Protease-activated receptors: protease signaling in the gastrointestinal tract

Serine proteases from the circulation, inflammatory cells, digestive glands and microorganisms can signal to cells by cleaving protease-activated receptors (PARs), a family of four G-protein-coupled receptors. Proteases cleave PARs at specific sites to expose tethered ligand domains that bind to and activate the cleaved receptors. Despite this irreversible mechanism of activation, PAR signaling is tightly regulated to prevent the uncontrolled stimulation of cells. Although PARs are found in all organ systems, protease signaling is of particular interest in the gastrointestinal tract, where proteases regulate neurotransmission, secretion, motility, epithelial permeability and intestinal inflammation, and can thus contribute to disease.

Comparative analysis of intestinal tract models

The human gut is a complex ecosystem occupied by a diverse microbial community. Modulation of this microbiota impacts health and disease. The definitive way to investigate the impact of dietary intervention on the gut microbiota is a human trial. However, human trials are expensive and can be difficult to control; thus, initial screening is desirable. Utilization of a range of in vitro and in vivo models means that useful information can be gathered prior to the necessity for human intervention. This review discusses the benefits and limitations of these approaches.

Using NMR-based metabolomics to evaluate postprandial urinary responses following consumption of minimally processed wheat bran or wheat aleurone by men and women

Wheat bran, and especially wheat aleurone fraction, are concentrated sources of a wide range of components which may contribute to the health benefits associated with higher consumption of whole-grain foods. This study used NMR metabolomics to evaluate urine samples from baseline at one and two hours postprandially, following the consumption of minimally processed bran, aleurone or control by 14 participants (7 Females; 7 Males) in a randomized crossover trial. The methodology discriminated between the urinary responses of control, and bran and aleurone, but not between the two fractions. Compared to control, consumption of aleurone or bran led to significantly and substantially higher urinary concentrations of lactate, alanine, N-acetylaspartate acid and N-acetylaspartylglutamate and significantly and substantially lower urinary betaine concentrations at one and two hours postprandially. There were sex related differences in urinary metabolite profiles with generally higher hippurate and citrate and lower betaine in females compared to males. Overall, this postprandial study suggests that acute consumption of bran or aleurone is associated with a number of physiological effects that may impact on energy metabolism and which are consistent with longer term human and animal metabolomic studies that used whole-grain wheat diets or wheat fractions.

Urinary metabolomic profiling to identify biomarkers of a flavonoid-rich and flavonoid-poor fruits and vegetables diet: the FLAVURS trial in adults: the FLAVURS trial

The present study aims to investigate the dose dependent effects of consuming diets enriched in flavonoid-rich and flavonoid-poor fruits and vegetables on the urine metabolome of adults who had a C1.5 fold increased risk of cardiovascular diseases. A single-blind, dose-dependent, parallel randomized controlled dietary intervention was conducted where volunteers (n = 126) were randomly assigned to one of three diets: high flavonoid diet, low flavonoid diet or habitual diet as a control for 18 weeks. High resolution LC– MS untargeted metabolomics with minimal sample cleanup was performed using an Orbitrap mass spectrometer. Putative biomarkers which characterize diets with high and low flavonoid content were selected by state-of-the-art data analysis strategies and identified by HR-MS and HR-MS/MS assays. Discrimination between diets was observed by application of two linear mixedmodels: one including a diet-time interaction effect and the second containing only a time effect. Valerolactones, phenolic acids and their derivatives were among sixteen biomarkers related to the high flavonoid dietary exposure. Four biomarkers related to the low flavonoid diet belonged to the family of phenolic acids. For the first time abscisic acid glucuronide was reported as a biomarker after a dietary intake, however its origins have to be examined by future hypothesis driven experiments using a more targeted approach. This metabolomic analysis has identified a number of dose dependent urinary biomarkers (i.e. proline betaine or iberin-N-acetyl cysteine), which can be used in future observation and intervention studies to assess flavonoids and nonflavonoid phenolic intakes and compliance to fruit and vegetable intervention.