Impact of international travel and diarrhea on gut microbiome and resistome dynamics

International travel contributes to the global spread of antimicrobial resistance. Travelers\u27 diarrhea exacerbates the risk of acquiring multidrug-resistant organisms and can lead to persistent gastrointestinal disturbance post-travel. However, little is known about the impact of diarrhea on travelers\u27 gut microbiomes, and the dynamics of these changes throughout travel. Here, we assembled a cohort of 159 international students visiting the Andean city of Cusco, Peru and applied next-generation sequencing techniques to 718 longitudinally-collected stool samples. We find that gut microbiome composition changed significantly throughout travel, but taxonomic diversity remained stable. However, diarrhea disrupted this stability and resulted in an increased abundance of antimicrobial resistance genes that can remain high for weeks. We also identified taxa differentially abundant between diarrheal and non-diarrheal samples, which were used to develop a classification model that distinguishes between these disease states. Additionally, we sequenced the genomes of 212 diarrheagenic Escherichia coli isolates and found those from travelers who experienced diarrhea encoded more antimicrobial resistance genes than those who did not. In this work, we find the gut microbiomes of international travelers\u27 are resilient to dysbiosis; however, they are also susceptible to colonization by multidrug-resistant bacteria, a risk that is more pronounced in travelers with diarrhea

A site assessment tool for inpatient controlled human infection models for enteric disease pathogens

The use of the controlled human infection model to facilitate product development and to advance understanding of host-pathogen interactions is of increasing interest. While administering a virulent (or infective) organism to a susceptible host necessitates an ongoing evaluation of safety and ethical considerations, a central theme in conducting these studies in a safe and ethical manner that yields actionable data is their conduct in facilities well-suited to address their unique attributes. To that end, we have developed a framework for evaluating potential sites in which to conduct inpatient enteric controlled human infection model to ensure consistency and increase the likelihood of success.publishedVersio

A systematic review of experimental infections with enterotoxigenic \u3ci\u3eEscherichia coli\u3c/i\u3e (ETEC)

Volunteer challenge with enterotoxigenic Escherichia coli (ETEC) has been used for four decades to elucidate the pathogenesis and immune responses and assess efficacy of various interventions. We performed a systematic review of these studies and a meta-analysis of individual patient-level data (IPD) from a subset of studies using standard methodology. We identified 27 studies of 11 ETEC strains administered to 443 naive subjects at doses from 1 × 106 to 1 × 1010 colony forming units (cfu). Diarrhea attack rates varied by strain, dose and enterotoxin. Similar rates were seen at doses of 5 × 108 to 1 × 1010 cfu with the three most commonly used strains B7A, E24377A, H10407. In IPD analysis, the highest diarrhea attack rates were seen with strains B7A, H10407 and E24377A. The H10407 induced significantly higher stool output than the other strains. Additionally, the rate of output was different across strains. The risk of diarrhea, abdominal cramps, nausea and headaches differed significantly by ETEC strain. An increased risk of nausea, abdominal cramps and headaches was seen for females. Baseline anti-LT IgG titers appeared to be associated with a decrease risk of diarrhea outcomes, a trend not seen with anti-LT IgA or seen consistently with anti-colonization factor antibodies. Neither early antibiotic treatment nor diarrhea duration significantly affected the frequency or magnitude of serologic responses. These studies have served as an invaluable tool in understanding disease course, pathogenicity, innate immune responses and an early assessment of product efficacy. When designing and planning experimental ETEC infection studies in this age of increased ethical scrutiny and growing appreciation of post-infectious sequelae, better understanding of available data is essential

Orally Ingested Probiotic, Prebiotic, and Synbiotic Interventions as Countermeasures for Gastrointestinal Tract Infections in Non-elderly Adults: A Systematic Review and Meta-analysis

Meta-analyses have not examined the prophylactic use of orally ingested probiotics, prebiotics, or synbiotics for preventing gastrointestinal tract infections (GTI) of various etiologies in adult populations despite evidence that these gut microbiota-targeted interventions can be effective in treating certain GTI. This systematic review and meta-analysis aimed to estimate the effects of prophylactic use of orally ingested probiotics, prebiotics, and synbiotics on GTI incidence, duration, and severity in non-elderly, non-hospitalized adults. CENTRAL, PubMed, Scopus, and Web of Science were searched through January 2022. English-language, peer-reviewed publications of randomized, placebo-controlled studies testing an orally ingested probiotic, prebiotic, or synbiotic intervention of any dose for ≥1 week in adults who were not hospitalized, immunosuppressed, or taking antibiotics were included. Results were analyzed using random-effects meta-analyses of intention-to-treat (ITT) and complete case (CC) cohorts. Heterogeneity was explored by subgroup meta-analysis and meta-regression. Risk of bias was assessed using the Cochrane RoB2 tool. Seventeen publications reporting 20 studies of probiotics (n=16), prebiotics (n=3), and synbiotics (n=1) were identified (n\u3e6,994 subjects). In CC and ITT analyses, risk of experiencing ≥1 GTI was reduced with probiotics (CC analysis: risk ratio=0.86 [95%CI: 0.73, 1.01]) and prebiotics (risk ratio=0.80 [95%CI: 0.66, 0.98]). No effects on GTI duration or severity were observed. Sources of heterogeneity included study population and number of probiotic strains administered, but were often unexplained, and a high risk of bias was observed for most studies. Specific effects of individual probiotic strains and prebiotic types could not be assessed due to a lack of confirmatory studies. Findings indicated that orally ingested probiotics and prebiotics, relative to placebo, both demonstrated modest benefit for reducing GTI risk in non-elderly adults. However, results should be interpreted cautiously due to the low number of studies, high risk of bias, and unexplained heterogeneity that may include probiotic strain- or prebiotic-specific effects. PROSPERO REGISTRATION: CRD42020200670

A site assessment tool for inpatient controlled human infection models for enteric disease pathogens

The use of the controlled human infection model to facilitate product development and to advance understanding of host-pathogen interactions is of increasing interest. While administering a virulent (or infective) organism to a susceptible host necessitates an ongoing evaluation of safety and ethical considerations, a central theme in conducting these studies in a safe and ethical manner that yields actionable data is their conduct in facilities well-suited to address their unique attributes. To that end, we have developed a framework for evaluating potential sites in which to conduct inpatient enteric controlled human infection model to ensure consistency and increase the likelihood of success