Adaptive strategies of the candidate probioticE. coliNissle in the mammalian gut

SummaryProbiotics are living microorganisms that are increasingly used as gastrointestinal therapeutics by virtue of their innate or engineered genetic function. Unlike abiotic therapeutics, probiotics can replicate in their intended site, subjecting their genomes and therapeutic properties to natural selection. By exposing the candidate probioticE. coliNissle (EcN) to the mouse gastrointestinal tract over several weeks, we uncovered the consequences of gut transit, inter-species competition, antibiotic pressure, and engineered genetic function on the processes under selective pressure during both within-genome and horizontal evolutionary modes. We then show the utility of EcN as a chassis for engineered function by achieving the highest reported reduction in serum phenylalanine levels in a mouse model of phenylketonuria using an engineered probiotic. Collectively, we demonstrate a generalizable pipeline which can be applied to other probiotic strains to better understand their safety and engineering potential.

Comparison of atherogenic risk factors among poorly controlled and well-controlled adolescent phenylketonuria patients

BackgroundPrevious studies investigating the known risk factors of atherosclerosis in phenylketonuria patients have shown conflicting results. The primary aim of our study was to investigate the serum atherogenic markers in adolescent classical phenylketonuria patients and compare these parameters with healthy peers. The secondary aim was to compare these atherogenic markers in well-controlled and poorly controlled patients.MethodsA total of 59 patients (median age: 12.6 years, range: 11–17 years) and 44 healthy controls (median age: 12.0 years, range: 11–15 years) were enrolled in our study. Phenylketonuria patients were divided into two groups: well-controlled (serum phenylalanine levels below 360 µmol/L; 24 patients) and poorly controlled patients (serum phenylalanine levels higher than 360 µmol/L).ResultsThe mean high-density lipoprotein cholesterol levels of well-controlled patients (1.0±0.2 mmol/L) were significantly lower compared with poorly controlled patients and controls (1.1±0.2 mmol/L, p=0.011 and 1.4±0.2 mmol/L, p<0.001, respectively). Poorly controlled patients had lower high-density lipoprotein cholesterol levels than healthy controls (p=0.003). Homocysteine levels of both well-controlled (9.8±6.4 µmol/L) and poorly controlled (9.2±5.6 µmol/L) patients were higher compared with controls (5.8±1.8 µmol/L, p<0.01). The mean platelet volume of well-controlled patients (9.5±1.1 fL) was higher than that of poorly controlled patients and controls (8.9±0.8 fL, p=0.024 and 7.7±0.6 fL, p<0.001, respectively).ConclusionLower high-density lipoprotein cholesterol and higher homocysteine and mean platelet volume levels were detected in phenylketonuria patients. In particular, these changes were more prominent in well-controlled patients. We conclude that phenylketonuria patients might be at risk for atherosclerosis, and therefore screening for atherosclerotic risk factors should be included in the phenylketonuria therapy and follow-up in addition to other parameters.