Antibiotic-induced gut microbiota depletion exacerbates host hypercholesterolemia.

Hypercholesterolemia is a major driver of atherosclerosis, thus contributing to high morbidity and mortality worldwide. Gut microbiota have been identified as modulator of blood lipids including cholesterol levels. Few studies have already linked certain bacteria and microbial mechanisms to host cholesterol. However, in particular mouse models revealed conflicting results depending on genetics and experimental protocol. To gain further insights into the relationship between intestinal bacteria and host cholesterol metabolism, we first performed fecal 16S rRNA targeted metagenomic sequencing in a human cohort (n = 24) naïve for cholesterol lowering drugs. Here, we show alterations in the gut microbiota composition of hypercholesterolemic patients with depletion of Bifidobacteria, expansion of Clostridia and increased Firmicutes/Bacteroidetes ratio. To test whether pharmacological intervention in gut microbiota impacts host serum levels of cholesterol, we treated hypercholesterolemic Apolipoprotein E knockout with oral largely non-absorbable antibiotics. Antibiotics increased serum cholesterol, but only when mice were fed normal chow diet and cholesterol was measured in the random fed state. These elevations in cholesterol already occurred few days after treatment initiation and were reversible after stopping antibiotics with re-acquisition of intestinal bacteria. Gene expression analyses pointed to increased intestinal cholesterol uptake mediated by antibiotics in the fed state. Non-targeted serum metabolomics suggested that diminished plant sterol levels and reduced bile acid cycling were involved microbial mechanisms. In conclusion, our work further enlightens the link between gut microbiota and host cholesterol metabolism. Pharmacological disruption of the gut flora by antibiotics was able to exacerbate serum cholesterol and may impact cardiovascular disease.

Non-targeted metabolomics identify polyamine metabolite acisoga as novel biomarker for reduced left ventricular function.

AIMS: Chronic heart failure with reduced ejection fraction remains a major health issue. To date, no reliable biomarker is available to predict reduced left ventricular ejection fraction (LV-EF). We aimed to identify novel circulating biomarkers for reduced left ventricular function using untargeted serum metabolomics in two independent patient cohorts. METHODS AND RESULTS: Echocardiography and non-targeted serum metabolomics were conducted in two patient cohorts with varying left ventricular function: (1) 25 patients with type 2 diabetes with established cardiovascular disease or high cardiovascular risk (LV-EF range 20-66%) (discovery cohort) and (2) 37 patients hospitalized for myocardial infarction (LV-EF range 25-60%) (validation cohort). In the discovery cohort, untargeted metabolomics revealed seven metabolites performing better than N-terminal pro-B-type natriuretic peptide in the prediction of impaired left ventricular function shown by LV-EF. For only one of the metabolites, acisoga, the predictive value for LV-EF could be confirmed in the validation cohort (r = -0.37, P = 0.02). In the discovery cohort, acisoga did not only correlate with LV-EF (r = -60, P = 0.0016), but also with global circumferential strain (r = 0.67, P = 0.0003) and global longitudinal strain (r = 0.68, P = 0.0002). Similar results could be detected in the discovery cohort in a 6 month follow-up proofing stability of these results over time. With an area under the curve of 0.86 in the receiver operating characteristic analysis, acisoga discriminated between patients with normal EF and LV-EF < 40%. Multivariate analysis exposed acisoga as independent marker for impairment of LV-EF (Beta = -0.71, P = 0.004). CONCLUSIONS: We found the polyamine metabolite acisoga to be elevated in patients with impaired LV-EF in two independent cohorts. Our analyses suggest that acisoga may be a valuable biomarker to detect patients with heart failure with reduced ejection fraction.

The Benefit of Benzodiazepine Reduction: Improving Sedation in Surgical Intensive Care.

AIMS: Sedation, as it is often required in critical care, is associated with immobilization, prolonged ventilation, and increased morbidity. Most sedation protocols are based on benzodiazepines. The presented study analyzes the benefit of benzodiazepine-free sedation. METHODS: In 2008, 134 patients were treated according to a protocol using benzodiazepine and propofol (Group 1). In 2009, we introduced a new sedation strategy based on sufentanil, nonsteroidal anti-inflammatory drugs, neuroleptics, and antidepressants, which was applied in 140 consecutive patients (Group 2). Depth of sedation, duration of mechanical ventilation, duration of Intensive Care Unit, and hospital stay were analyzed. RESULTS: Group 1 had both a longer duration of deep sedation (18.7 ± 2.5 days vs. 12.6 ± 1.85 days, P = 0.031) and a longer duration of controlled ventilation (311, 35 ± 32.69 vs. 143, 96 ± 20.76 h, P < 0.0001) than Group 2. Ventilator days were more frequent in Group 1 (653, 66 ± 98.37 h vs. 478, 89 ± 68.92 h, P = 0.128). CONCLUSIONS: The benzodiazepine-free sedation protocol has been shown to significantly reduce depth of sedation and controlled ventilation. Additional evidence is needed to ascertain reduction of ventilator days which would not only be of benefit for the patient but also for the hospital Management.