Alterations in fecal microbiota composition by probiotic supplementation in healthy adults:a systematic review of randomized controlled trials

BACKGROUND: The effects of probiotic supplementation on fecal microbiota composition in healthy adults have not been well established. We aimed to provide a systematic review of the potential evidence for an effect of probiotic supplementation on the composition of human fecal microbiota as assessed by high-throughput molecular approaches in randomized controlled trials (RCTs) of healthy adults. METHODS: The survey of peer-reviewed papers was performed on 17 August 2015 by a literature search through PubMed, SCOPUS, and ISI Web of Science. Additional papers were identified by checking references of relevant papers. Search terms included healthy adult, probiotic, bifidobacterium, lactobacillus, gut microbiota, fecal microbiota, intestinal microbiota, intervention, and (clinical) trial. RCTs of solely probiotic supplementation and placebo in healthy adults that examined alteration in composition of overall fecal microbiota structure assessed by shotgun metagenomic sequencing, 16S ribosomal RNA sequencing, or phylogenetic microarray methods were included. Independent collection and quality assessment of studies were performed by two authors using predefined criteria including methodological quality assessment of reports of the clinical trials based on revised tools from PRISMA/Cochrane and by the Jadad score. RESULTS: Seven RCTs investigating the effect of probiotic supplementation on fecal microbiota in healthy adults were identified and included in the present systematic review. The quality of the studies was assessed as medium to high. Still, no effects were observed on the fecal microbiota composition in terms of α-diversity, richness, or evenness in any of the included studies when compared to placebo. Only one study found that probiotic supplementation significantly modified the overall structure of the fecal bacterial community in terms of β-diversity when compared to placebo. CONCLUSIONS: This systematic review of the pertinent literature demonstrates a lack of evidence for an impact of probiotics on fecal microbiota composition in healthy adults. Future studies would benefit from pre-specifying the primary outcome and transparently reporting the results including effect sizes, confidence intervals, and P values as well as providing a clear distinction of between-group and within-group comparisons

Metformin-induced changes of the gut microbiota in healthy young men:results of a non-blinded, one-armed intervention study

Aims/hypothesis: Individuals with type 2 diabetes have an altered bacterial composition of their gut microbiota compared with non-diabetic individuals. However, these alterations may be confounded by medication, notably the blood-glucose-lowering biguanide, metformin. We undertook a clinical trial in healthy and previously drug-free men with the primary aim of investigating metformin-induced compositional changes in the non-diabetic state. A secondary aim was to examine whether the pre-treatment gut microbiota was related to gastrointestinal adverse effects during metformin treatment. Methods: Twenty-seven healthy young Danish men were included in an 18-week one-armed crossover trial consisting of a pre-intervention period, an intervention period and a post-intervention period, each period lasting 6 weeks. Inclusion criteria were men of age 18–35 years, BMI between 18.5 kg/m 2 and 27.5 kg/m 2 , HbA 1c &lt; 39 mmol/mol (5.7%) and plasma creatinine within the normal range. No prescribed medication, including antibiotics, for 2 months prior to recruitment were allowed and no previous gastrointestinal surgery, discounting appendectomy or chronic illness requiring medical treatment. During the intervention the participants were given metformin up to 1 g twice daily. Participants were examined five times in the fasting state with blood sampling and recording of gastrointestinal symptoms. Examinations took place at Frederiksberg Hospital, Denmark before and after the pre-intervention period, halfway through and immediately after the end of intervention and after the wash-out period. Faecal samples were collected at nine evenly distributed time points, and bacterial DNA was extracted and subjected to 16S rRNA gene amplicon sequencing in order to evaluate gut microbiota composition. Subjective gastrointestinal symptoms were reported at each visit. Results: Data from participants who completed visit 1 (n=23) are included in analyses. For the primary outcome the relative abundance of 11 bacterial genera significantly changed during the intervention but returned to baseline levels after treatment cessation. In line with previous reports, we observed a reduced abundance of Intestinibacter spp. and Clostridium spp., as well as an increased abundance of Escherichia/Shigella spp. and Bilophila wadsworthia. The relative abundance at baseline of 12 bacterial genera predicted self-reported gastrointestinal adverse effects. Conclusions/interpretation: Intake of metformin changes the gut microbiota composition in normoglycaemic young men. The microbiota changes induced by metformin extend and validate previous reports in individuals with type 2 diabetes. Secondary analyses suggest that pre-treatment gut microbiota composition may be a determinant for development of gastrointestinal adverse effects following metformin intake. These results require further investigation and replication in larger prospective studies. Trial registration: Clinicaltrialsregister.eu 2015-000199-86 and ClinicalTrials.gov NCT02546050 Funding: This project was funded by Danish Diabetes Association and The Novo Nordisk Foundation. </p

Tick-borne encephalitis in adults in Denmark: a nationwide prospective cohort study from 2015 to 2023

BACKGROUND: Our aim was to characterize the clinical presentation and outcome in adults with tick-borne encephalitis (TBE) and to determine the incidence and test activity of TBE in Denmark.METHODS: A nationwide prospective cohort study of all adults hospitalized with TBE at departments of infectious diseases in Denmark from 2015 to 2023. An age- and sex-matched cohort of herpes simplex virus type 1 (HSV-1) encephalitis patients was included to compare outcome.RESULTS: Fifty-two patients with TBE were included. Median age was 50 years, 32/52 (62%) were men, 1/52 (2%) was fully vaccinated against TBE at the time of infection, 29/52 (56%) were infected in Denmark. Upon admission 25/52 (48%) had meningitis, 27/52 (52%) encephalitis, three of the latter 3/52 (6%) with additional myelitis or radiculitis. Admission to the intensive care unit 6/52 (12%) and death 2/52 (4%) were associated with pre-existing comorbidities and older age. At 3-month follow-up, 16/50 (32%) had an unfavorable outcome (Glasgow Outcome Scale score 1-4) compared to 39/52 (75%) in the HSV-1 cohort. The most common residual symptoms at 6-month follow-up or later were headache, cognitive impairment, and fatigue. The TBE incidence increased from 0.03/100,000 in 2015 to 0.48/100,000 in 2023, and the test rate from 5.5/100,000 in 2015 to 14.4/100,000 in 2023, with a positivity rate of 0.6% in 2015 and 3.3% in 2023.CONCLUSION: The incidence of TBE in Denmark increased in the study period, with clinical characteristics and outcome of adult patients comparable to reports from other European countries.</p