Environmental and Nutritional Parameters Modulating Genetic Expression for Virulence Factors of Clostridioides difficile.

Clostridioides difficile infections (CDIs) continue to be a persistent healthcare concern despite newer antibiotic treatments, enhanced infection control practices, and preventive strategies focused on restoring the protective intestinal microbial barrier. Recent strides in gene sequencing research have identified many genes regulating diverse virulence factors for CDIs. These genes may be over- or under-expressed when triggered by various environmental and nutritional factors. The aims of this paper are to review the important genes involved in C. difficile pathogenesis and to identify modifiable environmental, nutritional, and other factors that may trigger the expression of these genes and thus offer new strategies to prevent CDIs.

Recommendations to Improve Quality of Probiotic Systematic Reviews With Meta-Analyses.

Importance: Systematic reviews and meta-analyses often report conflicting results when assessing evidence for probiotic efficacy, partially because of the lack of understanding of the unique features of probiotic trials. As a consequence, clinical decisions on the use of probiotics have been confusing. Objective: To provide recommendations to improve the quality and consistency of systematic reviews with meta-analyses on probiotics, so evidence-based clinical decisions can be made with more clarity. Evidence Review: For this consensus statement, an updated literature review was conducted (January 1, 2020, to June 30, 2022) to supplement a previously published 2018 literature search to identify areas where probiotic systematic reviews with meta-analyses might be improved. An expert panel of 21 scientists and physicians with experience on writing and reviewing probiotic reviews and meta-analyses was convened and used a modified Delphi method to develop recommendations for future probiotic reviews. Findings: A total of 206 systematic reviews with meta-analysis components on probiotics were screened and representative examples discussed to determine areas for improvement. The expert panel initially identified 36 items that were inconsistently reported or were considered important to consider in probiotic meta-analyses. Of these, a consensus was reached for 9 recommendations to improve the quality of future probiotic meta-analyses. Conclusions and Relevance: In this study, the expert panel reached a consensus on 9 recommendations that should promote improved reporting of probiotic systematic reviews with meta-analyses and, thereby, assist in clinical decisions regarding the use of probiotics.

Microbiome-Related and Infection Control Approaches to Primary and Secondary Prevention of Clostridioides difficile Infections.

Clostridioides difficile infections (CDIs) have decreased in the past years, but since 2021, some hospitals have reported an increase in CDI rates. CDI remains a global concern and has been identified as an urgent threat to healthcare. Although multiple treatment options are available, prevention strategies are more limited. As CDI is an opportunistic infection that arises after the normally protective microbiome has been disrupted, preventive measures aimed at restoring the microbiome have been tested. Our aim is to update the present knowledge on these various preventive strategies published in the past five years (2018-2023) to guide clinicians and healthcare systems on how to best prevent CDI. A literature search was conducted using databases (PubMed, Google Scholar, and clinicaltrials.gov) for phase 2-3 clinical trials for the primary or secondary prevention of CDI and microbiome and probiotics. As the main factor for Clostridium difficile infections is the disruption of the normally protective intestinal microbiome, strategies aimed at restoring the microbiome seem most rational. Some strains of probiotics, the use of fecal microbial therapy, and live biotherapeutic products offer promise to fill this niche; although, more large randomized controlled trials are needed that document the shifts in the microbiome population.

Lactobacillus Bacteremia and Probiotics: A Review.

Lactobacilli are widely found in nature, are commensal microbes in humans, and are commonly used as probiotics. Concerns about probiotic safety have arisen due to reports of bacteremia and other Lactobacillus-associated infections. We reviewed the literature for articles on the pathogenicity of Lactobacillus spp. bacteremia and reports of probiotics in these patients. Our aim is to review these articles and update the present knowledge on the epidemiology of Lactobacillus spp. bacteremia and determine the role of probiotics in Lactobacillus bacteremia. Lactobacillus bacteremia is infrequent but has a higher risk of mortality and risk factors, including severe underlying diseases, immune system suppression, admission to intensive care units, and use of central venous catheters. A variety of Lactobacillus species may cause bacteremia and may or may not be associated with probiotic exposure. To determine if oral probiotics are the source of these infections, the blood isolates and the oral probiotic strain(s) must be compared by sensitive identification methods. The prevalence of Lactobacillus bacteremia is infrequent but is more common in patients taking probiotics compared to those not taking probiotics. Three probiotics (Lacticaseibacillus rhamnosus GG, Lactiplantibacillus plantarum, and Lacticaseibacillus paracasei) were directly linked with blood isolates from bacteremia patients using molecular identification assays.

Transcriptome analysis of the Clostridioides difficile response to a specific lactobacilli probiotic formulation: explanations for its mechanisms of action.

AIMS: Clostridioides difficile infections (CDI) are a major cause of morbidity and mortality in hospitalized patients. A probiotic formulation (Bio-K+) comprised of Lactobacillus acidophilus CL1285, Lacticaseibacillus casei LBC80R, and Lacti. rhamnosus CLR2 strains have been shown to reduce the incidence of CDI and antibiotic-associated diarrhea (AAD). This research aims to therefore elucidate the mechanism of action of the three probiotic strained against C. difficile R20291, independently of the acidification of the environment. . METHODS AND RESULTS: Antitoxin activity was evaluated using ELISA method and the expression of C. difficile genes was evaluated using transcriptomic analysis in co-culture assays conducted in a bioreactor allowing precise control of the pH. The fermentation results demonstrated a decrease for toxin A and many genes directly related to C. difficile virulence were underexpressed in the co-cultures. CONCLUSIONS: The lactobacilli tested could have a role in the motility, the quorum sensing (QS), the survival of the spores, and the germination potential of the spores, which are essential elements for the virulence of C. difficile. .

Randomized, direct comparison study of Saccharomyces boulardii CNCM I-745 versus multi-strained Bacillus clausii probiotics for the treatment of pediatric acute gastroenteritis.

BACKGROUND: The choice of an appropriate probiotic for pediatric acute gastroenteritis (PAGE) can be confusing. Our aim was to compare the efficacy and safety of 2 probiotics (Saccharomyces boulardii CNCM I-745 vs a 4-strain mixture of Bacillus clausii O/C, SIN, N/R, T) for the treatment of PAGE. METHODS: A 2-arm parallel, randomized trial recruited children (6 months to 5 years old) with mild-moderate acute diarrhea, from 8 centers in Argentina. A total of 317 children were enrolled and blindly randomized to 5 days of either S boulardii CNCM I-745 (n = 159) or a 4-strain mixture of B clausii (n = 158), then followed for 7 days post-probiotic treatment. A stool sample was collected at inclusion for pathogen identification. The primary outcome was duration of diarrhea defined as the time from enrollment to the last loose stool followed by the first 24-hour period with stool consistency improvement. Secondary outcomes included frequency of loose stools/day, severity of diarrhea, number reporting no diarrhea at Day 6, time-to-first formed stool, recurrence of diarrhea by study end (Day 12) and safety outcomes. RESULTS: Three hundred twelve (98%) children completed the study. S boulardii CNCM I-745 showed a significant reduction (P = .04) in the mean duration of diarrhea (64.6 hours, 95% confidence interval [CI] 56.5-72.8) compared to those given B clausii (78.0 hours, 95% CI 69.9-86.1). Both probiotics showed improvement in secondary outcomes and were well-tolerated. CONCLUSION: In this study, S boulardii CNCM I-745 demonstrated better efficacy than B clausii mix for reducing the duration of pediatric acute diarrhea.

Best Practices for Probiotic Research in Athletic and Physically Active Populations: Guidance for Future Randomized Controlled Trials.

Probiotic supplementation, traditionally used for the prevention or treatment of a variety of disease indications, is now recognized in a variety of population groups including athletes and those physically active for improving general health and performance. However, experimental and clinical trials with probiotics commonly suffer from design flaws and different outcome measures, making comparison and synthesis of conclusions difficult. Here we review current randomized controlled trials (RCTs) using probiotics for performance improvement, prevention of common illnesses, or general health, in a specific target population (athletes and those physically active). Future RCTs should address the key elements of (1) properly defining and characterizing a probiotic intervention, (2) study design factors, (3) study population characteristics, and (4) outcome measures, that will allow valid conclusions to be drawn. Careful evaluation and implementation of these elements should yield improved trials, which will better facilitate the generation of evidence-based probiotic supplementation recommendations for athletes and physically active individuals.

Prologue: 2021 Annual Meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA).

The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) held its annual meeting in 2021 in an online format due to travel restrictions during the ongoing COVID-19 (coronavirus disease 2019) pandemic. The virtual meeting was attended by rheumatologists, dermatologists, representatives of biopharmaceutical companies, and patient research partners. Similar to previous years, GRAPPA's annual meeting focused on the 3 overlapping missions of education, research, and clinical care of psoriatic disease (PsD). The virtual meeting allowed a variety of different types of sessions to be held, including the trainee symposium, keynote lectures, interactive sessions (5 Meet the Experts sessions, a debate on first-line therapy, and 5 guided poster sessions), 4 workshops (trainee workshop focusing on the diagnosis of PsD, ultrasound, magnetic resonance imaging, and the International Dermatology Outcome Measures group), updates on a variety of research topics (research findings from the 2020 GRAPPA research grant awardees, 3 basic science talks, Outcome Measures in Rheumatology [OMERACT] Working Group efforts, and Collaborative Research Network progress), current "hot topics" (use of Janus kinase inhibitors, promoting diversity and inclusion in PsD, progress on the updated GRAPPA treatment recommendations, and the introduction of the Young GRAPPA member group), and the presentation of four 2021 GRAPPA grant awardees and election results. In this prologue, we introduce the papers that summarize this meeting.

Effects of Probiotics on Allergic Rhinitis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

BACKGROUND: The prevalence of allergic rhinitis has been estimated to range from 10 to 30% in adults and up to 40% in children. Probiotics have been tested as for this condition, but no census on which probiotic types are most effective. OBJECTIVE: Our aim of this study was to provide probiotic strain-specific evaluation for the treatment of allergic rhinitis. METHODS: Databases (PubMed, Google Scholar, and ScienceDirect) were searched (from inception to October 2020) to identify randomized controlled trials (RCTs) of probiotic treatments in allergic rhinitis patients. A systematic review was done comparing types of reported outcomes, clinical and immunological parameters and safety data. A meta-analysis was done for probiotics with at least two RCTs per probiotic strain(s) and sharing a common outcome. RESULTS: A total of 13 randomized, double-blind, placebo-controlled trials (N = 1591 participants) were included in the systematic review. Overall, 8 of 9 probiotic types alleviated at least one clinical symptom of allergic rhinitis. The meta-analysis results showed that, neither L. paracasei Lp33 (SMD = -1.61, 95% CI -4.67, 1.45) nor L. rhamnosus GG (SMD = -1.00, 95% CI -3.01, 1.00) had significant efficacy for reducing nasal symptom scores. CONCLUSIONS: Our analysis showed probiotics produced a slight improvement in some clinical and immunological measurements on allergic rhinitis. Due to the diversity of outcome measurements and lack of sufficient trials for each probiotic strain, future trials are needed with similar study design and uniform outcomes to better compare the effect of probiotics on allergic rhinitis.

Strain-specific and outcome-specific efficacy of probiotics for the treatment of irritable bowel syndrome: A systematic review and meta-analysis.

BACKGROUND: Consistent guidance for choosing an appropriate probiotic for the treatment of irritable bowel syndrome is lacking. METHODS: Literature databases searched included: PubMed, Google Scholar and NIH registry of clinical trials from inception to June 2021. Inclusion criteria: randomized controlled trials (RCTs) enrolling adult or pediatric IBS patients comparing probiotics against controls and ≥ 2 RCTs with common IBS outcome measures within each type of probiotic. Five common measures of IBS symptoms (changes in global Irritable Bowel Syndrome Severity Scoring System or IBS-SSS scores, frequency of global responders, changes in bloating or abdominal pain scores and frequency of abdominal pain relief) were used. This study was registered at Prospero (#CRD42018109169). FINDINGS: We screened 521 studies and included 42 randomized controlled trials (45 treatment arms, N = 3856). Four probiotics demonstrated significant reduction in abdominal pain relief: B. coagulans MTCC5260 (RR= 4.9, 95% C.I. 3.3, 7.3), L. plantarum 299v (RR= 4.6, 95% CI 1.9, 11.0), S. boulardii CNCM I-745 (RR= 1.5, 95% C.I. 1.1, 2.1) and S. cerevisiae CNCM I-3856 (RR= 1.3, 95% C.I. 1.04, 1.6). Mild-moderate adverse events were reported in 51% of the trials, none were more associated with the probiotic compared to controls. INTERPRETATION: Although the analysis of probiotic efficacy was limited by the diversity of IBS outcomes used in trials and lack of confirmatory trials for some strains, six single-strain probiotics and three different types of probiotic mixtures showed significant efficacy for at least one IBS outcome measure. These results might be relevant to clinical practice and policy.

Prologue: 2020 Annual Meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA).

The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) held its annual meeting in 2020 in an online format due to travel restrictions during the coronavirus disease 2019 (COVID-19; caused by SARS-CoV-2) pandemic. The virtual meeting was attended by 351 rheumatologists, dermatologists, representatives of biopharmaceutical companies, and patient research partners. Similar to previous years, GRAPPA's annual meeting focused on the 3 overlapping missions of education, research, and clinical care of psoriatic disease. Trainee sessions this year included the annual trainee symposium and a grant-writing workshop. Plenary sessions included updates on COVID-19 and psoriatic disease from multispecialty and patient perspectives, and updates on pustular psoriasis and associated musculoskeletal manifestations. Progress on research and updates were presented for the following groups: Collaborative Research Network, Outcome Measures in Rheumatology (OMERACT) Psoriatic Arthritis Working Group, International Dermatology Outcome Measures, Composite Measures, Education Committee, and Treatment Guidelines. New this year were 3 concurrent workshops on ultrasound assessment of joints and entheses, magnetic resonance imaging of psoriatic arthritis, and pustular psoriasis efficacy endpoints; 6 "Meet the Expert" sessions; and facilitated "poster tours." In our prologue, we introduce the papers that summarize this meeting.

Potential Roles for Probiotics in the Treatment of COVID-19 Patients and Prevention of Complications Associated with Increased Antibiotic Use.

Medical care for patients hospitalized with COVID-19 is an evolving process. Most COVID-19 inpatients (58-95%) received empiric antibiotics to prevent the increased mortality due to ventilator-associated pneumonia and other secondary infections observed in COVID-19 patients. The expected consequences of increased antibiotic use include antibiotic-associated diarrhea (AAD) and Clostridioides difficile infections (CDI). We reviewed the literature (January 2020-March 2021) to explore strategies to reduce these consequences. Antimicrobial stewardship programs were effective in controlling antibiotic use during past influenza epidemics and have also been shown to reduce healthcare-associated rates of CDI. Another potential strategy is the use of specific strains of probiotics shown to be effective for the prevention of AAD and CDI prior to the pandemic. During 2020, there was a paucity of published trials using these two strategies in COVID-19 patients, but trials are currently ongoing. A multi-strain probiotic mixture was found to be effective in reducing COVID-19-associated diarrhea in one trial. These strategies are promising but need further evidence from trials in COVID-19 patients.

Prologue: 2020 Annual Meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA).

The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) held its annual meeting in 2020 in an online format due to travel restrictions during the coronavirus disease 2019 (COVID­19; caused by SARS-CoV-2) pandemic. The virtual meeting was attended by 351 rheumatologists, dermatologists, representatives of biopharmaceutical companies, and patient research partners. Similar to previous years, GRAPPA's annual meeting focused on the 3 overlapping missions of education, research, and clinical care of psoriatic disease. Trainee sessions this year included the annual trainee symposium and a grant-writing workshop. Plenary sessions included updates on COVID-19 and psoriatic disease from multispecialty and patient perspectives, and updates on pustular psoriasis and associated musculoskeletal manifestations. Progress on research and updates were presented for the following groups: Collaborative Research Network, Outcome Measures in Rheumatology (OMERACT) Psoriatic Arthritis Working Group, International Dermatology Outcome Measures, Composite Measures, Education Committee, and Treatment Guidelines. New this year were 3 concurrent workshops on ultrasound assessment of joints and entheses, magnetic resonance imaging of psoriatic arthritis, and pustular psoriasis efficacy endpoints; 6 "Meet the Expert" sessions; and facilitated "poster tours." In our prologue, we introduce the papers that summarize this meeting.

Potential role of probiotics in reducing Clostridioides difficile virulence: Interference with quorum sensing systems.

Opportunistic pathogenic bacteria may cause disease after the normally protective microbiome is disrupted (typically by antibiotic exposure). Clostridioides difficile is one such pathogen having a severe impact on healthcare facilities and increasing costs of medical care. The search for new therapeutic strategies that are not reliant on additional antibiotic exposures are currently being explored. One such strategy is to disrupt the production of C. difficile virulence factors by interfering with quorum sensing (QS) systems. QS has been well studied in other bacteria, but our understanding in C. difficile is not so well understood. Some probiotic strains or combinations of strains have been shown to be effective in the treatment or primary prevention of C. difficile infections and may possess multiple mechanisms of action. One mechanism of probiotics might be the inhibition of QS, but their role has not been clearly defined yet. A literature search was conducted using standard databases (PubMed, Google Scholar) from database inception to August 2020. The objective of this paper is to update our understanding of how QS leads to toxin production by C. difficile, which is important in pathogenesis, and how QS inhibitors or probiotics may disrupt this pathway. We found two main QS systems for C. difficile (Agr and Lux systems) that are involved in C. difficile pathogenesis by regulating toxin production, motility and adherence. Probiotics and other QS inhibitors targeting QS systems may represent important new directions of therapy and prevention of CDI.

Specific Probiotics for the Treatment of Pediatric Acute Gastroenteritis in India: A Systematic Review and Meta-Analysis.

Pediatric acute gastroenteritis (PAGE) is a significant cause of morbidity, mortality and healthcare costs in many countries, but differences in PAGE vary from country-to-country; thus, we limited our analysis to 1 country. Probiotics have been recommended as an adjunct to standard treatment, but the choice of probiotic is unclear. PubMed, Google Scholar, and reviews were searched from inception to May 2020 for randomized controlled trials (RCTs) in India using probiotics for a treatment for PAGE. Meta-analyses using subgroups of identical probiotic types (≥2 RCT/type) were conducted for primary outcomes (duration of diarrhea, cured by day 3, rapidity of response, and length of hospital stay). Twenty-two RCTs were included in the systematic review (N = 4059 participants) including 5 single-strained probiotics and 3 multi-strained mixtures. For the meta-analyses, 17 RCT (20 treatment arms) were included. Saccharomyces boulardii CNCM I-745 had the strongest effect on shortening the duration of diarrhea (standardized mean difference, -1.86 d; 95% confidence interval, -2.8 to -0.9), while both Lactobacillus rhamnosus GG and a mixture of 4 Bacillus clausii strains (O/C, SIN, N/R, T) significantly reduced the duration of diarrhea (-1.7 and -1.4 d, respectively). S. boulardii and L. rhamnosus GG significantly reduced hospital stays (-1.8 and -1.1 d, respectively), while B. clausii had no effect. The frequency of stools/day was significantly reduced by day 4 for S. boulardii and by day 5 for L. rhamnosus GG. In India, 2 types of probiotics (S. boulardii CNCM I-745 and L. rhamnosus GG) significantly shortened both the duration of diarrhea and hospitalization stays in pediatric patients with PAGE. While these 2 probiotic strains were safe and effective for children in India, further research is needed to confirm if other probiotic strains or mixtures may be effective.

Perils and pitfalls of probiotic quasi-experimental studies for primary prevention of Clostridioides difficile infection: A review of the evidence.

BACKGROUND: Primary prevention of Clostridioides (Clostridium) difficile infections (CDI) is an important but challenging infection control goal for hospitals and health care facilities. Enhanced infection control protocols have reduced CDI rates, but the problem persists and administration of probiotics to patients at risk could be very useful if shown to be safe and effective. Randomized controlled trials are largely impractical for primary prevention CDI trials due to large required study sizes and quasi-experimental studies are becoming more frequent as a method to assess this problem. OBJECTIVE: Our goal is to review the published quasi-experimental studies adding probiotics to their infection control protocols to reduce CDI and determine the strengths and limitations for this type of study design. METHODS: The literature was searched using PubMed, Google Scholar, Medline and Cochrane Databases and gastrointestinal meeting abstracts from January 2000 to January 2020 for quasi-experimental intervention studies testing various probiotics for the primary prevention of CDI. RESULTS: We found 28 studies with 7 different types of probiotics (10 studies implementing a hospital-wide intervention, 6 studies targeting 1-3 wards, and 12 studies on either sustainability, cost-effectiveness or subgroup analysis). Some probiotics demonstrated a significant reduction in CDI rates; all four of the probiotic types given only on specific wards and 3 of the 4 probiotics given facility-wide. However, this type of study design was influenced by numerous factors which must be carefully accounted for in the analysis. CONCLUSIONS: Some probiotics may be an effective addition to infection control protocols to prevent C. difficile infections, but careful study design considerations are needed.