability scores, MS-related fatigue, and metabolic features. Probiotic mixtures showed promising results on MS-related fatigue, EDSS parameters, inflammation; meanwhile, FMT-though a limited number of studies was included-indicated some clinical improvement in similar variables. IF showed reductions in EDSS scores and significant improvement in patients' emotional statuses. Conclusions: In dietary protocols, clinical MS parameters, including relapse rate, EDSS, MFIS, FSS, and MSQoL54 scales, were significantly improved through the application of a specific diet each time. Probiotic nutritional mixtures promote a shift in inflammation towards an anti-inflammatory cytokine profile in patients with MS. The administration of such mixtures affected disability, mood levels, and quality of life among patients with MS. FMT protocols possibly demonstrate a therapeutic effect in some case reports. IF protocols were found to ameliorate EDSS and FAMS scores. All interventional means of gut microbiome modulation provided significant conclusions on several clinical aspects of MS and highlight the complexity in the relationship between MS and the gut microbiome.
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Advancements in Nutritional Strategies for Gestational Diabetes Management: A Systematic Review of Recent Evidence.
Sánchez-García, JC, Saraceno López-Palop, I, Piqueras-Sola, B, Cortés-Martín, J, Mellado-García, E, Muñóz Sánchez, I, Rodríguez-Blanque, R
Journal of clinical medicine. 2023;13(1)
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Gestational Diabetes Mellitus (GDM) causes hyperglycaemia due to the deficit of insulin during pregnancy. Dietary and lifestyle management plays a vital role in maintaining glycaemic control in women with GDM to avoid health risks to the mother and baby. Therefore, this systematic review of fourteen randomised controlled trials evaluated the latest research advancements to identify effective nutritional strategies for managing hyperglycaemia in women with GDM. Among all the dietary strategies implemented in the included randomised controlled trials, probiotic supplementation and supplementation of probiotics and vitamin D were most effective in GDM. Further robust studies are required to evaluate the potential effectiveness of different nutritional strategies for managing GDM. Healthcare professionals can use the results of this systematic review to understand the latest evidence supporting nutritional strategy for women with GDM and the need for personalised support for managing hyperglycaemia in GDM.
Abstract
Gestational diabetes mellitus (GDM) is defined as hyperglycaemia first detected at any time during pregnancy with values lower than those determined by the WHO for diabetes diagnosis in adults. This pathology, with a worldwide prevalence of 13.4%, causes significant maternal and foetal risks. The first line of treatment consists of maintaining normo-glycaemia through an adequate diet and lifestyle changes. The aim is to synthesize the scientific evidence updating the nutritional recommendations for the effective management of GDM. A systematic review of the scientific literature was conducted following the PRISMA guidelines. Randomized clinical trials published within the last five years and providing information on nutritional recommendations to achieve an effective management of gestational diabetes were selected. The databases searched were PubMed, the WOS Core Collection, SCOPUS, and CINAHL, using the MeSH terms: "Diabetes, Gestational"; "Nutrition Assessment (nutrition*)"; "Diet"; "Eating"; and "Food"; with the Boolean operators "AND" and "OR". The PEDro scale (Physiotherapy Evidence Database) was used to assess the scientific quality of the studies, with a mean score of 8.9, indicating an average good scientific quality. Results: A total of 809 papers were collected, of which, after applying the inclusion and exclusion criteria, 14 randomized clinical trials were selected. Probiotic supplementation and co-supplementation with vitamin D have been found to be the most beneficial options for both mothers with GDM and neonates, but the most effective regimens are not known. Diets enriched with extra virgin olive oil (EVOO) and oat bran, as well as some recommendations focused on carbohydrates also seem effective, as well as diets designed for this group of women with GDM such as "CHOICE". Conclusions: Although there are numerous proposals that have been published in recent years focused on the diet of women with GDM in order to improve their results and those of their children, it is the supplementation with probiotics and the co-supplementation with vitamin D that is most agreed upon as beneficial; however, more research is needed into which protocols are most effective. Other proposals that could also be beneficial should be further studied.
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Efficacy and Safety of the Adjuvant Use of Probiotic Bacillus clausii Strains in Pediatric Irritable Bowel Syndrome: A Randomized, Double-Blind, Placebo-Controlled Study.
Vázquez-Frias, R, Consuelo-Sánchez, A, Acosta-Rodríguez-Bueno, CP, Blanco-Montero, A, Robles, DC, Cohen, V, Márquez, D, Perez, M
Paediatric drugs. 2023;25(1):115-126
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Irritable bowel syndrome (IBS) is considered both a health and a socioeconomic burden. Curative treatment for IBS is currently not available and current management strategies vary. Gut microbiota dysbiosis is increasingly considered as a vital factor in the etiopathogenetic of IBS; thus, gut microbiota are a potential therapeutic target. The aim of this study was to investigate the efficacy and safety of Bacillus clausii plus conventional treatment, compared with placebo plus conventional treatment, in children with IBS in Mexico. This study is a phase III, multicentre, randomised, placebo-controlled, double-blind, parallel clinical trial. Patients (n=259) were centrally randomised 1:1 to treatment with either B. clausii or placebo. Results show that IBS symptom relief in children was very high in both groups (B. clausii and placebo). In fact, there weren’t any significant differences between groups for proportion of patients with clinical improvements at Week 8 or any of the key secondary endpoints. Furthermore, the adverse event profile was similar between groups. Authors conclude that their study was not able to demonstrate the efficacy of B. clausii as an adjuvant to conventional treatment of patients with IBS.
Abstract
OBJECTIVES Current irritable bowel syndrome (IBS) treatments have limited efficacy and probiotics like Bacillus clausii (B. clausii) were found to be effective in the management of several gastrointestinal disorders. This phase III trial assessed the efficacy and safety of adding B. clausii (four strains: O/C, N/R, SIN, T), versus placebo, to conventional treatment of pediatric IBS in Mexico. METHODS Patients aged 6-17 years 11 months with IBS (Rome IV) for at least 2 months were randomized to receive either B. clausii (oral suspension, total dose 4 billion spores/day) or placebo once daily for 8 weeks. All patients also received conventional treatment. The primary endpoint was the difference in the proportion of patients with clinical improvements at Week 8 (Global Assessment Questions [GAQ]). Secondary endpoints included responders by Subject's Global Assessment of Relief for Children with IBS (SGARC); number/consistency of stools; abdominal distention/bloating; abdominal pain/intensity; and IBS behavior. RESULTS 73.6% (95% confidence interval [CI] 67.3-80.0; B. clausii n = 129) and 78.5% (95% CI 72.5-84.4; placebo n = 130) of patients had symptom improvement (p = 0.8182). For Week 8 SGARC, 19.2% (B. clausii) and 20.9% (placebo) reported complete symptom relief. Stool evaluations, bloating, abdominal pain/intensity, and IBS behavior were similar between groups. Both treatments were well tolerated. CONCLUSION No significant differences in efficacy between B. clausii and placebo were demonstrated in addition to conventional treatment. The sample size calculation was based on an expected placebo/conventional treatment response of 30-40%. However, the actual treatment response observed was 80% and, thus, a study with larger population would be warranted. In addition, this study was conducted during the COVID-19 pandemic, when such controlled social conditions may have resulted in better diet, greater family stability, less psychological stress, and lower risk of infections exacerbating IBS, thereby improving symptoms in both groups. EUDRACT NUMBER 2018-004519-31.
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The Gut Microbiome in Early Life Stress: A Systematic Review.
Agusti, A, Lamers, F, Tamayo, M, Benito-Amat, C, Molina-Mendoza, GV, Penninx, BWJH, Sanz, Y
Nutrients. 2023;15(11)
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Children exposed to early life stress (ELS) show alterations in brain development and are at increased risk of developing mental illness. This study aims to clarify whether ELS influences the gut microbiome and whether this can be a predictor for the development of mental disorders. 13 articles were included in this systemic review. 4 looked at pre-natal stress and 9 at post-natal stress. Prenatal stress (via maternal stress) may be associated with an increase in Proteobacteria phylum and with a lower abundance of Bifidobacterium and lactic acid bacteria. In the postnatal group, greater microbiome diversity was related to lower depression and anxiety. In boys scores for adaptive skills were higher in those with good levels of Bifidobacterium. A positive association was found between EA (early adversity) experiences and gastrointestinal symptoms and anxiety. This review demonstrates links between ELS and gut microbiome changes. Further research will be necessary to draw more robust conclusions.
Expert Review
Conflicts of interest:
None
Take Home Message:
- This systematic review consolidated and discussed existing evidence on the link between early life stress (ELS) and changes to the human microbiome
- Exposure to ELS, prenatal or postnatal during childhood and adolescence, may impact mental and physical health.
Evidence Category:
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A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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X
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 systematic review was conducted to consolidate clinical evidence examining the impact of early life stress (ELS) on the human intestinal microbiome.
Method
Thirteen observational studies were included in the review, sourced from Pubmed, Scopus, Web of Science, and EMBASE. Methodological quality was assessed using the Newcastle-Ottawa Assessment Scale (NOS), with most studies scoring seven or eight out of nine stars.
Study designs varied, including prospective prenatal studies, postnatal longitudinal studies, case-control studies, and cross-sectional studies. Four prenatal studies were prospective in design. The other nine postnatal studies included one longitudinal study, five case-control studies, and three cross-sectional studies. All 13 studies were published between 2015 and 2022. Because study designs and outcome assessments varied, the results were presented in a narrative form. Data was extracted by 2 independent authors.
Results
The primary findings from the review were as follows:
- Four longitudinal stress studies indicated that pregnant mothers experiencing psychological stress, increased cortisol levels, HIV, and lack of social support exhibited a lower abundance of beneficial Bifidobacterium and an increased abundance of Enterobacter genus.
- One postnatal stress longitudinal study (n=260) demonstrated lower depression and anxiety and improved internalising behaviour in patients with high microbiome diversity.
- . One postnatal stress case-control study (n=344) showed changes in the microbiome and an abundance of several bacterial taxa in stressed groups, including genera Prevotella, Bacteroides (Bacteroidetes), Coprococcus, Streptococcus, and Escherichia.
- One cross-sectional study of 128 adults without psychiatric conditions revealed that higher stress correlated with increased levels of Bacteroides, Parabacteroides, Rhodococcus, Methanobrevibacter, and Roseburia at the genus level, as well as lower Phascolarcto bacterium and Firmicutes at the phylum level.
- One large prospective study (n=446) found infants exposed to higher cumulative stress exhibited an increased relative abundance of Proteobacteria groups and lower Bifidobacterium.
Conclusion:
Due to the inconsistency of study designs and their results this review failed to find consensus microbiome signatures associated with pre- or postnatal stress, or both.
Clinical practice applications:
- Early life stress, and alterations in the gut microbiome, have been linked to mental health conditions
- Maternal prenatal stress may be linked to emotional, behavioural, and cognitive outcomes in infants.
Considerations for future research:
- Future research should standardise questionnaires, to ensure consistency and comparability across studies
- Additionally, future studies should consider using standard procedures and specific species and strain resolution shotgun metagenomics sequencing
- Consideration should be given to the influence of environmental variables (diet, physical activity, etc.) and sex in gut microbiome analysis.
Abstract
Exposure to early life stress (ELS), prenatal or postnatal during childhood and adolescence, can significantly impact mental and physical health. The role of the intestinal microbiome in human health, and particularly mental health, is becoming increasingly evident. This systematic review aims to summarize the clinical data evaluating the effect of ELS on the human intestinal microbiome. The systematic review (CRD42022351092) was performed following PRISMA guidelines, with ELS considered as exposure to psychological stressors prenatally and during early life (childhood and adolescence). Thirteen articles met all inclusion criteria, and all studies reviewed found a link between ELS and the gut microbiome in both prenatal and postnatal periods. However, we failed to find consensus microbiome signatures associated with pre- or postnatal stress, or both. The inconsistency of results is likely attributed to various factors such as different experimental designs, ages examined, questionnaires, timing of sample collection and analysis methods, small population sizes, and the type of stressors. Additional studies using similar stressors and validated stress measures, as well as higher-resolution microbiome analytical approaches, are needed to draw definitive conclusions about the links between stress and the human gut microbiome.
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Effects of dietary fibers or probiotics on functional constipation symptoms and roles of gut microbiota: a double-blinded randomized placebo trial.
Lai, H, Li, Y, He, Y, Chen, F, Mi, B, Li, J, Xie, J, Ma, G, Yang, J, Xu, K, et al
Gut microbes. 2023;15(1):2197837
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Plain language summary
Functional constipation is characterised by continuously difficult, incomplete, or infrequent defecation, without an organic origin. Effective intervention strategies are required to relieve the functional constipation difficulties, particularly in rapidly aging populations, such as Chinese populations. The aim of this study was to evaluate the effectiveness of three dietary fibre formulas (polydextrose, psyllium husk, and wheat bran + psyllium husk) and one probiotic supplement on the improvement of constipation symptoms among Chinese adults with functional constipation. This study was a double-blinded randomised placebo-controlled trial which enrolled 250 participants who were randomly assigned to one of the five groups. Results showed: - that daily supplement of three prebiotic formulas with dietary fibres, or a probiotic formula effectively relieved hard stool in functional constipation patients after 4 weeks intervention. - the capacity of gut microbial genera in shaping the intervention responsiveness in the improvement of bowel movement frequency, Bristol stool scale score, and degree of defecation straining. Authors conclude that the pre or probiotic interventions may modulate gut microbiota, associated with intestinal health.
Abstract
Dietary fibers/probiotics may relieve constipation via optimizing gut microbiome, yet with limited trial-based evidences. We aimed to evaluate the effects of formulas with dietary fibers or probiotics on functional constipation symptoms, and to identify modulations of gut microbiota of relevance. We conducted a 4-week double-blinded randomized placebo-controlled trial in 250 adults with functional constipation. Intervention: A: polydextrose; B: psyllium husk; C: wheat bran + psyllium husk; D: Bifidobacterium animalis subsp. lactis HN019 + Lacticaseibacillus rhamnosus HN001; Placebo: maltodextrin. Oligosaccharides were also included in group A to D. 16S rRNA sequencing was used to assess the gut microbiota at weeks 0, 2, and 4. A total of 242 participants completed the study. No time-by-group effect was observed for bowel movement frequency (BMF), Bristol stool scale score (BSS), and degree of defecation straining (DDS), while BSS showed mean increases of 0.95-1.05 in group A to D (all P < 0.05), but not significantly changed in placebo (P = 0.170), and 4-week change of BSS showed similarly superior effects of the interventions as compared placebo. Group D showed a marginal reduction in plasma 5-hydroxytryptamine. Group A resulted in a higher Bifidobacterium abundance than placebo at week 2 and 4. Fourteen genera showed intervention-specific increasing or decreasing trends continuously, among which Anaerostipes showed increasing trends in groups B and C, associated with BMF increase. Random forest models identified specific baseline microbial genera panels predicting intervention responders. In conclusion, we found that the dietary fibers or probiotics may relieve hard stool, with intervention-specific changes in gut microbiota relevant to constipation relief. Baseline gut microbiota may predispose the intervention responsiveness. ClincialTrials.gov number, NCT04667884. What is the context?Supplementation of dietary fibers, such as psyllium husk or wheat bran (10 ~ 15 g/day) may relieve constipation symptoms, but bloating and flatulence are major concerns on a high fiber intake.Functional constipation patients had alternated gut microbiota profiles, while meta-analysis suggested that multispecies probiotics may increase bowel movement frequency and relieve hard stool in functional constipation.Dietary fibers or probiotics may lead to before-after changes of gut microbiota in patients with functional constipation, but time-series continued changes of gut microbiota during the intervention are unknown.Elevation of 5-hydroxytryptamine synthesis in enterochromaffin cells may affect bowel movement. And the elevated plasma 5-hydroxytryptamine was observed in functional constipation patients.What is new? Daily supplement of three prebiotic formulas with dietary fibers (polydextrose, psyllium husk, wheat bran, together with oligosaccharides), or a probiotic formula with Bifidobacterium animalis subsp. lactis HN019 + Lacticaseibacillus rhamnosus HN001 effectively relieved hard stool in functional constipation patients after 4 weeks intervention.We identified continued increasing or decreasing gut microbial genera over the intervention. Dietary fiber – gut microbiota (Anaerostipes)—constipation relieve (bowel movement frequency) evidence axis was identified in this human trial.Probiotic supplementation marginally reduced plasma 5-hydroxytryptamine, possibly associated with changes in BMF-related gut microbial genera.Intervention-specific baseline gut microbiota well predicted the responsiveness of constipation symptom relief.What is the impact? We provided references for the dosage and duration of dietary fiber/probiotics recommendations for adults with functional constipation, and advanced the microbial genera evidences of the fibers/probiotics-microbiota-laxation theory in humans.