NMN synbiotics intervention modulates gut microbiota and metabolism in APP/PS1 Alzheimer's disease mouse models.

Alzheimer's disease (AD) is a complex neurodegenerative condition with growing evidence implicating the gut microbiota in its pathogenesis. This study aimed to investigate the effects of NMN synbiotics, a combination of ß-nicotinamide mononucleotide (NMN), Lactobacillus plantarum, and lactulose, on the gut microbiota composition and metabolic profiles in APP/PS1 transgenic mice. Results demonstrated that NMN synbiotics led to a notable restructuring of the gut microbiota, with a decreased Firmicutes/Bacteroidetes ratio in the AD mice, suggesting a potential amelioration of gut dysbiosis. Alpha diversity indices indicated a reduction in microbial diversity following NMN synbiotics supplementation, while beta diversity analyses revealed a shift towards a more balanced microbial community structure. Functional predictions based on the 16S rRNA data highlighted alterations in metabolic pathways, particularly those related to amino acid and energy metabolism, which are crucial for neuronal health. The metabolomic analysis uncovered a significant impact of NMN synbiotics on the gut metabolome, with normalization of metabolic composition in AD mice. Differential metabolite functions were enriched in pathways associated with neurotransmitter synthesis and energy metabolism, pointing to the potential therapeutic effects of NMN synbiotics in modulating the gut-brain axis and synaptic function in AD. Immunohistochemical staining observed a significant reduction of amyloid plaques formed by Aß deposition in the brain of AD mice after NMN synbiotics intervention. The findings underscore the potential of using synbiotics to ameliorate the neurodegenerative processes associated with Alzheimer's disease, opening new avenues for therapeutic interventions.

Synergistic immunomodulatory effect of synbiotics pre- and postoperative resection of pancreatic ductal adenocarcinoma: a randomized controlled study.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a highly immunosuppressive microenvironment. This single-blind, randomized study aimed to evaluate the synergistic immunomodulatory effects of synbiotics (probiotics and inulin prebiotics), as well as their impact on postoperative complications and outcomes, compared to the use of probiotics alone. Ninety patients diagnosed with PDAC were enrolled and randomly assigned into three groups: the placebo group, the probiotics group (receiving a mixture of ten strains of Lactobacillus, Bifidobacterium, and Streptococcus bacteria at a dose of 25 billion CFUs), and the synbiotics group (the same probiotics along with inulin prebiotics). The interventions were administered for 14 days before the surgery and continued for one month postoperatively. Tumor tissue infiltration of CD8 + T cells and the expression of IFN γ were assessed by immunohistochemistry (IHC). Inflammatory cytokines concentrations, including Il 1 B, IL 6, and IL 10, were evaluated as well by ELISA at various time points pre- and postoperative. Furthermore, patients were followed up after the surgery to assess postoperative short-term outcomes. Our results showed a significant elevation of CD8 + T cell proportion and IFN γ expression in the synbiotics group compared to the probiotics group (p = 0.049, p = 0.013, respectively). Inflammatory cytokines showed a significant gradual decrease in the synbiotics group compared to placebo and probiotics-treated groups (p = 0.000 for both). Administration of synbiotics and probiotics significantly decreased the rate of postoperative complications including anastomotic leakage, diarrhea, and abdominal distension (p = 0.032, p = 0.044, p = 0.042, respectively), with a remarkable reduction in bacteremia in the synbiotics group. These results revealed that this synbiotics formulation potentially enhances the immune response and reduces complications associated with surgery.Clinical trial identification: NCT06199752 (27-12-2023).

Evaluation of the synbiotic effects of Saccharomyces cerevisiae and mushroom extract on the growth performance, digestive enzyme activity, and immune status of zebrafish danio rerio.

BACKGROUND: The quest for candidate probiotics and prebiotics to develop novel synbiotics for sustainable and profitable fish farming remains a major focus for various stakeholders. In this study, we examined the effects of combining two fungal probiotics, Saccharomyces cerevisiae and Aspergillus niger with extracts of Jerusalem artichoke and white button mushroom to develop a synbiotic formulation to improve the growth and health status of zebrafish (Danio rerio). An initial in vitro study determined the most effective synbiotic combination, which was then tested in a 60-day in vivo nutritional trial using zebrafish (80 ± 1.0 mg) as a model animal. Four experimental diets were prepared: a control diet (basal diet), a prebiotic diet with 100% selected mushroom extract, a probiotic diet with 107 CFU of S. cerevisiae/g of diet, and a synbiotic diet with 107 CFU of S. cerevisiae/g of diet and 100% mushroom extract. As readouts, growth performance, survival, digestive enzyme activity and innate immune responses were evaluated. RESULTS: In vitro results showed that the S. cerevisiae cultured in a medium containing 100% mushroom extract exhibited the maximum specific growth rate and shortest doubling time. In the in vivo test with zebrafish, feeding them with a synbiotic diet, developed with S. cerevisiae and mushroom extract, led to a significant improvement in the growth performance of zebrafish (P < 0.05). The group of zebrafish fed with the synbiotic diet showed significantly higher levels of digestive enzyme activity and immune responses compared to the control group (P < 0.05). CONCLUSION: Taken together, these results indicated that the combination of S. cerevisiae and mushroom extract forms an effective synbiotic, capable of enhancing growth performance and immune response in zebrafish.

Multi-species synbiotic supplementation increased fecal short chain fatty acids and anti-inflammatory cytokine interleukin-10 in adult men with dyslipidemia; A randomized, double-blind, clinical trial.

BACKGROUND: Mounting evidence revealed that an imbalance of Gut Microbiota (GM) leads to metabolic disorders. Synbiotics through regulation of GM composition can be an effective intervention in the management of metabolic diseases. This study aimed to investigate the effects of multi-species synbiotic supplementation on serum interleukin10 (IL-10) and fecal Short Chain Fatty Acids (SCFAs) in patients with dyslipidemia. METHODS: In this double-blind, randomized, placebo-controlled clinical trial, fifty-six adult men with dyslipidemia were randomly allocated to intervention and control groups and received either synbiotic or placebo powder twice a day for 12 weeks. Each synbiotic sachet contained 6 species of probiotic microorganisms with a total dose of 3 × 1010 Colony Forming Unit (CFU) and 5 gr inulin and Fructooligosaccharide (FOS) as prebiotics. Blood and stool samples were collected at the baseline and end of the study. Dietary intake, physical activity, anthropometric measurements, serum IL-10, and fecal SCFAs were assessed before and after the intervention. RESULT: There were no significant differences between the baseline characteristics of patients in the two groups. Serum IL-10 was increased in the synbiotic group (p < 0.0001). Moreover, synbiotic supplementation increased fecal concentration of acetate (p < 0.0001), butyrate (p = 0.043), propionate (p < 0.0001), and valerate (p < 0.026). A significant positive correlation was observed between the changes in fecal butyrate level and serum IL-10 concentration in the control group (r = 0.48, p = 0.01). CONCLUSIONS: A Twelve-week synbiotic supplementation increased fecal SCFAs and improved inflammation in adult men with dyslipidemia.

Efficacy of a synbiotic in the management of adults with Attention-Deficit and Hyperactivity Disorder and/or Borderline Personality Disorder and high levels of irritability: Results from a multicenter, randomized, placebo-controlled, "basket" trial.

Irritability worsens prognosis and increases mortality in individuals with Attention-Deficit and Hyperactivity Disorder (ADHD) and/or Borderline Personality Disorder (BPD). However, treatment options are still insufficient. The aim of this randomized, double blind, placebo-controlled study was to investigate the superiority of a synbiotic over placebo in the management of adults with ADHD and/or BPD and high levels of irritability. The study was conducted between February 2019 and October 2020 at three European clinical centers located in Hungary, Spain and Germany. Included were patients aged 18-65 years old diagnosed with ADHD and/or BPD and high levels of irritability (i.e., an Affectivity Reactivity Index (ARI-S) ≥ 5, plus a Clinical Global Impression-Severity Scale (CGI-S) score ≥ 4). Subjects were randomized 1(synbiotic):1(placebo); the agent was administered each day, for 10 consecutive weeks. The primary outcome measure was end-of-treatment response (i.e., a reduction ≥ 30 % in the ARI-S total score compared to baseline, plus a Clinical Global Impression-Improvement (CGI-I) total score of < 3 (very much, or much improved) at week 10). Between-treatment differences in secondary outcomes, as well as safety were also investigated. Of the 231 included participants, 180 (90:90) were randomized and included in the intention-to-treat-analyses. Of these, 117 (65 %) were females, the mean age was 38 years, ADHD was diagnosed in 113 (63 %), BPD in 44 (24 %), both in 23 (13 %). The synbiotic was well tolerated. At week 10, patients allocated to the synbiotic experienced a significantly higher response rate compared to those allocated to placebo (OR: 0.2, 95 % CI:0.1 to 0.7; P = 0.01). These findings suggest that that (add-on) treatment with a synbiotic may be associated with a clinically meaningful improvement in irritability in, at least, a subgroup of adults with ADHD and/or BPD. A superiority of the synbiotic over placebo in the management of emotional dysregulation (-3.6, 95 % CI:-6.8 to -0.3; P = 0.03), emotional symptoms (-0.6, 95 % CI:-1.2 to -0.05; P = 0.03), inattention (-1.8, 95 % CI: -3.2 to -0.4; P = 0.01), functioning (-2.7, 95 % CI: -5.2 to -0.2; P = 0.03) and perceived stress levels (-0.6, 95 % CI: -1.2 to -0.05; P = 0.03) was also suggested. Higher baseline RANK-L protein levels were associated with a significantly lower response rate, but only in the synbiotic group (OR: 0.1, 95 % CI: -4.3 to - 0.3, P = 0.02). In the placebo group, higher IL-17A levels at baseline were significantly associated with a higher improvement in in particular, emotional dysregulation (P = 0.04), opening a door for new (targeted) drug intervention. However, larger prospective studies are warranted to confirm the findings. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03495375.

NMN Synbiotics: A Multifaceted Therapeutic Approach for Alzheimer's Disease.

With the aging global population, Alzheimer's disease (AD) has become a significant social and economic burden, necessitating the development of novel therapeutic strategies. This study investigates the therapeutic potential of nicotinamide mononucleotide (NMN) synbiotics, a combination of NMN, Lactiplantibacillus plantarum CGMCC 1.16089, and lactulose, in mitigating AD pathology. APP/PS1 mice were supplemented with NMN synbiotics and compared against control groups. The effects on amyloid-ß (Aß) deposition, intestinal histopathology, tight junction proteins, inflammatory cytokines, and reactive oxygen species (ROS) levels were assessed. NMN synbiotics intervention significantly reduced Aß deposition in the cerebral cortex and hippocampus by 67% and 60%, respectively. It also ameliorated histopathological changes in the colon, reducing crypt depth and restoring goblet cell numbers. The expression of tight junction proteins Claudin-1 and ZO-1 was significantly upregulated, enhancing intestinal barrier integrity. Furthermore, NMN synbiotics decreased the expression of proinflammatory cytokines IL-1ß, IL-6, and TNF-α, and reduced ROS levels, indicative of attenuated oxidative stress. The reduction in Aß deposition, enhancement of intestinal barrier function, decrease in neuroinflammation, and alleviation of oxidative stress suggest that NMN synbiotics present a promising therapeutic intervention for AD by modulating multiple pathological pathways. Further research is required to elucidate the precise mechanisms, particularly the role of the NLRP3 inflammasome pathway, which may offer a novel target for AD treatment.

The effect of synbiotics on liver enzymes, obesity indices, blood pressure, lipid profile, and inflammation in patients with non-alcoholic fatty liver: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Patients with non-alcoholic fatty liver disease (NAFLD) benefit from using synbiotics. However, findings from existing trials remain contentious. Therefore, this meta-analysis evaluated the effects of synbiotics on liver enzymes, blood pressure, inflammation, and lipid profiles in patients with NAFLD. METHODS: We searched PubMed, Embase, Cochrane, Scopus, and Web of Science for randomized controlled trials (RCTs) regarding synbiotics supplementation in patients with NAFLD. RESULTS: The meta-analysis revealed that synbiotics supplementation significantly improved liver enzymes (AST, WMD: -9.12 IU/L; 95 % CI: -13.19 to -5.05; ALT, WMD: -8.53 IU/L; 95 % CI: -15.07 to -1.99; GGT, WMD: -10.42 IU/L; 95 % CI: -15.19 to -5.65), lipid profile (TC, WMD: -7.74 mg/dL; 95 % CI: -12.56 to -2.92), obesity indices (body weight, WMD: -1.95 kg; 95 % CI: -3.69 to -0.22; WC, WMD: -1.40 cm; 95 % CI: -2.71 to -0.10), systolic blood pressure (SBP, WMD: -6.00 mmHg; 95 % CI: -11.52 to -0.49), and inflammatory markers (CRP, WMD: -0.69 mg/L; 95 % CI: -1.17 to -0.21; TNF-α, WMD: -14.01 pg/mL; 95 % CI: -21.81 to -6.20). CONCLUSION: Overall, supplementation with synbiotics positively improved liver enzymes, obesity indices, and inflammatory cytokines in patients with NAFLD.

Efficacy of probiotics, prebiotics, and synbiotics on liver enzymes, lipid profiles, and inflammation in patients with non-alcoholic fatty liver disease: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: There is a contradiction in the use of microbiota-therapies, including probiotics, prebiotics, and synbiotics, to improve the condition of patients with nonalcoholic fatty liver disease (NAFLD). The aim of this review was to evaluate the effect of microbiota-therapy on liver injury, inflammation, and lipid levels in individuals with NAFLD. METHODS: Using Pubmed, Embase, Cochrane Library, and Web of Science databases were searched for articles on the use of prebiotic, probiotic, or synbiotic for the treatment of patients with NAFLD up to March 2024. RESULTS: Thirty-four studies involving 12,682 individuals were included. Meta-analysis indicated that probiotic, prebiotic, and synbiotic supplementation significantly improved liver injury (hepatic fibrosis, SMD = -0.31; 95% CI: -0.53, -0.09; aspartate aminotransferase, SMD = -0.35; 95% CI: -0.55, -0.15; alanine aminotransferase, SMD = -0.48; 95% CI: -0.71, -0.25; alkaline phosphatase, SMD = -0.81; 95% CI: -1.55, -0.08), lipid profiles (triglycerides, SMD = -0.22; 95% CI: -0.43, -0.02), and inflammatory factors (high-density lipoprotein, SMD = -0.47; 95% CI: -0.88, -0.06; tumour necrosis factor alpha, SMD = -0.86 95% CI: -1.56, -0.56). CONCLUSION: Overall, supplementation with probiotic, prebiotic, or synbiotic had a positive effect on reducing liver enzymes, lipid profiles, and inflammatory cytokines in patients with NAFLD.

Network meta-analysis of probiotics, prebiotics, and synbiotics for the treatment of chronic constipation in adults.

OBJECTIVE: To compare the outcomes associated with the use of probiotics, prebiotics, and synbiotics for the treatment of chronic constipation in adults. METHODS: We searched eight electronic databases from database inception to July 11, 2023, to identify randomized controlled trials (RCTs) that report efficacy and safety for the treatment of chronic constipation. The risk of bias in the included RCTs was evaluated according to the Cochrane tool, and the certainty of the evidence was assessed using the Confidence in Network Meta-Analysis framework. The analysis was conducted using R version 4.3.0. RESULTS: Out of the 37 RCTs, a total of 21 different types of interventions were reported, involving 3,903 patients. This NMA demonstrated that both prebiotics and synbiotics resulted in an increase in frequency of stool movements per week. Compared to placebo, lactulose (Mean difference [MD] = 3.39, 95% Confdence interval [CI] [1.13, 5.65], moderate certainty), mix2 (consisting of Lactulose and Bacillus coagulans) (MD = 3.63, 95% CI [1.37, 5.89], moderate certainty), mix6 (consisting of Lactulose and Bifidobacterium coagulans) (MD = 4.30, 95% CI [1.04, 7.54], low certainty), and mix7 (consisting of Lactulose, Bifidobacterium subtilis, and Enterococcus faecium) (MD = 4.58, 95% CI [1.35, 7.78], moderate certainty) exhibited a significant effect. Notably, mix7 demonstrated the highest probability of being the most effective intervention (94.8%). Furthermore, when compared to L. plantarum, four probiotics and two synbiotics showed significant advantages in the Patient Assessment of Constipation Symptoms (PAC-SYM) score. L. reuteri (MD = -13.74, 95% CI [-22.20, -4.66], very low certainty) exhibited a significant effect in improving the Patient Assessment of Constipation Quality of Life (PAC-QoL) score. In terms of safety, there were no statistically significant differences between the intervention and control groups in all adverse event analyses. CONCLUSIONS: Moderate to very low evidence supports the use of lactulose and synbiotics to increase the number of weekly stool movements in patients, particularly highlighting the significant impact of synbiotics in increasing the number of weekly stool movements in patients with constipation. The use of L. paracasei showed improvements in PAC-SYM scores, while L. reuteri demonstrated enhancements in PAC-QoL scores.

Effects of synbiotic supplementation on the components of metabolic syndrome in patients with schizophrenia: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Antipsychotic drugs may have adverse effects on the components of metabolic syndrome. Previous studies have shown that changes in the intestinal microbiome are associated with metabolic disturbances in patients with schizophrenia. The objective of this study was to determine the effects of synbiotics on the components of metabolic syndrome as primary outcomes in patients with schizophrenia. Secondary outcomes were HbA1c, insulin resistance, LDL-c, and anthropometric measurements. METHODS: In this double-blind, placebo-controlled trial, seventy patients with schizophrenia receiving antipsychotic drugs who had at least two criteria of metabolic syndrome were randomly divided into two groups to receive either two capsules of a synbiotic supplement or a placebo daily for 8 weeks. Anthropometric indices and biochemical parameters were measured at baseline and after the intervention. RESULTS: Fifty-five patients completed the study. The synbiotic supplement significantly decreased waist circumference and HbA1C compared to placebo (-2.66 ± 4.20 vs. 3.03 ± 4.50 and - 0.26 ± 0.54 vs. 0.20 ± 0.75, respectively). Although BMI did not change significantly in the synbiotic + antipsychotic group, it increased in the placebo + antipsychotic group (-0.37 ± 1.00 vs. 0.61 ± 1.09 P < 0.5). LDL-c and triglyceride (TG) levels decreased significantly in the synbiotic + antipsychotic group, but the change was not significantly different from that of the placebo + antipsychotic group. FBS, HDL-c, systolic and diastolic blood pressure, insulin resistance, and total cholesterol were not significantly different between the two groups after intervention. CONCLUSION: Synbiotic supplement may decrease waist circumference, HbA1c, LDL and TG and prevent BMI increase in patients receiving antipsychotic drugs. TRIAL REGISTRATION: Iranian Registry of Clinical Trials (IRCT Number: IRCT20090901002394N45), Date: 26-12-2019.

Assessment of the Prophylactic Effects of Probiotics, Prebiotics, and Synbiotics Against COVID-19 Infection: A Systematic Review of Randomized Controlled Trials.

Background: Although various treatments are developed against COVID-19 variants, probiotic, and synbiotic adjunct therapy with several benefits such as safety, low cost, and availability could be needed for preventing or treating COVID-19 infection.Objective: The present systematic review aimed to assess the prophylactic efficacy of the probiotic, prebiotic, and synbiotic administration against COVID-19.Methods: The protocol of this systematic review was registered at the PROSPERO (Code number: CRD42023418900). The Scopus, Cochrane Library, Web of Sciences, and PubMed databases were systematically searched to define the clinical trials published up to November 2022 in the English language. The comparison of the incidence of COVID-19 disease and levels of specific antibodies against SARS-cov2 between the intervention and placebo groups were evaluated in this systematic review.Results: According to the five included trials, four indicated the incidence of COVID-19, and no significant differences were observed between the probiotic and placebo groups during 1, 2, or 3 months of follow-up in the mentioned studies. Regarding the antibody assays against SARS-Cov2 including IgM, IgG, or IgA reported by three eligible trials, there were no significant differences between the intervention and control groups.Conclusion: It seems that the administration of single or multi-strain probiotics or synbiotics had no prophylactic effects in different populations such as high-risk staff exposed to COVID-19, elderly nursing home residents, healthy adults, and household contact with COVID-19 patients during 1-to-3-months of intervention.

Nutritional Interventions, Probiotics, Synbiotics and Fecal Microbiota Transplantation in Steatotic Liver Disease : Pediatric Fatty Liver and Probiotics.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major health problem worldwide, and the strongest determinant of liver disease in children. The possible influence of high-fat/low-fiber dietary patterns with microbiota (e.g., increased Firmicutes/Bacteroidetes ratio), and ultimately with MASLD occurrence and progression has been elucidated by several association studies. The possible mechanisms through which microbes exert their detrimental effects on MASLD include gut vascular barrier damage, a shift towards non-tolerogenic immunologic environment, and the detrimental metabolic changes, including a relative reduction of propionate and butyrate in favor of acetate, endogenous ethanol production, and impairment of the unconjugated bile acid-driven FXR-mediated gut-liver axis. The impact of nutritional and probiotic interventions in children with MASLD is described.

A new intestinal supplement 'Synbiotics' therapeutically regulates gut microbiota and activates PPARs pathway to inhibit Alzheimer's disease progression in mouse models.

We aimed to investigate the role of Synbiotic preparations on the interaction of gut microbiota with AD development. APP/PS1 mice were randomized into APP/PS1 and Synbiotics groups, and C57BL/6J mice were used as wild type (WT) control group. The mice in the Synbiotics group and the APP/PS1 group were given Synbiotics and xylo-oligosaccharides for 3 months, respectively. The mice in the WT group were given the same amount of normal saline. Cognitive function was measured. Positron emission computed tomography/magnetic resonance imaging (PET/MRI) was used to detect fasting blood glucose level. Immunohistochemical assay, ELISA, western blot and qRT-PCR were carried out to detect inflammatory factors. DNA extraction of fecal sample was performed to carry out sequencing. Bioinformatics analysis, metabolites sample preparation and Liquid Chromatograph Mass Spectrometer (LC/MS) analysis were also performed. Synbiotics treatment can significantly ameliorate learning and memory competence by inhibiting Aß protein deposition. Different bacteria in the intestine were significantly improved and changes in gut microbiota can affect the intestinal metabolism to affect multiple potential pathways after Synbiotics treatment. Synbiotics treatment can activate peroxisome proliferator activated receptor (PPARs) signaling pathway and significantly reduce neuroinflammation in APP/PS1 mice brains. Synbiotics treatment can effectively reduce neuro-inflammatory response through the regulation of intestinal microflora to delay AD development.

Effect of Lacticaseibacillus paracasei K56 with galactooligosaccharide synbiotics on obese individuals: an in vitro fermentation model.

BACKGROUND: The use of synbiotics is emerging as a promising intervention strategy for regulating the gut microbiota and for preventing or reducing obesity, in comparison with the use of probiotics or prebiotics alone. A previous in vivo study revealed that Lacticaseibacillus paracasei K56 (L. paracasei K56) could alleviate obesity induced in high-fat-diet mice; however, the effect of the synbiotic combination of L. paracasei K56 and prebiotics in obese individuals has not been explored fully. RESULTS: The effect of prebiotics on the proliferation of L. paracasei K56 was determined by spectrophotometry. The results showed that polydextrose (PG), xylooligosaccharide (XOS), and galactooligosaccharide (GOS) had a greater potential to be used as substrates for L. paracasei K56 than three other prebiotics (melitose, stachyose, and mannan-oligosaccharide). An in vitro fermentation model based on the feces of ten obese female volunteers was then established. The results revealed that K56_GOS showed a significant increase in GOS degradation rate and short-chain fatty acid (SCFA) content, and a decrease in gas levels, compared with PG, XOS, GOS, K56_PG, and K56_XOS. Changes in these microbial biomarkers, including a significant increase in Bacteroidota, Bifidobacterium, Lactobacillus, Faecalibacterium, and Blautia and a decrease in the Firmicutes/Bacteroidota ratio and Escherichia-Shigella in the K56_GOS group, were associated with increased SCFA content and decreased gas levels. CONCLUSION: This study demonstrates the effect of the synbiotic combination of L. paracasei K56 and GOS on obese individuals and indicates its potential therapeutic role in obesity treatment. © 2024 Society of Chemical Industry.

A randomized synbiotic trial to prevent sepsis among infants in rural India.

Sepsis in early infancy results in one million annual deaths worldwide, most of them in developing countries. No efficient means of prevention is currently available. Here we report on a randomized, double-blind, placebo-controlled trial of an oral synbiotic preparation (Lactobacillus plantarum plus fructooligosaccharide) in rural Indian newborns. We enrolled 4,556 infants that were at least 2,000 g at birth, at least 35 weeks of gestation, and with no signs of sepsis or other morbidity, and monitored them for 60 days. We show a significant reduction in the primary outcome (combination of sepsis and death) in the treatment arm (risk ratio 0.60, 95% confidence interval 0.48-0.74), with few deaths (4 placebo, 6 synbiotic). Significant reductions were also observed for culture-positive and culture-negative sepsis and lower respiratory tract infections. These findings suggest that a large proportion of neonatal sepsis in developing countries could be effectively prevented using a synbiotic containing L. plantarum ATCC-202195.

Tolerance development in cow's milk-allergic infants receiving amino acid-based formula: A randomized controlled trial.

BACKGROUND: Tolerance development is an important clinical outcome for infants with cow's milk allergy. OBJECTIVE: This multicenter, prospective, randomized, double-blind, controlled clinical study (NTR3725) evaluated tolerance development to cow's milk (CM) and safety of an amino acid-based formula (AAF) including synbiotics (AAF-S) comprising prebiotic oligosaccharides (oligofructose, inulin) and probiotic Bifidobacterium breve M-16V in infants with confirmed IgE-mediated CM allergy. METHODS: Subjects aged ≤13 months with IgE-mediated CM allergy were randomized to receive AAF-S (n = 80) or AAF (n = 89) for 12 months. Stratification was based on CM skin prick test wheal size and study site. After 12 and 24 months, CM tolerance was evaluated by double-blind, placebo-controlled food challenge. A logistic regression model used the all-subjects randomized data set. RESULTS: At baseline, mean ± SD age was 9.36 ± 2.53 months. At 12 and 24 months, respectively, 49% and 62% of subjects were CM tolerant (AAF-S 45% and 64%; AAF 52% and 59%), and not differ significantly between groups. During the 12-month intervention, the number of subjects reporting at least 1 adverse event did not significantly differ between groups; however, fewer subjects required hospitalization due to serious adverse events categorized as infections in the AAF-S versus AAF group (9% vs 20%; P = .036). CONCLUSIONS: After 12 and 24 months, CM tolerance was not different between groups and was in line with natural outgrowth. Results suggest that during the intervention, fewer subjects receiving AAF-S required hospitalization due to infections.

The effect of probiotics, prebiotics or synbiotics on metabolic outcomes in individuals with diabetes: a systematic review and meta-analysis.

AIMS/HYPOTHESIS: The aim was to conduct a systematic review and meta-analysis of randomised controlled clinical trials assessing the effect of probiotic, prebiotic or synbiotic supplementation on gut microbiota and glucose control and lipid levels in individuals with diabetes. METHODS: MEDLINE, EMBASE and the Cochrane Library were searched. The eligibility criteria for the studies was involvement of participants with a diagnosis of type 1 or type 2 diabetes. Metabolic outcomes (glucose control, insulinaemia, and lipid profile) of any probiotic, prebiotic or synbiotic supplementation related to modification of gut microbiota (prebiotics, probiotics and synbiotics) were analysed. We provided a narrative synthesis and meta-analysis of the findings on metabolic outcomes from the studies. Metabolic outcomes were extracted post-intervention and expressed as mean differences (MDs) and 95% CIs between treatment and comparator groups. We pooled the results using a random-effects meta-analysis. The meta-analysis was conducted using Review Manager (RevMan) software. RESULTS: After the removal of duplicates and ineligible studies, 5219 studies were retained for review of titles and abstracts. The number of articles was reduced to 130 by review, for which the full-text articles were obtained and reassessed, 38 of which were included in the final meta-analysis. Overall, the use of prebiotics, probiotics or synbiotics reduced HbA1c levels, but did not reach the threshold for significance (-2.17 mmol/mol, 95% CI -4.37, 0.03; p = 0.05, [-0.20%, 95% CI -0.40 to 0.00; p = 0.05, I2 = 66%]) and had no effect on LDL-cholesterol levels (-0.05 mmol/l; 95% CI -0.14, 0.05, p = 0.35, I2 = 37%). However, their consumption decreased levels of fasting blood glucose (-0.58 mmol/l; 95% CI -0.86, -0.30; p < 0.01, I2 = 60%), total cholesterol (-0.14 mmol/l; 95% CI -0.26, -0.02, p = 0.02, I2 = 39%), triacylglycerols (-0.11 mmol/l; 95% CI -0.20, -0.02, p = 0.01, I2= 21%) and insulinaemia (-10.51 pmol/l; 95% CI -16.68,-4.33, p < 0.01, I2 = 74%), and increased HDL-cholesterol levels (0.04 mmol/l; 95% CI 0.01, 0.07, p < 0.01, I2= 24%). CONCLUSIONS/INTERPRETATION: In individuals with diabetes mellitus, supplementation with probiotics, prebiotics or synbiotics improved metabolic variables, although the magnitude of this effect is low. Our results suggest that consumption of probiotics, prebiotics or synbiotics may be a potential adjuvant treatment for improving metabolic outcomes. REGISTRATION: PROSPERO ID CRD42017080071. Graphical abstract.

Synbiotics Alter Fecal Microbiomes, But Not Liver Fat or Fibrosis, in a Randomized Trial of Patients With Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: Dysbiosis of the intestinal microbiota has been associated with nonalcoholic fatty liver disease (NAFLD). We investigated whether administration of a synbiotic combination of probiotic and prebiotic agents affected liver fat content, biomarkers of liver fibrosis, and the composition of the fecal microbiome in patients with NAFLD. METHODS: We performed a double-blind phase 2 trial of 104 patients with NAFLD in the United Kingdom. Participants (mean age, 50.8 ± 12.6 years; 65% men; 37% with diabetes) were randomly assigned to groups given the synbiotic agents (fructo-oligosaccharides, 4 g twice per day, plus Bifidobacterium animalis subspecies lactis BB-12; n = 55) or placebo (n = 49) for 10-14 months. Liver fat content was measured at the start and end of the study by magnetic resonance spectroscopy, and liver fibrosis was determined from a validated biomarker scoring system and vibration-controlled transient elastography. Fecal samples were collected at the start and end of the study, the fecal microbiome were analyzed by 16S ribosomal DNA sequencing. RESULTS: Mean baseline and end-of-study magnetic resonance spectroscopy liver fat percentage values were 32.3% ± 24.8% and 28.5% ± 20.1% in the synbiotic group and 31.3% ± 22% and 25.2% ± 17.2% in the placebo group. In the unadjusted intention-to-treat analysis, we found no significant difference in liver fat reduction between groups (ß = 2.8; 95% confidence interval, -2.2 to 7.8; P = .30). In a fully adjusted regression model (adjusted for baseline measurement of the outcome plus age, sex, weight difference, and baseline weight), only weight loss was associated with a significant decrease in liver fat (ß = 2; 95% confidence interval, 1.5-2.6; P = .03). Fecal samples from patients who received the synbiotic had higher proportions of Bifidobacterium and Faecalibacterium species, and reductions in Oscillibacter and Alistipes species, compared with baseline; these changes were not observed in the placebo group. Changes in the composition of fecal microbiota were not associated with liver fat or markers of fibrosis. CONCLUSIONS: In a randomized trial of patients with NAFLD, 1 year of administration of a synbiotic combination (probiotic and prebiotic) altered the fecal microbiome but did not reduce liver fat content or markers of liver fibrosis. (ClinicalTrials.gov, Number: NCT01680640).

Microbiome modulation as a novel therapeutic approach in chronic kidney disease.

PURPOSE OF REVIEW: Gut dysbiosis has been implicated in the pathogenesis of chronic kidney disease (CKD). Interventions aimed at restoring gut microbiota have emerged as a potential therapeutic option in CKD. This review summarizes the current evidence on gut microbiota-targeted strategies in patients with CKD. RECENT FINDINGS: A growing number of studies have shown that plant-based diets, low-protein diets, prebiotic, probiotic, and synbiotic supplementation, and constipation treatment may lead to favorable alterations in the gut microbiota. Current evidence suggests that the implementation of both plant-based and low-protein diets has potential benefits for the primary prevention of CKD, and for slowing CKD progression, with minimal risk of hyperkalemia and/or cachexia. The use of prebiotics, probiotics, and synbiotics and laxatives may have beneficial effects on uremic toxin generation, but their evidence is limited for the prevention and treatment of CKD. Recent advances in diagnostic technologies (e.g., high-throughput sequencing and nanotechnology) could enhance rapid diagnosis, monitoring, and design of effective therapeutic strategies for mitigating gut dysbiosis in CKD. SUMMARY: Plant-based and low-protein diets, prebiotic, probiotic, and synbiotic supplementation, and constipation treatment represent novel gut microbiota-targeted strategies in the conservative management of CKD, which could improve clinical outcomes in CKD.

Effect of synbiotic supplementation on migraine characteristics and inflammatory biomarkers in women with migraine: Results of a randomized controlled trial.

Literature suggests a relationship between gut microbiome and migraine headache pathogenesis. However, the effect of manipulating gut microbiome on migraine remains unclear. This study aimed to investigate the effect of synbiotics on migraine characteristics and inflammatory markers in women with migraines. Sixty-nine participants completed a randomized double-blind controlled trial, receiving synbiotic (109 CFU of 12 types of probiotics + fructooligosaccharides prebiotic) or placebo supplementation, twice per day for 12 weeks. Migraine severity, migraine days per month, frequency and duration of attacks, number of painkillers consumed, gastrointestinal problems, serum High sensitive C-Reactive Protein (Hs-CRP) (a marker of inflammation) and zonulin (a marker of gut permeability) levels were measured at baseline and the end of the intervention. Bivariate comparison and intention-to-treat (ITT) were used for analysis. Synbiotic supplementation compare to the placebo resulted in a significant reduction in the mean frequency of migraine attacks (-1.02 vs -0.30, respectively, P = 0.011), percentage change of the number of painkillers used (-7.5% vs 27.5%, respectively, P = 0.008) and gastrointestinal problems (-35% vs -2.5%, respectively, P = 0.005), zonulin level (-4.12 vs 0.85 ng/ml, respectively, P = 0.034), and Hs-CRP level (-0.43 vs -0.09 mg/l, respectively, P = 0.022). Reduction in the migraine severity and duration did not reach a statistically significant level. Synbiotic supplementation may be considered as a complementary treatment for women with migraines to improve migraine characteristics and markers of inflammation and gut permeability and reduce the burden of disease.