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Effectiveness and safety of Bifidobacterium and berberine in human hyperglycemia and their regulatory effect on the gut microbiota: a multi-center, double-blind, randomized, parallel-controlled study.
Ming, J, Yu, X, Xu, X, Wang, L, Ding, C, Wang, Z, Xie, X, Li, S, Yang, W, Luo, S, et al
Genome medicine. 2021;(1):125
Abstract
BACKGROUND Berberine and Bifidobacterium have been reported to improve glucose tolerance in people with hyperglycemia or other metabolic disorders. This study aimed to assess the hypoglycemic effect and the regulation of the gut microbiota caused by berberine and Bifidobacterium and the possible additive benefits of their combination. METHODS This was an 18-week, multi-center, randomized, double-blind, parallel-controlled study of patients newly diagnosed with hyperglycemia. After a 2-week run-in period, 300 participants were randomly assigned to the following four groups for 16 weeks of treatment: berberine (Be), Bifidobacterium (Bi), berberine and Bifidobacterium (BB), and placebo group. The primary efficacy endpoint was the absolute value of fasting plasma glucose (FPG) compared with baseline after 16 weeks of treatment. RESULTS Between October 2015 and April 2018, a total of 297 participants were included in the primary analysis. Significant reductions of FPG were observed in the Be and BB groups compared with the placebo group, with a least square (LS) mean difference of - 0.50, 95% CI [- 0.85, - 0.15] mmol/L, and - 0.55, 95% CI [- 0.91, - 0.20] mmol/L, respectively. The Be and BB groups also showed significant reductions in 2-h postprandial plasma glucose. A pronounced decrease in HbA1c occurred in the BB group compared to the placebo group. Moreover, compared with the Bi and placebo groups, the Be and BB groups had more changes in the gut microbiota from the baseline. CONCLUSIONS Berberine could regulate the structure and function of the human gut microbiota, and Bifidobacterium has the potential to enhance the hypoglycemic effect of berberine. These findings provide new insights into the hypoglycemic potential of berberine and Bifidobacterium. TRIAL REGISTRATION ClinicalTrials.gov , NCT03330184. Retrospectively registered on 18 October 2017.
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A double-blind, 377-subject randomized study identifies Ruminococcus, Coprococcus, Christensenella, and Collinsella as long-term potential key players in the modulation of the gut microbiome of lactose intolerant individuals by galacto-oligosaccharides.
Azcarate-Peril, MA, Roach, J, Marsh, A, Chey, WD, Sandborn, WJ, Ritter, AJ, Savaiano, DA, Klaenhammer, TR
Gut microbes. 2021;(1):1957536
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Background. Our recent publication (Chey et al., Nutrients 2020) showed that a 30-day administration of pure galacto-oligosaccharides (GOS) significantly reduced symptoms and altered the fecal microbiome in patients with lactose intolerance (LI). Results. In this addendum, we performed an in-depth analysis of the fecal microbiome of the 377 LI patients randomized to one of two GOS doses (Low, 10-15 grams/day or High, 15-20 grams/day), or placebo in a multi-center, double-blinded, placebo-controlled trial. Sequencing of 16S rRNA amplicons was done on GOS or placebo groups at weeks zero (baseline), four (end of treatment), nine, 16 and 22. Taxa impacted by treatment and subsequent dairy consumption included lactose-fermenting species of Bifidobacterium, Lactobacillus, Lactococcus, and Streptococcus. Increased secondary fermentation microorganisms included Coprococcus and Ruminococcus species, Blautia producta, and Methanobrevibacterium. Finally, tertiary fermenters that use acetate to generate butyrate were also increased, including Faecalibacterium prausnitzii, Roseburia faecis, and C. eutactus. Conclusions. Results confirmed and expanded data on GOS microbiome modulation in LI individuals. Microbiome analysis at 16 and 22 weeks after treatment further suggested relatively long-term benefits when individuals continued consumption of dairy products.
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Evaluation of the gut microbiota after metformin intervention in children with obesity: A metagenomic study of a randomized controlled trial.
Pastor-Villaescusa, B, Plaza-Díaz, J, Egea-Zorrilla, A, Leis, R, Bueno, G, Hoyos, R, Vázquez-Cobela, R, Latorre, M, Cañete, MD, Caballero-Villarraso, J, et al
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2021;:111117
Abstract
BACKGROUND Metformin, a first-line oral antidiabetic agent that has shown promising results in terms of treating childhood and adolescent obesity, might influence the composition of the gut microbiota. We aimed to evaluate whether the gut microbiota of non-diabetic children with obesity changes after a metformin intervention. METHODS The study was a multicenter and double-blind randomized controlled trial in 160 children with obesity. Children were randomly assigned to receive either metformin (1 g/day) or placebo for 6 months in combination with healthy lifestyle recommendations in both groups. Then, we conducted a metagenomic analysis in a subsample obtained from 33 children (15 metformin, 18 placebo). A linear mixed-effects model (LMM) was used to determine the abundance changes from baseline to six months according to treatment. To analyze the data by clusters, a principal component analysis was performed to understand whether lifestyle habits have a different influence on the microbiota depending on the treatment group. RESULTS Actinobacteria abundance was higher after placebo treatment compared with metformin. However, the interaction time x treatment just showed a trend to be significant (4.6% to 8.1% after placebo vs. 3.8 % to 2.6 % after metformin treatment, p = 0.055). At genus level, only the abundance of Bacillus was significantly higher after the placebo intervention compared with metformin (2.5% to 5.7% after placebo vs. 1.5 % to 0.8 % after metformin treatment, p = 0.044). Furthermore, different ensembles formed by Firmicutes, Bacteroidetes, and Verrucomicrobia were found according to the interventions under a similar food consumption. CONCLUSION Further studies with a large sample size controlled by lifestyle patterns are required in obese children and adolescents to clarify whether metformin might trigger gut microbiota alterations. TRIAL REGISTRATION Registered on the European Clinical Trials Database (EudraCT, ID: 2010-023061-21) on 14 November 2011.
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Fecal Microbiota Transplant in Cirrhosis Reduces Gut Microbial Antibiotic Resistance Genes: Analysis of Two Trials.
Bajaj, JS, Shamsaddini, A, Fagan, A, Sterling, RK, Gavis, E, Khoruts, A, Fuchs, M, Lee, H, Sikaroodi, M, Gillevet, PM
Hepatology communications. 2021;(2):258-271
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Antibiotic resistance leads to poor outcomes in cirrhosis. Fecal microbiota transplant (FMT) is associated with reduction in antibiotic resistance gene (ARG) burden in patients without cirrhosis; however, the impact in cirrhosis is unclear. We aimed to study the effect of capsule and enema FMT on ARG abundance in fecal samples, which were collected during two published FMT trials in patients with cirrhosis on rifaximin, lactulose, and proton pump inhibitors. ARGs were identified using metagenomics and mapped against the Comprehensive Antibiotic Resistance Database. Changes in ARG abundance were studied within/between groups. The capsule FMT trial involved a one-time FMT or placebo capsule administration with stool collection at baseline and week 4 postintervention. Antibiotics+enema FMT included preprocedure antibiotics followed by FMT enema versus standard-of-care (SOC). Stool was collected at baseline, postantibiotics, and day 7/15 postintervention. Both trials included 20 patients each. There was no safety/infection signal linked to FMT. In the capsule trial, beta-lactamase (OXY/LEN) expression decreased post-FMT versus baseline. Compared to placebo, patients who were post-FMT had lower abundance of vancomycin (VanH), beta-lactamase (ACT), and rifamycin ARGs; the latter was associated with cognitive improvement. No changes were seen within patients treated with placebo. In the antibiotics+enema trial for postantibiotics at day 7 versus baseline, there was an increase in vancomycin and beta-lactamase ARGs, which decreased at day 15. However, quinolone resistance increased at day 15 versus baseline. Between SOC and FMT, day 7 had largely lower ARG (CfxA beta-lactamase, VanW, and VanX) that continued at day 15 (cepA beta-lactamase, VanW). No changes were seen within the SOC group. Conclusion: Despite differences in routes of administration and preintervention antibiotics, we found that ARG abundance is largely reduced after FMT compared to pre-FMT baseline and non-FMT groups in decompensated cirrhosis.
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Beneficial effects of lactitol on the composition of gut microbiota in constipated patients.
Li, XQ, Zhang, XM, Wu, X, Lan, Y, Xu, L, Meng, XC, Li, JN
Journal of digestive diseases. 2020;(8):445-453
Abstract
OBJECTIVE To explore the changes in microbial composition and the corresponding impact after lactitol treatment in constipated patients. METHODS Altogether 29 consecutive outpatients diagnosed with chronic constipation from three centers were recruited and stratified based on their history of diabetes mellitus. All patients were administered with oral lactitol for 2 weeks, and a symptoms diary of constipation was recorded. Fecal samples were collected before and after lactitol treatment, and were analyzed by 16S rRNA sequencing and real-time polymerase chain reaction (PCR) to detect gut microbiota. RESULTS Twenty patients with diabetes mellitus and nine without, all with chronic constipation, were enrolled in this study. After 2-week administration of lactitol, their subscale scores and constipation symptoms significantly decreased (P < 0.05). An analysis of fecal flora using 16S rRNA sequencing found an increasing trend of abundance of Bifidobacterium in the post-lactitol group (P = 0.08). Actinobacteria, Actinobacteria, Bifidobacteriales, Bifidobacteriaceae and Bifidobacterium were significantly more abundant after lactitol administration. Real-time PCR showed significantly high DNA copy numbers of Bifidobacterium after lactitol treatment (1.39 × 1010 vs 2.74 × 109 copies/μL, P = 0.01). The results of 16S rRNA sequencing and real-time PCR illustrated an increasing trend of Bifidobacterium in both patients with and without diabetes. In addition, Bifidobacterium was negatively correlated with constipation subscale scores. CONCLUSIONS Alterations in fecal flora composition after lactitol supplementation, especially in terms of an increasing trend of Bifidobacterium, alleviated constipation symptoms. Lactitol may be a promising prebiotic candidate for patients with constipation, regardless of diabetes mellitus.
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Effects of Low FODMAP Diet on Symptoms, Fecal Microbiome, and Markers of Inflammation in Patients With Quiescent Inflammatory Bowel Disease in a Randomized Trial.
Cox, SR, Lindsay, JO, Fromentin, S, Stagg, AJ, McCarthy, NE, Galleron, N, Ibraim, SB, Roume, H, Levenez, F, Pons, N, et al
Gastroenterology. 2020;(1):176-188.e7
Abstract
BACKGROUND & AIMS There is limited evidence that a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) reduces gut symptoms in quiescent inflammatory bowel disease (IBD). We performed a randomized, controlled trial to investigate the effects of a low FODMAP diet on persistent gut symptoms, the intestinal microbiome, and circulating markers of inflammation in patients with quiescent IBD. METHODS We performed a single-blind trial of 52 patients with quiescent Crohn's disease or ulcerative colitis and persistent gut symptoms at 2 large gastroenterology clinics in the United Kingdom. Patients were randomly assigned to groups that followed a diet low in FODMAPs (n = 27) or a control diet (n = 25), with dietary advice, for 4 weeks. Gut symptoms and health-related quality of life were measured using validated questionnaires. Stool and blood samples were collected at baseline and end of trial. We assessed fecal microbiome composition and function using shotgun metagenomic sequencing and phenotypes of T cells in blood using flow cytometry. RESULTS A higher proportion of patients reported adequate relief of gut symptoms following the low FODMAP diet (14/27, 52%) than the control diet (4/25, 16%, P=.007). Patients had a greater reduction in irritable bowel syndrome severity scores following the low FODMAP diet (mean reduction of 67; standard error, 78) than the control diet (mean reduction of 34; standard error, 50), although this difference was not statistically significant (P = .075). Following the low FODMAP diet, patients had higher health-related quality of life scores (81.9 ± 1.2) than patients on the control diet (78.3 ± 1.2, P = .042). A targeted analysis revealed that in stool samples collected at the end of the study period, patients on the low FODMAP diet had significantly lower abundance of Bifidobacterium adolescentis, Bifidobacterium longum, and Faecalibacterium prausnitzii than patients on control diet. However, microbiome diversity and markers of inflammation did not differ significantly between groups. CONCLUSIONS In a trial of the low FODMAP diet vs a control diet in patients with quiescent IBD, we found no significant difference after 4 weeks in change in irritable bowel syndrome severity scores, but significant improvements in specific symptom scores and numbers reporting adequate symptom relief. The low FODMAP diet reduced fecal abundance of microbes believed to regulate the immune response, compared with the control diet, but had no significant effect on markers of inflammation. We conclude that a 4-week diet low in FODMAPs is safe and effective for managing persistent gut symptoms in patients with quiescent IBD. www.isrctn.com no.: ISRCTN17061468.
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Gut microbiota metabolites, amino acid metabolites and improvements in insulin sensitivity and glucose metabolism: the POUNDS Lost trial.
Heianza, Y, Sun, D, Li, X, DiDonato, JA, Bray, GA, Sacks, FM, Qi, L
Gut. 2019;(2):263-270
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OBJECTIVE Alterations in gut microbiota have been linked to host insulin resistance, diabetes and impaired amino acid metabolism. We investigated whether changes in gut microbiota-dependent metabolite of trimethylamine N-oxide (TMAO) and its nutrient precursors (choline and L-carnitine) were associated with improvements in glucose metabolism and diabetes-related amino acids in a weight-loss diet intervention. DESIGN We included 504 overweight and obese adults who were randomly assigned to one of four energy-reduced diets varying in macronutrient intake. The 6-month changes (Δ) in TMAO, choline and L-carnitine levels after the intervention were calculated. RESULTS Greater decreases in choline and L-carnitine were significantly (p<0.05) associated with greater improvements in fasting insulin concentrations and homeostasis model assessment of insulin resistance (HOMA-IR) at 6 months. The reduction of choline was significantly related to 2-year improvements in glucose and insulin resistance. We found significant linkages between dietary fat intake and ΔTMAO for changes in fasting glucose, insulin and HOMA-IR (pinteraction <0.05); a greater increase in TMAO was related to lesser improvements in the outcomes among participants who consumed a high-fat diet. In addition, ΔL-carnitine and Δcholine were significantly related to changes in amino acids (including branched-chain and aromatic amino acids). Interestingly, the associations of ΔTMAO, Δcholine and ΔL-carnitine with diabetes-related traits were independent of the changes in amino acids. CONCLUSION Our findings underscore the importance of changes in TMAO, choline and L-carnitine in improving insulin sensitivity during a weight-loss intervention for obese patients. Dietary fat intake may modify the associations of TMAO with insulin sensitivity and glucose metabolism. TRIAL REGISTRATION NUMBER NCT00072995.
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Lactulose improves cognition, quality of life, and gut microbiota in minimal hepatic encephalopathy: A multicenter, randomized controlled trial.
Wang, JY, Bajaj, JS, Wang, JB, Shang, J, Zhou, XM, Guo, XL, Zhu, X, Meng, LN, Jiang, HX, Mi, YQ, et al
Journal of digestive diseases. 2019;(10):547-556
Abstract
OBJECTIVE Lactulose is effective in the treatment and prevention of overt hepatic encephalopathy (OHE), but there are limited data on its use on microbiota in relations to minimal hepatic encephalopathy (MHE) recovery. The present study aimed to assess the efficacy of lactulose in recovery of MHE in aspects of cognitive function, quality of life, and impact on intestinal microbiota. METHODS This multicenter, open-label randomized controlled trial was conducted in 11 teaching hospitals in China. Participants were randomly allocated on a 2:1 basis to receive lactulose (Gp-L) or no therapy as control (Gp-NL) for 60 days. The primary endpoint was the MHE reversal rate. Gut microbiota were compared between MHE patients and healthy volunteers, as well as lactulose-responders and non-responders. RESULTS A total of 98 cirrhotic patients were included in the study, with 31 patients in the Gp-NL group and 67 patients in the Gp-L group. At day 60, the MHE reversal rate in Gp-L (64.18%) was significantly higher than that in Gp-NL (22.58%) (P = .0002) with a relative risk of 0.46 (95% confidence interval 0.32-0.67). Number needed to treat was 2.4. Further, there was significantly more improvement in physical functioning in Gp-L (4.62 ± 6.16) than in Gp-NL (1.50 ± 5.34) (P = .0212). Proteobacteria was significantly higher in MHE patients compared with healthy volunteers (12.27% vs 4.65%, P < .05). Significant differences were found between lactulose responders and non-responders in Actinobacteria, Bacteroidetes, Firmicutes, and Proteobacteria. CONCLUSIONS Treatment with lactulose significantly improves MHE recovery rate, and gut microbiota change in MHE patients can modulate the effectiveness of this therapy. Chinese Clinical Trial Register (ChiCTR) (ID: ChiCTR-TRC-12002342).
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Association Between Antibiotics in the First Year of Life and Celiac Disease.
Dydensborg Sander, S, Nybo Andersen, AM, Murray, JA, Karlstad, Ø, Husby, S, Størdal, K
Gastroenterology. 2019;(8):2217-2229
Abstract
BACKGROUND & AIMS The intestinal microbiota is believed to be involved in the pathogenesis of celiac disease, in addition to genetic variants and dietary gluten. The gut microbiota is strongly influenced by systemic antibiotics-especially in early life. We explored the association between exposure to a systemic antibiotic in the first year of life and risk of diagnosed celiac disease. METHODS We performed an observational nationwide register-based cohort study. We included all children born in Denmark from 1995 through 2012 or Norway from 2004 through 2012. Children born in Denmark were followed until May 8, 2015 (age at end of follow-up was 2.3-20.3 years) and children born in Norway were followed until December 31, 2013 (age at end of follow-up was 1-10 years). We collected medical information from more than 1.7 million children, including 3346 with a diagnosis of celiac disease. Exposure to systemic antibiotics was defined as a dispensed systemic antibiotic in the first year of life. RESULTS Exposure to systemic antibiotics in the first year of life was positively associated with diagnosed celiac disease in the Danish and Norwegian cohorts (pooled odds ratio 1.26, 95% confidence interval 1.16-1.36). We found a dose-dependent relation between an increasing number of dispensed antibiotics and the risk of celiac disease (pooled odds ratio for each additional dispensed antibiotic 1.08, 95% confidence interval 1.05-1.11). No specific type of antibiotic or age period within the first year of life was prominent. Adjustment for hospital admissions with an infectious disease in the first year of life did not change the estimates; adjustment for the number of maternally reported infections in the child in 2 large sub-cohorts decreased the association slightly (pooled odds ratio 1.18, 95% confidence interval 0.98-1.39). CONCLUSION In a nationwide study of children in Denmark and Norway, we found exposure to systemic antibiotics in the first year of life to be associated with a later diagnosis of celiac disease. These findings indicate that childhood exposure to systemic antibiotics could be a risk factor for celiac disease.
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Azithromycin and metronidazole versus metronidazole-based therapy for the induction of remission in mild to moderate paediatric Crohn's disease : a randomised controlled trial.
Levine, A, Kori, M, Kierkus, J, Sigall Boneh, R, Sladek, M, Escher, JC, Wine, E, Yerushalmi, B, Amil Dias, J, Shaoul, R, et al
Gut. 2019;(2):239-247
Abstract
OBJECTIVE Crohn's disease (CD) pathogenesis associated with dysbiosis and presence of pathobionts in the lumen, intracellular compartments and epithelial biofilms. Azithromycin is active in all three compartments. Our goal was to evaluate if azithromycin-based therapy can improve response and induce remission compared with metronidazole alone in paediatric CD.
DESIGN This blinded randomised controlled trial allocated children 5-18 years with 10
12.5 or remission using intention to treat analysis. RESULTS 73 patients (mean age 13.8±3.1 years) were enrolled, 35 to group 1 and 38 to group 2. Response and remission rates at week 8 were identical 23/35 (66%) in group 1 and 17/38 (45%) and 15/38 (39%) in group 2 (P=0.07 and P=0.025, respectively). The needed to treat for remission was 3.7. Faecal calprotectin declined significantly in group 1 (P=0.003) but not in group 2 (p=0.33), and was lower at week 8 (P=0.052). Additional therapy was required in 6/35(17%) from group 1 versus 16/38(42%) in group 2 (P=0.027) by week 8. Among 12 failures in group 2, open-label azithromycin led to remission in 10/12 (83%). CONCLUSIONS The combination of azithromycin and metronidazole failed to improve response but was superior for induction of remission and reduction in calprotectin. TRIAL REGISTRATION NUMBER NCT01596894.