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A double-blind, randomized, placebo-controlled study assessing the impact of probiotic supplementation on the symptoms of irritable bowel syndrome in females.
Mullish, BH, Michael, DR, Dabcheva, M, Webberley, TS, Coates, N, John, DA, Wang, D, Luo, Y, Plummer, SF, Marchesi, JR
Neurogastroenterology and motility. 2024;(4):e14751
Abstract
BACKGROUND A previous exploratory study demonstrated the ability of the Lab4 probiotic to alleviate the symptoms of IBS, and post hoc data analysis indicated greatest improvements in the female subgroup. The aim of this study is to confirm the impact of this multistrain probiotic on IBS symptom severity in females. METHODS An 8-week, single-center, randomized, double-blinded, placebo-controlled, superiority study in 70 females with Rome IV-diagnosed irritable bowel syndrome (IBS) receiving the Lab4 probiotic (25 billion colony-forming units) daily or a matched placebo. Changes from baseline in the IBS-symptom severity score (IBS-SSS), daily bowel habits, anxiety, depression, IBS-related control, and avoidance behavior, executive function, and the fecal microbiota composition were assessed. The study was prospectively registered: ISRCTN 14866272 (registration date 20/07/22). KEY RESULTS At the end of the study, there were significant between-group reductions in IBS-SSS (-85.0, p < 0.0001), anxiety and depression scores (-1.9, p = 0.0002 and -2.4, p < 0.0001, respectively), and the IBS-related control and avoidance behavior score (-7.5, p = 0.0002), all favoring the probiotic group. A higher proportion of the participants in the probiotic group had normal stool form (p = 0.0106) and/or fewer defecations with loose stool form (p = 0.0311). There was little impact on the overall diversity of the fecal microbiota but there were significant differences in Roseburia, Holdemanella, Blautia, Agathobacter, Ruminococcus, Prevotella, Bacteroides, and Anaerostipes between the probiotic and placebo groups at the end of the study. CONCLUSIONS & INFERENCES Daily supplementation with this probiotic may represent an option to be considered in the management of IBS.
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Pathobionts in the tumour microbiota predict survival following resection for colorectal cancer.
Alexander, JL, Posma, JM, Scott, A, Poynter, L, Mason, SE, Doria, ML, Herendi, L, Roberts, L, McDonald, JAK, Cameron, S, et al
Microbiome. 2023;(1):100
Abstract
BACKGROUND AND AIMS The gut microbiota is implicated in the pathogenesis of colorectal cancer (CRC). We aimed to map the CRC mucosal microbiota and metabolome and define the influence of the tumoral microbiota on oncological outcomes. METHODS A multicentre, prospective observational study was conducted of CRC patients undergoing primary surgical resection in the UK (n = 74) and Czech Republic (n = 61). Analysis was performed using metataxonomics, ultra-performance liquid chromatography-mass spectrometry (UPLC-MS), targeted bacterial qPCR and tumour exome sequencing. Hierarchical clustering accounting for clinical and oncological covariates was performed to identify clusters of bacteria and metabolites linked to CRC. Cox proportional hazards regression was used to ascertain clusters associated with disease-free survival over median follow-up of 50 months. RESULTS Thirteen mucosal microbiota clusters were identified, of which five were significantly different between tumour and paired normal mucosa. Cluster 7, containing the pathobionts Fusobacterium nucleatum and Granulicatella adiacens, was strongly associated with CRC (PFDR = 0.0002). Additionally, tumoral dominance of cluster 7 independently predicted favourable disease-free survival (adjusted p = 0.031). Cluster 1, containing Faecalibacterium prausnitzii and Ruminococcus gnavus, was negatively associated with cancer (PFDR = 0.0009), and abundance was independently predictive of worse disease-free survival (adjusted p = 0.0009). UPLC-MS analysis revealed two major metabolic (Met) clusters. Met 1, composed of medium chain (MCFA), long-chain (LCFA) and very long-chain (VLCFA) fatty acid species, ceramides and lysophospholipids, was negatively associated with CRC (PFDR = 2.61 × 10-11); Met 2, composed of phosphatidylcholine species, nucleosides and amino acids, was strongly associated with CRC (PFDR = 1.30 × 10-12), but metabolite clusters were not associated with disease-free survival (p = 0.358). An association was identified between Met 1 and DNA mismatch-repair deficiency (p = 0.005). FBXW7 mutations were only found in cancers predominant in microbiota cluster 7. CONCLUSIONS Networks of pathobionts in the tumour mucosal niche are associated with tumour mutation and metabolic subtypes and predict favourable outcome following CRC resection. Video Abstract.
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A Double-Blind, Randomized, Placebo-Controlled Trial of Ursodeoxycholic Acid (UDCA) in Parkinson's Disease.
Payne, T, Appleby, M, Buckley, E, van Gelder, LMA, Mullish, BH, Sassani, M, Dunning, MJ, Hernandez, D, Scholz, SW, McNeill, A, et al
Movement disorders : official journal of the Movement Disorder Society. 2023;(8):1493-1502
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Abstract
BACKGROUND Rescue of mitochondrial function is a promising neuroprotective strategy for Parkinson's disease (PD). Ursodeoxycholic acid (UDCA) has shown considerable promise as a mitochondrial rescue agent across a range of preclinical in vitro and in vivo models of PD. OBJECTIVES To investigate the safety and tolerability of high-dose UDCA in PD and determine midbrain target engagement. METHODS The UP (UDCA in PD) study was a phase II, randomized, double-blind, placebo-controlled trial of UDCA (30 mg/kg daily, 2:1 randomization UDCA vs. placebo) in 30 participants with PD for 48 weeks. The primary outcome was safety and tolerability. Secondary outcomes included 31-phosphorus magnetic resonance spectroscopy (31 P-MRS) to explore target engagement of UDCA in PD midbrain and assessment of motor progression, applying both the Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS-III) and objective, motion sensor-based quantification of gait impairment. RESULTS UDCA was safe and well tolerated, and only mild transient gastrointestinal adverse events were more frequent in the UDCA treatment group. Midbrain 31 P-MRS demonstrated an increase in both Gibbs free energy and inorganic phosphate levels in the UDCA treatment group compared to placebo, reflecting improved ATP hydrolysis. Sensor-based gait analysis indicated a possible improvement of cadence (steps per minute) and other gait parameters in the UDCA group compared to placebo. In contrast, subjective assessment applying the MDS-UPDRS-III failed to detect a difference between treatment groups. CONCLUSIONS High-dose UDCA is safe and well tolerated in early PD. Larger trials are needed to further evaluate the disease-modifying effect of UDCA in PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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An observational investigation of the faical microbiota and metabonome of gastrostomy fed children, on blended and formula diets.
Marchesi, JR, Allen, S, Scott, E, Jenkins, H, Sadlier, C, Thomas, S
Gut microbes. 2022;(1):2138661
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Gastrostomy fed children traditionally have a Formulae diet (FD), which fulfills nutritional requirements; however, many families are adopting Blended diets (BD), which are what the whole family would eat. We undertook an observational investigation of the colonic microbiota and metabonome in a small group of gastrostomy fed children, who were either on an FD or BD, and compared, where possible to their siblings (17 FD, 28 BD, 19 HS). There was no increase in complications in tube blockage or infection rates, but a significant improvement in the prevalence of bowel problems, a reduction in medication and an increase in quality of life. Metataxonomic analysis showed that the FD group was significantly different to the Sibling group, and that families did not cluster together. Whole sample metabonomics showed no differences between groups; however, univariate analysis of biologically important metabolites did differ. Changing to a BD resulted in no increase in complications or risks, but improved the overall quality of life for the children and families.
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Systematic review: the association between the gut microbiota and medical therapies in inflammatory bowel disease.
Radhakrishnan, ST, Alexander, JL, Mullish, BH, Gallagher, KI, Powell, N, Hicks, LC, Hart, AL, Li, JV, Marchesi, JR, Williams, HRT
Alimentary pharmacology & therapeutics. 2022;(1):26-48
Abstract
BACKGROUND The gut microbiota has been implicated in the pathogenesis of inflammatory bowel disease (IBD), with Faecalibacterium prausnitizii associated with protection, and certain genera (including Shigella and Escherichia) associated with adverse features. The variability of patient response to medical therapies in IBD is incompletely understood. Given the recognised contribution of the microbiota to treatment efficacy in other conditions, there may be interplay between the gut microbiota, IBD medical therapy and IBD phenotype. AIMS To evaluate the bidirectional relationship between IBD medical therapies and the gut microbiota. METHODS We conducted a systematic search of MEDLINE and EMBASE. All original studies analysing interactions between the gut microbiota and established IBD medical therapies were included. RESULTS We screened 1296 records; 19 studies were eligible. There was heterogeneity in terms of sample analysis, treatment protocols, and outcome reporting. Increased baseline α-diversity was observed in responders versus non-responders treated with exclusive enteral nutrition (EEN), infliximab, ustekinumab or vedolizumab. Higher baseline Faecalibacterium predicted response to infliximab and ustekinumab. A post-treatment increase in Faecalibacterium prausnitzii was noted in responders to aminosalicylates, anti-TNF medications and ustekinumab; conversely, this species decreased in responders to EEN. Escherichia was a consistent marker of unfavourable drug response, and its presence in the gut mucosa correlated with inflammation in aminosalicylate-treated patients. CONCLUSIONS Both gut microbiota diversity and specific taxonomic features (including high abundance of Faecalibacterium) are associated with the efficacy of a range of IBD therapies. These findings hold promise for a potential role for the gut microbiota in explaining the heterogeneity of patient response to IBD treatments.
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Impact of Fecal Microbiota Transplantation on Gut Bacterial Bile Acid Metabolism in Humans.
Bustamante, JM, Dawson, T, Loeffler, C, Marfori, Z, Marchesi, JR, Mullish, BH, Thompson, CC, Crandall, KA, Rahnavard, A, Allegretti, JR, et al
Nutrients. 2022;(24)
Abstract
Fecal microbiota transplantation (FMT) is a promising therapeutic modality for the treatment and prevention of metabolic disease. We previously conducted a double-blind, randomized, placebo-controlled pilot trial of FMT in obese metabolically healthy patients in which we found that FMT enhanced gut bacterial bile acid metabolism and delayed the development of impaired glucose tolerance relative to the placebo control group. Therefore, we conducted a secondary analysis of fecal samples collected from these patients to assess the potential gut microbial species contributing to the effect of FMT to improve metabolic health and increase gut bacterial bile acid metabolism. Fecal samples collected at baseline and after 4 weeks of FMT or placebo treatment underwent shotgun metagenomic analysis. Ultra-high-performance liquid chromatography-mass spectrometry was used to profile fecal bile acids. FMT-enriched bacteria that have been implicated in gut bile acid metabolism included Desulfovibrio fairfieldensis and Clostridium hylemonae. To identify candidate bacteria involved in gut microbial bile acid metabolism, we assessed correlations between bacterial species abundance and bile acid profile, with a focus on bile acid products of gut bacterial metabolism. Bacteroides ovatus and Phocaeicola dorei were positively correlated with unconjugated bile acids. Bifidobacterium adolescentis, Collinsella aerofaciens, and Faecalibacterium prausnitzii were positively correlated with secondary bile acids. Together, these data identify several candidate bacteria that may contribute to the metabolic benefits of FMT and gut bacterial bile acid metabolism that requires further functional validation.
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The association of weight loss with changes in the gut microbiota diversity, composition, and intestinal permeability: a systematic review and meta-analysis.
Koutoukidis, DA, Jebb, SA, Zimmerman, M, Otunla, A, Henry, JA, Ferrey, A, Schofield, E, Kinton, J, Aveyard, P, Marchesi, JR
Gut microbes. 2022;(1):2020068
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The gut microbiome may be a mediator between obesity and health outcomes. However, it is unclear how intentional weight loss changes the gut microbiota and intestinal permeability. We aimed to systematically review and quantify this association. We searched Medline, Embase, CINAHL, Cochrane databases, and trial registries until June 2020 (PROSPERO CRD42020205292). We included trials of weight loss interventions (energy-restricted diets, pharmacotherapy, bariatric surgery) reporting on the microbiome. Two reviewers independently completed screening, extraction, and risk assessment with the ROBINS-I tool. Pooled standardized mean differences (SMDs) were obtained from random-effects meta-analyses. Forty-seven trials with 1,916 participants (81% female) and a median follow-up of 6 months (range: 2-24) were included. Based on imprecise evidence but with fairly consistent direction of effect, weight loss was associated with a statistically significant increase in α-diversity [SMD: 0.4 (95% CI: 0.2, 0.6], p < .0001, I2 = 70%, n = 30 studies) and a statistically significant reduction in intestinal permeability [SMD: -0.7 (95% CI: -0.9, -0.4), p < .0001, I2 = 83%, n = 17 studies]. Each kg of weight loss was associated with a 0.012 (95% CI: 0.0003, 0.024, p = .045) increase in α-diversity and a -0.017 (95% CI: -0.034, -0.001, p = .038) reduction in intestinal permeability. There was clear evidence of increases in the relative abundance of Akkermansia, but no clear evidence of changes in individual phyla, species, or fecal short-chain fatty acids. Restricting the analyses to the studies with lower risk of bias did not materially alter the estimates. Increasing weight loss is positively associated with increases in gut microbiota α-diversity and reductions in intestinal permeability.
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The impact of almonds and almond processing on gastrointestinal physiology, luminal microbiology, and gastrointestinal symptoms: a randomized controlled trial and mastication study.
Creedon, AC, Dimidi, E, Hung, ES, Rossi, M, Probert, C, Grassby, T, Miguens-Blanco, J, Marchesi, JR, Scott, SM, Berry, SE, et al
The American journal of clinical nutrition. 2022;(6):1790-1804
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BACKGROUND Almonds contain lipid, fiber, and polyphenols and possess physicochemical properties that affect nutrient bioaccessibility, which are hypothesized to affect gut physiology and microbiota. OBJECTIVES To investigate the impact of whole almonds and ground almonds (almond flour) on fecal bifidobacteria (primary outcome), gut microbiota composition, and gut transit time. METHODS Healthy adults (n = 87) participated in a parallel, 3-arm randomized controlled trial. Participants received whole almonds (56 g/d), ground almonds (56 g/d), or an isocaloric control in place of habitual snacks for 4 wk. Gut microbiota composition and diversity (16S rRNA gene sequencing), SCFAs (GC), volatile organic compounds (GC-MS), gut transit time (wireless motility capsule), stool output and gut symptoms (7-d diary) were measured at baseline and endpoint. The impact of almond form on particle size distribution (PSD) and predicted lipid release was measured (n = 31). RESULTS Modified intention-to-treat analysis was performed on 79 participants. There were no significant differences in mean ± SD abundance of fecal bifidobacteria after consumption of whole almonds (8.7% ± 7.7%), ground almonds (7.8% ± 6.9%), or control (13.0% ± 10.2%; q = 0.613). Consumption of almonds (whole and ground pooled) resulted in higher mean ± SD butyrate (24.1 ± 15.0 μmol/g) than control (18.2 ± 9.1 μmol/g; P = 0.046). There was no effect of almonds on gut microbiota at the phylum level or diversity, gut transit time, stool consistency, or gut symptoms. Almond form (whole compared with ground) had no effect on study outcomes. Ground almonds resulted in significantly smaller PSD and higher mean ± SD predicted lipid release (10.4% ± 1.8%) than whole almonds (9.3% ± 2.0%; P = 0.017). CONCLUSIONS Almond consumption has limited impact on microbiota composition but increases butyrate in adults, suggesting positive alterations to microbiota functionality. Almonds can be incorporated into the diet to increase fiber consumption without gut symptoms.This trial was registered at clinicaltrials.gov as NCT03581812.
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Daily supplementation with the Lab4P probiotic consortium induces significant weight loss in overweight adults.
Michael, DR, Davies, TS, Jack, AA, Masetti, G, Marchesi, JR, Wang, D, Mullish, BH, Plummer, SF
Scientific reports. 2021;(1):5
Abstract
This 9-month randomised, parallel, double-blind, single-centre, placebo-controlled study (PROBE, ISRCTN18030882) assessed the impact of probiotic supplementation on bodyweight. Seventy overweight Bulgarian participants aged 45-65 years with BMI 25-29.9 kg/m2 received a daily dose of the Lab4P probiotic comprising lactobacilli and bifidobacteria (50 billion cfu/day). Participants maintained their normal diet and lifestyle over the duration of the study. The primary outcome was change from baseline in body weight and secondary outcomes included changes in waist circumference, hip circumference and blood pressure. A significant between group decrease in body weight (3.16 kg, 95% CI 3.94, 2.38, p < 0.0001) was detected favouring the probiotic group. Supplementation also resulted in significant between group decreases in waist circumference (2.58 cm, 95% CI 3.23, 1.94, p < 0.0001) and hip circumference (2.66 cm, 95% CI 3.28, 2.05, p < 0.0001) but no changes in blood pressure were observed. These findings support the outcomes of a previous shorter-term Lab4P intervention study in overweight and obese participants (PROMAGEN, ISRCTN12562026). We conclude that Lab4P has consistent weight modulation capability in free-living overweight adults.
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Probiotics reduce self-reported symptoms of upper respiratory tract infection in overweight and obese adults: should we be considering probiotics during viral pandemics?
Mullish, BH, Marchesi, JR, McDonald, JAK, Pass, DA, Masetti, G, Michael, DR, Plummer, S, Jack, AA, Davies, TS, Hughes, TR, et al
Gut microbes. 2021;(1):1-9
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Gut microbiome manipulation to alter the gut-lung axis may potentially protect humans against respiratory infections, and clinical trials of probiotics show promise in this regard in healthy adults and children. However, comparable studies are lacking in overweight/obese people, who have increased risks in particular of viral upper respiratory tract infections (URTI). This Addendum further analyses our recent placebo-controlled trial of probiotics in overweight/obese people (focused initially on weight loss) to investigate the impact of probiotics upon the occurrence of URTI symptoms. As well as undergoing loss of weight and improvement in certain metabolic parameters, study participants taking probiotics experienced a 27% reduction in URTI symptoms versus control, with those ≥45 years or BMI ≥30 kg/m2 experiencing greater reductions. This symptom reduction is apparent within 2 weeks of probiotic use. Gut microbiome diversity remained stable throughout the study in probiotic-treated participants. Our data provide support for further trials to assess the potential role of probiotics in preventing viral URTI (and possibly also COVID-19), particularly in overweight/obese people.