TLR2 Controls Intestinal Carcinogen Detoxication by CYP1A1

Intestinal cytochrome P450 subclass 1A1 (CYP1A1) contributes to a metabolic “shield” protecting the host from ingested carcinogens such as polycyclic aromatic hydrocarbons (PAH). The expression of CYP1 (including CYP1A2 and CYP1B1) is considered to depend solely on a heterodimeric transcription factor consisting of the arylhydrocarbon receptor (AHR) and the AHR nuclear translocator (ARNT). So far, no interference has been noted between the regulation of CYP1 and the activation of Toll-like receptor 2 (TLR2), which modulates the inflammatory response to bacterial cell wall components in immune cells and enterocytes. Here we report that intestinal CYP1A1 is silenced in TLR2-deficient mice, even when under exposure to the carcinogenic PAH benzo[a]pyrene (BaP). In contrast, hepatic CYP1A1 was moderately induced in TLR2-deficient mice without restoring their ability to clear BaP from systemic circulation, as present in wild-type animals. After feeding of BaP for 21 days, only TLR2−/− mice, but not their wild type littermates developed polyps in the colon. Gene expressions and protein concentrations of AHR and ARNT in the intestine did not differ between the genotypes. In conclusion, the presence of ligands for TLR2 of bacterial origin seems to be crucial for detoxication of luminal carcinogens by CYP1A1 in the intestine. This unprecedented finding indicates a complex interplay between the immune system of the host and intestinal bacteria with detoxication mechanisms. This highlights the relevance of intestinal microbiota when trying to unravel pathways present in mammals and opens new perspectives for research in human health

Probiotic yogurt in the elderly with intestinal bacterial overgrowth: endotoxaemia and innate immune functions

A study was conducted in healthy elderly living independently in senior housing to assess the impact of a probiotic yoghurt supplement on small intestinal bacterial overgrowth. Twenty-three participants with positive and thirteen participants with negative hydrogen breath test were studied before and after a period of 4 weeks of probiotic yoghurt administration. Intestinal permeability, plasma endotoxin levels, phagocytic activity of leucocytes, cytokine production by monocytes and free radical response of neutrophils were determined. Intestinal permeability was similar for the two groups and was unaffected by probiotic treatment. Both plasma endotoxin levels and the basal phagocytic activity of leucocytes decreased after yoghurt intake in the two groups. Exposure of monocytes and neutrophils ex vivo led to an increased cytokine response and free radical response, respectively. The normalisation of the various cytokine responses was more apparent in the group with positive breath test. In addition, the plasma levels of lipoplysaccharide binding protein and soluble CD14, lipoplysaccharide pattern recognition receptors and surrogate markers of lipoplysaccharide permeability were diminished by the end of the study. In conclusion, probiotic administration in the elderly normalises the response to endotoxin, and modulates activation markers in blood phagocytes, and therefore may help reduce low-grade chronic inflammatio

Pathways to "5-a-day": modeling the health impacts and environmental footprints of meeting the target for fruit and vegetable intake in the United Kingdom.

BACKGROUND: Fruit and vegetable consumption in the United Kingdom is currently well below recommended levels, with a significant associated public health burden. The United Kingdom has committed to reducing its carbon emissions to net zero by 2050, and this transition will require shifts towards plant-based diets. OBJECTIVE: The aim was to quantify the health effects, environmental footprints, and cost associated with 4 different pathways to meeting the United Kingdom's "5-a-day" recommendation for fruit and vegetable consumption. METHODS: Dietary data based on 18,006 food diaries from 4528 individuals participating in the UK National Diet and Nutrition Survey (2012/13-2016/17) constituted the baseline diet. Linear programming was used to model the hypothetical adoption of the 5-a-day (400 g) recommendation, which was assessed according to 4 pathways differing in their prioritization of fruits versus vegetables and UK-produced versus imported varieties. Increases in fruit and vegetable consumption were substituted for consumption of sweet snacks and meat, respectively. Changes in life expectancy were assessed using the IOMLIFET life table model. Greenhouse gas emissions (GHGEs), blue water footprint (WF), and total diet cost were quantified for each 5-a-day diet. RESULTS: Achieving the 5-a-day target in the United Kingdom could increase average life expectancy at birth by 7-8 mo and reduce diet-related GHGEs by 6.1 to 12.2 Mt carbon dioxide equivalents/y; blue WFs would change by -0.14 to +0.07 km3/y. Greater reductions in GHGEs were achieved by prioritizing increased vegetable consumption over fruit, whereas the greatest reduction in WF was obtained by prioritizing vegetable varieties produced in the United Kingdom. All consumption pathways increased diet cost (£0.34-£0.46/d). CONCLUSIONS: Benefits to both population and environmental health could be expected from consumption pathways that meet the United Kingdom's 5-a-day target for fruit and vegetables. Our analysis identifies cross-sectoral trade-offs and opportunities for national policy to promote fruit and vegetable consumption in the United Kingdom

Distribution of cytochrome P450 2C, 2E1, 3A4, and 3A5 in human colon mucosa

BACKGROUND: Despite the fact that the alimentary tract is part of the body's first line of defense against orally ingested xenobiotica, little is known about the distribution and expression of cytochrome P450 (CYP) enzymes in human colon. Therefore, expression and protein levels of four representative CYPs (CYP2C(8), CYP2E1, CYP3A4, and CYP3A5) were determined in human colon mucosa biopsies obtained from ascending, descending and sigmoid colon. METHODS: Expression of CYP2C, CYP2E1, CYP3A4, and CYP3A5 mRNA in colon mucosa was determined by RT-PCR. Protein concentration of CYPs was determined using Western blot methods. RESULTS: Extensive interindividual variability was found for the expression of most of the genes. However, expression of CYP2C mRNA levels were significantly higher in the ascending colon than in the sigmoid colon. In contrast, mRNA levels of CYP2E1 and CYP3A5 were significantly lower in the ascending colon in comparison to the descending and sigmoid colon. In sigmoid colon protein levels of CYP2C8 were significantly higher by ~73% than in the descending colon. In contrast, protein concentration of CYP2E1 was significantly lower by ~81% in the sigmoid colon in comparison to the descending colon. CONCLUSION: The current data suggest that the expression of CYP2C, CYP2E1, and CYP3A5 varies in different parts of the colon