EED INTERVENTIONS: PRE- AND PRO-BIOTIC SAFETY

Transcription

1 EED INTERVENTIONS: PRE- AND PRO-BIOTIC SAFETY Produced by: Dietrich, C.; Kidane, L.; Babigumira, J.

2 Agenda Agenda Timeline Project Background and Objectives Key Takeaways Approach & Rationale Methods Results Discussion and Next Steps

3 Timeline Timeline Scoping Confirm work plan and scope Strategize approach = Check-In Point Landscape Analysis Review relevant literature & extract data Relay initial findings & finalize results

4 Project Background and Objectives Work Order to the UW START Team Background The Enteric and Diarrheal Disease Team of the Bill & Melinda Gates Foundation previously engaged the START team to conduct a landscape analysis of intervention trials for Environmental Enteric Dysfunction (EED). During the course of this analysis, an additional but parallel track of work was identified to do a similar landscape analysis for pre- and probiotic interventions for growth faltering that may be caused by EED. Objectives To examine pre- and pro-biotic interventions Diagnosis of EED by gut biopsy is an invasive and resource-intensive process and is often not feasible in vulnerable populations. Having previously focused on EED biomarkers in Phase I, outcomes of interest for this review include safety and efficacy endpoints for pre- and pro- biotic use in infants and children.

5 Takeaways Key Takeaways Very few studies conducted in LMICs Bifidobacteria and Lactobacillus are the most common genus of bacteria studied; GOS, most common prebiotic Majority of studies demonstrated no differences in SAEs, adverse events and tolerability between interventions and controls If there were differences, typically pre- and pro-biotics had positive effects Difficult to detect significant growth changes in healthy children

6 Approach & Rationale Probiotic and Prebiotic Safety with Stunting Endpoints Focus on the inclusion of a stunting measures such as growth velocity or LAZ Probiotic or prebiotic as an intervention, no observational studies Expanded to populations beyond LMICs Analyze safety and efficacy of probiotics in children Adverse events Infection

7 Methods Targeted Database and Search Phase 1 efficacy and safety Database: Embase 'phase 1 trial'/exp OR 'phase 1 trial' OR 'safety' OR 'safety'/exp OR safety OR ('safety' OR 'safety'/exp OR safety AND efficacy) AND ('probio<c'/exp OR 'probio<c' OR 'prebio<c'/exp OR 'prebio<c' OR 'lactobacillus'/exp OR 'lactobacillus' OR 'vsl3'/exp OR 'vsl3' OR 'bacillus'/exp OR 'bacillus' OR 'bifidobacterium'/exp OR 'bifidobacterium' OR 'escherichia coli nissle 1917' OR 'e. coli nissle 1917' OR 'streptococcus thermophilus'/exp OR 'streptococcus thermophilus' OR 'saccharomyces'/exp OR 'saccharomyces') AND ([newborn]/lim OR [infant]/lim OR [child]/lim OR [preschool]/lim OR [school]/lim) AND [humans]/lim AND [english]/lim 403 hits

8 Methods Inclusion and Exclusion Criteria Inclusion Exclusion Prospective studies investigating prebiotics and probiotics Human Subjects Children <18 Safety and efficacy trials Key words: tolerability, safety, adverse events Bactermia or microbiome related to potentially harmful bacteria Prioritized: Growth measurements Retrospective studies, editorials and reviews Animal models/in vitro studies Adults, including provision to pregnant mothers Combination interventions E.g. Abx+probiotics Oral health, potentially noningested No indication of safety other than non-stunting endpoint

9 Methods Literature Review Flowchart Title Review (n=403) Exclusions (n=189) Abstract Review (n=214) Exclusions (n=104) Embase Search Results: ~27% of titles originally qualified for full text review Prioritized abstracts with growth measurements Full Text Review (n=110) Prioritized Articles (n=25) Exclusions (n=4)

10 Ages Represented 14 Earliest age of enrollment in trials In Utero - Birth Birth - 4 weeks 1-2 months 3-6 months 6-12 months 1-4 years

11 Prebiotics Covered Galacto-oligosaccharide (GOS) Combo prebiotic LCPUFA Fructooligosaccharides GOS-scFOS Combo prebiotic with LCPUFA short-chain fructo-oligosaccharides (scfos)

12 Probiotics Covered Bifidobacterium Lactobacillus Propionibacterium Streptococcus Bifidobacterium animalis ssp. lactis Bifidobacterium breve Bifidobacterium infantis Bifidobacterium lactis Bifidobacterium longum Lactobacillus fermentum Lactobacillus paracasei Lactobacillus reuteri Lactobacillus rhamnosus Lactobacillus rhamnosus GG Lactobacillus salivarius Propionibacterium freudenreichii Streptococcus thermophilus

13 Serious Adverse Events Studies: Serious Adverse Events None related to study formula 2 6 No sepsis detected related to probiotic organisms Mentioned SAEs but not explicit on relationship to study formulas Not reported Related to Study Formula

14 Infections Intervention Resulted in Significant Positive Result for Infections or Infectionrelated Endpoints Antibiotics B. lactis; Streptococcus thermophilus B. breve + Combo prebiotic LGG + B. breve + Propionibacterium + GOS Drugs for functional GI disorders B. breve + Combo prebiotic GI infection L. fermentum + GOS Infection Combo prebiotic + B. breve Intervention Resulted in Significant Negative Result for Infections or Infection-related Endpoints Respiratory infections L. Salivarius 7 studies reported non-significant differences in a variety of infectious outcomes 2 NEC; 3 GI related 4 Abx, 4 Respiratory infections Otitis media, mean titres for anti-bodies, hospitalization

15 Adverse Events: General Vomiting Bifidobacterium lactis Colic & Irritability Bifidobacterium lactis & Streptococcus thermophilus Loose stools Oligofructose, & Long-chain inulin Rash GOS, Lactobacillus paracasei, Bifidobacterium animalis ssp. lactis

16 Adverse Events: Diarrhea Frequency Bifidobacterium breve chicory-derived neutral oligofructose, long-chain inulin, & pectinderived acidic oligosaccharide (paos) Relative Risk Bifidobacterium longum Lactobacillus rhamnosus Inulin & Fructo-oligosaccharide LCPUFA Episodes Lactobacillus salivarius

17 Tolerability: General Mean daily volume of formula intake Yellow stool Colic Bifidobacterium lactis Oligosaccharide, Lactobacillus rhamnosus, Bifidobacterium longum Oligosaccharide, Lactobacillus rhamnosus, & Bifidobacterium longum Frequency of vomiting Green stool scfos Oligosaccharide, Lactobacillus rhamnosus, Bifidobacterium longum

18 Tolerability: Stool Frequency Bifidobacterium longum, Lactobacillus rhamnosus, GOS/scFOS BMOS, Lactobacillus rhamnosus, Bifidobacterium longum Bifidobacterium longum, GOS, Fructo-oligosaccharides Lactobacillus paracasei, Bifidobacterium animalis, GOS Lactobacillus rhamnosus GG and LC705, Bifidobacterium breve, Propionibacterium freudenreichii spp shermanii JS, GOS

19 Tolerability: Improved Stool Consistency Bifidobacterium longum, Lactobacillus rhamnosussc, FOS Oligosaccharide, Lactobacillus rhamnosus, Bifidobacterium longum GOS Lactobacillus paracasei, Bifidobacterium animalis, GOS scfos

20 Length and Weight Results - LBW Hosni et al, 2012 Extremely low-birth-weight infants Enteral feeding LGG million CFU + Bifidobacterium infan:s million CFU Growth velocity: 14.9 ± 6.5 g/day vs ± 4.5 g/day (p=0.05) Hays et al, 2015 LBW infants (GA between 25 and 31 weeks, birthweight: g) Bifidobacterium lac:c; Bifidobacterium longum; or combina<on No significant differences in LAZ, WAZ, weight gain or head circumference in comparison with those in the control group

21 Length and Weight Results Healthy Infants Non-significant differences across the majority of studies, as expected Firmansyah et al, 2011 Change in WAZ ITT (12 to 16 months) Syn: 0.11 ± 0.40 vs. Ctl: 0.02 ± 0.40 Gil-campos et al, 2011 LAZ: p=0.021; Syn higher than Ctl w/ Pre (curves shown in Fig. 3) Length gain (cm/day): Syn higher than Ctl w/ Pre p = 0.038

22 Microbiota Composition GOS scfos scfos Bifidobacteria Lactobacilli B. lactic and B. longum Bifidobacteria B. longum, L. rhamnosus, Inulin, & FOS Bifidobacteria Lactobacilli L. salivarius Bifidobacterium spp Lactobacilli/ Enterococci Lactobacilli Enterobacteria Clostridia Bacteroides

23 Microbiota Composition Oligofructose B. breve and prebio<c combo BMOS Bifidobacterium Bifidobacterium Bifidobacteria Enterobacteriaceae C. histolyticum E. rectale /C. coccoides Lactobacilli Clostridia

24 Discussion and Next Steps

25 Timeline Timeline Scoping Confirm work plan and scope Strategize approach = Check-In Point Landscape Analysis Review relevant literature & extract data Relay initial findings & finalize results