Studies of probiotics, fructan-type prebiotics, and synbiotics in patients with ulcerative colitis (UC) show significant heterogeneity in methodology and results. Here, we study the efficacy of such ...interventions and the reasons for the heterogeneity of their results. Eligible random controlled trials were collected from the PUBMED and SCOPUS databases. A total of 18 placebo-controlled and active treatment-controlled (i.e., mesalazine) studies were selected with a Jadad score ≥ 3, including 1491 patients with UC. Data for prebiotics and synbiotics were sparse and consequently these studies were excluded from the meta-analysis. The UC remission efficacy of probiotics was measured in terms of relative risk (RR) and odds ratio (OR). Significant effects were observed in patients with active UC whenever probiotics containing bifidobacteria were used, or when adopting the US Food and Drug Administration (FDA)-recommended scales (UC Disease Activity Index and Disease Activity Index). By the FDA recommended scales, the RR was 1.55 (CI95%: 1.13⁻2.15,
-value = 0.007,
² = 29%); for bifidobacteria-containing probiotics, the RR was 1.73 (CI95%: 1.23⁻2.43,
-value = 0.002,
² = 35%). No significant effects were observed on the maintenance of remission for placebo-controlled or mesalazine-controlled studies. We conclude that a validated scale is necessary to determine the state of patients with UC. However, probiotics containing bifidobacteria are promising for the treatment of active UC.
Dietary supplements have been proposed to help manage blood cholesterol, including red yeast rice (RYR) extracts, plant sterols and stanols, beta-glucans, and some probiotics. This study was ...conducted to evaluate the efficacy of RYR (containing 10 mg of monacolin K) combined with 10
CFU of three
strains (CECT7527, CECT7528, and CECT7529).
A 12-week randomized, double-blinded, placebo-controlled clinical trial was conducted. In total, 39 adult patients were enrolled, having total cholesterol (TC) ≥200 mg/dL, and being statin-naïve or having recently stopped statin treatment because of intolerance. Active product or placebo were taken once daily, and subjects were evaluated at baseline, 6, and 12 weeks.
Study groups were comparable at baseline, except for history of recent hypercholesterolemia treatment (81% in active vs. 22% in placebo). Changes in LDL cholesterol and TC became significant compared to placebo (mean difference between groups and standard error of the mean = 23.6 ± 1.5 mg/dL,
= 0.023 and 31.4 ± 1.9 mg/dL,
= 0.011, respectively) upon adjusting for the baseline imbalance in hypercholesterolemia treatment. No adverse effects were noted during the study.
This combination of 10 mg of monacolin K and
strains was well tolerated and achieved a statistically significant greater reduction in LDL-C and TC in the intervention group compared to the placebo, once adjusting for recent history of hypercholesterolemia treatment.
Intestinal bacteria may influence lung homeostasis via the gut-lung axis. We conducted a single-center, quadruple-blinded, randomized trial in adult symptomatic Coronavirus Disease 2019 (Covid19) ...outpatients. Subjects were allocated 1:1 to probiotic formula (strains Lactiplantibacillus plantarum KABP022, KABP023, and KAPB033, plus strain Pediococcus acidilactici KABP021, totaling 2 × 10
9
colony-forming units (CFU)) or placebo, for 30 days. Co-primary endpoints included: i) proportion of patients in complete symptomatic and viral remission; ii) proportion progressing to moderate or severe disease with hospitalization, or death; and iii) days on Intensive Care Unit (ICU). Three hundred subjects were randomized (median age 37.0 years range 18 to 60, 161 53.7% women, 126 42.0% having known metabolic risk factors), and 293 completed the study (97.7%). Complete remission was achieved by 78 of 147 (53.1%) in probiotic group compared to 41 of 146 (28.1%) in placebo (RR: 1.89 95 CI 1.40-2.55; P < .001), significant after multiplicity correction. No hospitalizations or deaths occurred during the study, precluding the assessment of remaining co-primary outcomes. Probiotic supplementation was well-tolerated and reduced nasopharyngeal viral load, lung infiltrates and duration of both digestive and non-digestive symptoms, compared to placebo. No significant compositional changes were detected in fecal microbiota between probiotic and placebo, but probiotic supplementation significantly increased specific IgM and IgG against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) compared to placebo. It is thus hypothesized this probiotic primarily acts by interacting with the host's immune system rather than changing colonic microbiota composition. Future studies should replicate these findings and elucidate its mechanism of action (Registration: NCT04517422).
Abbreviations: AE: Adverse Event; BMI: Body Mass Index; CONSORT: CONsolidated Standards of Reporting Trials; CFU: Colony-Forming Units; eDRF: Electronic Daily Report Form; GLA: Gut-Lung Axis; GSRS: Gastrointestinal Symptoms Rating Scale; hsCRP: High-sensitivity C-Reactive Protein; HR: Hazard Ratio; ICU: Intensive Care Unit; OR: Odds Ratio; PCoA: Principal Coordinate Analysis; RR: Relative Risk; RT-qPCR: Real-Time Quantitative Polymerase Chain Reaction; SARS-CoV2: Severe acute respiratory syndrome coronavirus 2; SpO
2
: Peripheral Oxygen Saturation; WHO: World Health Organization
Prebiotic supplements are used to promote gastrointestinal health by stimulating beneficial bacteria. The aim of this study was to compare the potential prebiotic effects of fructans with increasing ...degrees of polymerization, namely fructooligosaccharides (FOS) and inulins with a low and high polymerization degree (LPDI and HPDI, respectively), using an ex vivo fermentation system to simulate the colonic environment. The system was inoculated with pooled feces from three healthy donors with the same baseline enterotype. Changes in microbiota composition were measured by 16S metagenomic sequencing after 2, 7, and 14 days of fermentation, and acid production was measured throughout the experiment. Alpha-diversity decreased upon inoculation of the ex vivo fermentation under all treatments. Composition changed significantly across both treatments and time (ANOSIM
< 0.005 for both factors). HPDI and LPDI seemed to be similar to each other regarding composition and acidification activity, but different from the control and FOS. FOS differed from the control in terms of composition but not acidification. HDPI restored alpha-diversity on day 14 as compared to the control (Bonferroni
< 0.05). In conclusion, the prebiotic activity of fructans appears to depend on the degree of polymerization, with LPDI and especially HPDI having a greater effect than FOS.
Functional gastrointestinal disorders (FGIDs) are a common concern during the first year of life. Recognized as gut-brain axis disorders by Rome IV criteria, FGIDs etiology is linked to altered ...gut-brain interaction, intestinal physiology, and microbiota. In this regard, probiotics have emerged as a promising therapy for infant FGIDs. In this study, we have investigated the probiotic potential of the strains
KABP042 and
KABP041-isolated from healthy children's feces-in the treatment of FGIDs. To this scope, genome sequences of both strains were obtained and subjected to
analyses. No virulence factors were detected for any strain and only the non-transferable
gene, which confers resistance to erythromycin and clindamycin, was identified in the genome of
KABP042. Safety of both strains was confirmed by acute oral toxicity in rats.
characterization revealed that the strains tolerate gastric and bile challenges and display a great adhesion capacity to human intestinal cells. The two strains mediate adhesion by different mechanisms and, when combined, synergically induce the expression of Caco-2 tight junction proteins. Moreover, growth inhibition experiments demonstrated the ability of the two strains alone and in combination to antagonize diverse Gram-negative and Gram-positive bacterial pathogens during sessile and planktonic growth. Pathogens' inhibition was mostly mediated by the production of organic acids, but neutralization experiments strongly suggested the presence of additional antimicrobial compounds in probiotic culture supernatants such as the bacteriocin Lantibiotic B, whose gene was detected in the genome of
KABP042. Finally, an exploratory, observational, pilot study involving 36 infants diagnosed with at least one FGID (infant colic and/or functional constipation) showed the probiotic formula was well tolerated and FGID severity was significantly reduced after 14 days of treatment with the 2 strains. Overall, this work provides evidence of the probiotic and synergic properties of strains
KABP042 and
KABP041, and of their potential to treat pediatric FGIDs.
www.ClinicalTrials.gov, identifier NCT04944628.
Several pharmacogenetic-based decision support tools for psychoactive medication selection are available. However, the scientific evidence of the gene-drug pairs analyzed is mainly based on ...pharmacogenetic studies in patients with major depression or schizophrenia, and their clinical utility is mostly assessed in major depression. This study aimed at evaluating the impact of individual genes, with pharmacogenetic relevance in other psychiatric conditions, in the response to treatment in bipolar depression. Seventy-six patients diagnosed with bipolar disorder and an index major depressive episode were included in an observational retrospective study. Sociodemographic and clinical data were collected, and all patients were genotyped using a commercial multigene pharmacogenomic-based tool (Neuropharmagen
, AB-Biotics S.A., Barcelona, Spain). Multiple linear regression was used to identify pharmacogenetic and clinical predictors of efficacy and tolerability of medications. The pharmacogenetic variables response to serotonin-norepinephrine reuptake inhibitors (SNRIs) (
) and reduced metabolism of quetiapine (
) predicted patient response to these medications, respectively.
was also linked to the tolerability of SNRIs. An mTOR-related multigenic predictor was also associated with a lower number of adverse effects when including switch and autolytical ideation. Our results suggest that the predictors identified could be useful to guide the pharmacological treatment in bipolar disorder. Additional clinical studies are necessary to confirm these findings.
Polyphosphate (poly-P) biosynthesis in bacteria has been linked to many physiological processes and has been characterized as an interesting functional molecule involved in intestinal homeostasis. We ...determined the capacity for poly-P production of 18 probiotic strains mainly belonging to Bifidobacterium and former Lactobacillus genera, showing that poly-P synthesis varied widely between strains and is dependent on the availability of phosphate and the growth phase. Bifidobacteria were especially capable of poly-P synthesis and poly-P kinase (ppk) genes were identified in their genomes together with a repertoire of genes involved in phosphate transport and metabolism. In Bifidobacterium longum KABP042, the strain we found with highest poly-P production, variations in ppk expression were linked to growth conditions and presence of phosphate in the medium. Moreover, the strain produced poly-P in presence of breast milk and lacto-N-tetraose increased the amount of poly-P synthesized. Compared to KABP042 supernatants low in poly-P, exposure of Caco-2 cells to KABP042 supernatants rich in poly-P resulted in decreased epithelial permeability and increased barrier resistance, induction of epithelial protecting factors such as HSP27 and enhanced expression of tight junction protein genes. These results highlight the role of bifidobacteria-derived poly-P as a strain-dependent functional factor acting on epithelial integrity.
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Some HIV-1 infected patients are unable to completely recover normal CD4+ T-cell (CD4+) counts after achieving HIV-1 suppression with combined Antiretroviral Therapy (cART), hence being classified as ...immuno-discordant. The human microbiome plays a crucial role in maintaining immune homeostasis and is a potential target towards immune reconstitution.
RECOVER (NCT03542786) was a double-blind placebo-controlled clinical trial designed to evaluate if the novel probiotic i3.1 (AB-Biotics, Sant Cugat del Vallès, Spain) was able to improve immune reconstitution in HIV-1 infected immuno-discordant patients with stable cART and CD4+ counts <500 cells/mm3. The mixture consisted of two strains of
and one of
, given with or without a fiber-based prebiotic.
71 patients were randomized 1:2:2 to Placebo, Probiotic or probiotic + prebiotic (Synbiotic), and were followed over 6 months + 3-month washout period, in which changes on systemic immune status and gut microbiome were evaluated. Primary endpoints were safety and tolerability of the investigational product. Secondary endpoints were changes on CD4+ and CD8+ T-cell (CD8+) counts, inflammation markers and faecal microbiome structure, defined by alpha diversity (Gene Richness), beta diversity (Bray-Curtis) and functional profile. Comparisons across/within groups were performed using standard/paired Wilcoxon test, respectively.
Adverse event (AE) incidence was similar among groups (53%, 33%, and 55% in the Placebo, Probiotic and Synbiotic groups, respectively, the most common being grade 1 digestive AEs: flatulence, bloating and diarrhoea. Two grade 3 AEs were reported, all in the Synbiotic group: abdominal distension (possibly related) and malignant lung neoplasm (unrelated), and 1 grade 4 AE in the Placebo: hepatocarcinoma (unrelated). Synbiotic exposure was associated with a higher increase in CD4+/CD8+ T-cell (CD4/CD8) ratio at 6 months vs baseline (median=0.76(IQR=0.51) vs 0.72(0. 45), median change= 0.04(IQR=0.19), p = 0.03). At month 9, the Synbiotic group had a significant increase in CD4/CD8 ratio (0.827(0.55) vs 0.825(0.53), median change = 0.04(IQR=0.15), p= 0.02) relative to baseline, and higher CD4+ counts (447 (157) vs. 342(73) counts/ml, p = 0.03), and lower sCD14 values (2.16(0.67) vs 3.18(0.8), p = 0.008) than Placebo. No effect in immune parameters was observed in the Probiotic arm. None of the two interventions modified microbial gene richness (alpha diversity). However, intervention as categorical variable was associated with slight but significant effect on Bray-Curtis distance variance (Adonis R2 = 0.02, p = 0.005). Additionally, at month 6, Synbiotic intervention was associated with lower pathway abundances vs Placebo of Assimilatory Sulphate Reduction (8.79·10
(1.25·10
) vs. 1.61·10
(2.77·10
), p = 0.03) and biosynthesis of methionine (2.3·10
(3.17·10
) vs. 4·10
(5.66·10
), p = 0.03) and cysteine (1.83·10
(2.56·10
) vs. 3.3·10
(4.62·10
, p = 0.03). At month 6, probiotic detection in faeces was associated with significant decreases in C Reactive Protein (CRP) vs baseline (11.1(22) vs. 19.2(66), median change= -2.7 (13.2) ug/ml, p = 0.04) and lower IL-6 values (0.58(1.13) vs. 1.17(1.59) ug/ml, p = 0.02) when compared with samples with no detectable probiotic. No detection of the probiotic was associated with higher CD4/CD8 ratio at month 6 vs baseline (0.718(0.57) vs. 0.58(0.4), median change = 0.4(0.2), p = 0.02). After washout, probiotic non-detection was also associated with a significant increase in CD4+ counts (457(153) vs. 416(142), median change = 45(75), counts/ml, p = 0.005) and CD4/CD8 ratio (0.67(0.5) vs 0.59(0.49), median change = 0.04 (0.18), p = 0.02).
A synbiotic intervention with
and
was safe and led to small increases in CD4/CD8 ratio and minor reductions in sCD14 of uncertain clinical significance. A probiotic with the same composition was also safe but did not achieve any impact on immune parameters or faecal microbiome composition.
Application of beneficial microorganisms as probiotics targets a broad range of intended uses, from maintaining health and supporting normal bodily functions to curing and preventing diseases. ...Currently, three main regulatory fields of probiotic products can be defined depending on their intended use: the more similar probiotic foods and probiotic dietary supplements, and live biotherapeutic products. However, it is not always straightforward to classify a probiotic product into one of these categories. The regulatory nuances of developing, manufacturing, investigating and applying each category of probiotic products are not universal, and not always apparent to those unfamiliar with the various global probiotic regulatory guidelines. Various global markets can be significantly different regarding legislation, possible claims, market value and quality requirements for the development and commercialization of probiotic products. Furthermore, different probiotic product categories are also linked with variable costs at different stages of product development. This review outlines the current landscape comparing probiotic foods, probiotic dietary supplements, and live biotherapeutics as probiotic products from a regulatory lens, focusing on product development, manufacturing and production, and clinical research agenda. The aim is to inform and promote a better understanding among stakeholders by outlining the expectations and performance for each probiotic product category, depending on their intended use and targeted geographical region.
Objectives and Hypothesis
Gut microbiota has been reported to protect from lung viral infection in animal models by stimulating type‐I interferon signaling. Type‐I interferons can have direct ...antiviral activity while also stimulating antibody‐producing B cells. Antibodies against Severe Acute Respiratory Syndrome coronavirus 2 (SARS‐CoV2) have been correlated to faster infection clearance and protection against reinfection. A specific 4‐strain probiotic combination (Pediococcus acidilactici CECT7483 plus Lactoplantibacillus plantarum CECT7484, CECT7485 and CECT30292) was recently studied in a randomized, quadruple‐blinded, placebo‐controlled trial in 300 SARS‐CoV2‐infected, symptomatic ambulatory patients (NCT04517422). Study subjects did not receive corticosteroids or antivirals. Compared to placebo, probiotic intervention (2x109cfu/day for 30 days) achieved faster symptom clearance and increased SARS‐CoV2‐specific immunoglobulins M and G (IgM and IgG). We hypothesize these effects could be related to increased type‐I interferon signaling.
Methods
A random subset of 70 subjects (35 probiotic and 35 placebo) was selected out of the 300 participants in the clinical study. Stored serum samples collected on day 0 (baseline), 15 and 30 (end of intervention) were analyzed for interferon‐alpha 2a (IFNa) and interferon‐beta 1a (IFNb) using enzyme‐linked immunosorbent assay. Demographic data, baseline viral load, symptom duration and SARS‐CoV2‐specific IgM and IgG serum titers were retrieved from patient case report forms. Differences between probiotic and placebo were compared using Mann‐Whitney or Chi‐squared tests, as appropriate. Correlations between type‐I interferons and other variables were assessed by Spearman correlation. All procedures on study subjects had been approved by the Internal Review Board of Hospital General Dr. Manuel Gea (Mexico City) and adhered to Helsinki Declaration.
Summary of Results
In the selected subset of patients, study groups were comparable at baseline (all p>0.10, Table 1). Probiotic treatment was associated to a larger increase of IFNa on day 30 (p=0.007) and of IFNb on days 15 and 30 (both p<0.001), compared to placebo (Figure 1). Similarly, SARS‐CoV2‐specific IgM and IgG were higher on days 15 and 30 (all p<0.001) and duration of fever, cough, headache and myalgia were shorter (all p<0.05) in probiotic compared to placebo. Increase in IFNb across the study correlated to increase in SARS‐CoV2‐specific IgM (rho=0.55, p<0.001) and IgG (rho=0.61, p<0.001), and inversely correlated to duration of cough (rho=‐0.26, p=0.033) and fever (rho=‐0.24, p=0.042). Conversely, increase in IFNa correlated to increase in SARS‐CoV2‐specific IgM (rho=0.33, p=0.005) only. Neither increase in IFNa nor IFNb correlated to age, number of metabolic comorbidities or days from onset of symptoms.
Conclusion
Compared to placebo, oral administration of a specific 4‐strain probiotic combination resulted in significant increase in type‐I interferons in serum, especially IFNb, correlating to higher SARS‐CoV2‐specific IgM and IgG antibodies and faster clearance of some symptoms.
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