Team 1

Image

Human micronutrition

Supervisor
Image
Patrick Borel

Team members


Bioavailability : from foods to postprandial phase 

Emmanuelle Reboul

The work carried out by the group “Bioavailability” explores the different stages (from digestion to the production of chylomicrons) and the different factors (lipid and non-lipid food intake, food matrix, hormones, factors circulating as free fatty acids, genetic variations, circadian rhythms, drug treatments and bariatric surgery) that govern the absorption and postprandial metabolism of lipids, glucose and lipid micronutrients.

Factors modulating the bioaccessibility of lipid micronutrients

Patrick Borel, Charles Desmarchelier & Emmanuelle Reboul

Lipid micronutrient absorption efficiency can be very low (a few % of the ingested dose) and is very variable as it is affected by many factors (dietary matrix in which micronutrients are ingested, interactions with macronutrients, absorption capacity related to individuals...). Two key limiting steps of lipid micronutrient absorption are their extraction from the food matrix and their incorporation into micelles (bioaccessibility), which allow their transport to enterocytes. Our team is internationally recognized for its work on this topic. We have recently studied the stability of these compounds in the acid and pro-oxidative environment of the digestive tract, the physicochemical mechanisms that govern their micellization, and the effect of the food matrix on their micellization efficiency.

Keywords: bioaccessibility, digestion, food matrix, micelles, digestive tract.
Main publications of recent years:

Bioavailability of lipid micronutrients in the context of sustainable diets

Patrick Borel & Emmanuelle Reboul

Sustainable diets are protective of the environment, economically equitable and affordable, but also culturally acceptable, nutritionally adequate, safe and healthy. The current food supply, however, is generally unsustainable: it has not been able to tackle malnutrition and malnutrition prevalence is still elevated, under the threat of environmental crisis. Part of the team's work is therefore to identify new sources of lipid micronutrients that could be compatible with a sustainable diet (i.e. plant enrichment in lipid micronutrients by exposure to light (UV-C) or water stress, enrichment of insects in lipid micronutrients using vegetable waste from food industry).

Some "sustainable" food matrices, such as legumes and vegetable protein sources in the broad sense, are also carriers of compounds (polyphenols, phytates, saponins, etc.) that can alter the bioavailability of lipid micronutrients. We therefore study the interactions between the compounds of these matrices and the lipid micronutrients to propose dietary and technological solutions to overcome these effects.

This is performed by quantifying lipid micronutrients in different food sources, evaluating their bioaccessibility using in vitro digestions, and validating these results by measuring bioavailability in rodents and humans (clinical trials).

Main publications of recent years:
Key words: pulses, vegetal proteins, insects, environment, sustainability

Mechanisms of intestinal transport of lipid micronutrients

Emmanuelle Reboul

The molecular mechanisms of the intestinal absorption of fat-soluble vitamins and carotenoids remain poorly understood.

We seek to evaluate how dietary compounds (fatty acids, phenolic compounds, …) modulate the transport of micronutrients through the enterocyte.

Our goal is also to identify membrane proteins involved in the transport of lipid micronutrients at the enterocyte level and to evaluate their respective contribution to the absorption of their different ligands. For example, cholesterol transporters have been implicated in the absorption of vitamin D, E, K and some carotenoids.

Finally, we have recently shown that the intestine is not a simple entry for lipid micronutrients in the body. The intestine can also limit the absorption of micronutrients by excreting them from the enterocytes into the intestinal lumen, or even by effluxing them from the bloodstream to the intestinal lumen. These new metabolic pathways are thus being investigated.

A better understanding of all these transport pathways is essential since some dietary or therapeutic approaches (aimed at decreasing the absorption efficiency of cholesterol, for example) can negatively impact on the bioavailability of lipid micronutrients.

This part of our work is mainly carried out by evaluating the absorption of lipid micronutrients in cultured cell models (Caco-2 TC7 human intestinal cells modified or not using CRISPR/CAS9 technology, transfected human HEK cells, etc.), before in vivo validation.

Main publications of recent years:
Keywords : enterocyte,membrane transporter, absorption, efflux.

Genetic and epigenetic factors modulating lipid micronutrient bioavailability and metabolism

Charles Desmarchelier & Patrick Borel

Some genetic or epigenetic variations in the genes coding for the many proteins involved in the transport and metabolism of lipid micronutrients can modulate these processes and therefore lead to different health effects from one individual to another.

We have recently shown that combinations of single nucleotide polymorphisms (SNPs) are associated with the variability in the bioavailability of vitamin D and E as well as carotenoids (β-carotene, lutein, lycopene).

We are currently seeking to extend these observations to other micronutrients (cholesterol, water-soluble vitamins) as well as to identify SNPs involved in the variability of their tissue deposition.

We also seek to characterize the impact of these genetic variations on the health effects of lipid micronutrients or their metabolites by measuring the prevalence of pathologies (cancer, dyslipidemia, obesity) in participants with or without some of these SNPs.

The identification of these variations will allow nutritionists to propose dietary recommendations tailored to an individual’s genetic characteristics in order to optimize the health effects of micronutrients.

This part of our work is carried out by bioinformatic analyses of data from clinical and epidemiological studies carried out by our team or in collaboration with international teams.

Main publications of recent years:
Keywords: genetic polymorphisms, personalized nutrition, nutrigenetics, epigenetics, perinatal nutrition.

Role of the intestine in the regulation of postprandial metabolism of lipids and lipid micronutrients and in the pathophysiological mechanisms of atherogenic dyslipidemia in insulin-resistant patients

René Valéro, Sophie Béliard & Marie Maraninchi

The current global "epidemic" of obesity, type 2 diabetes and metabolic syndrome represents a major public health problem, as it is accompanied by an increase in cardiovascular complications which represent the leading cause of morbidity and mortality. These diseases, which often share an insulin-resistant state, are characterized by a specific atherogenic dyslipidemia (AD): hypertriglyceridemia, postprandial hyperlipidemia, decreased level of HDL-cholesterol and increase of small and dense LDL. The main pathophysiological mechanism of this AD is the blood accumulation of triglyceride-rich lipoproteins (TRL) of intestinal (chylomicrons) and hepatic (VLDL) origin. This accumulation is secondary to an overproduction of chylomicrons and VLDL and a defective TRL clearance. The overproduction of intestinal TRL is a newly recognized component of insulin resistance. Fasting and postprandial blood elevation in TRL concentration, which is mainly due to an increased production of chylomicrons, is now considered a causal risk factor for low-grade inflammation, cardiovascular diseases and total mortality.

It now appears that chylomicron intestinal production, and consequently postprandial lipemia, is highly regulated by many factors: lipid and non-lipid food intakes, food matrix, circulating free fatty acids, hormones, genetic variations, circadian rhythms, but also drugs and bariatric surgery.

Our objective is to better understand the different factors that modulate both absorption and postprandial metabolism of lipids and lipid micronutrients. In particular, we are trying to understand what are the pathophysiological mechanisms responsible for this AD. Using human clinical studies and stable isotope lipoprotein kinetic studies, our research team has gathered groundbreaking data on factors modulating postprandial lipemia and AD. We have recently shown significant changes in the metabolism of TRL in relation to the improvement of insulin-resistance and the lipid profile after bariatric surgery. In a recent publication, we have shown that the beneficial effects of bariatric surgery on the lipid profile were associated with a reduction and a redistribution of apolipoprotein C-III, which is a key factor in the regulation of TRL metabolism. Finally, works in progress aim to better understand the link between lipid micronutrient status in obese patients and defect of absorption, in particular due to changes in expression of carriers of the enterocytic membrane.

The atherogenic potential of these TRL makes it particularly necessary to understand the factors regulating their production but also the mechanisms of their intestinal hyperproduction and their plasma accumulation in insulin resistance syndromes in order to develop new treatments targeted on the enterocyte to improve the lipid micronutrient status and lipid profile of these patients and thereby reduce the incidence of cardiovascular diseases.

Main publications of recent years:
KEY WORDS: INTESTINE, INSULIN RESISTANCE, TRIGLYCERIDE RICH LIPOPROTEINS (LRT), POST-PRANDIAL LIPEMIA, KINETIC STUDY OF LIPOPROTEIN METABOLISM, BARIATRIC SURGERY

GLUT4, postprandial glucose homeostasis and fat-soluble micronutrients

Roland Govers

Type 2 diabetes (T2D) prevalence is exceedingly high in modern society and is still increasing at an alarming rate worldwide. It is associated with obesity, unhealthy diets, and lack of physical activity. Diabetes has become one of the major causes of premature illness and death in many countries, mainly through the increased risk of cardiovascular disease.

Glucose transporter GLUT4, a key molecule in T2D, is responsible for the insulin-regulated uptake of excess glucose from the blood by adipose tissue and muscle, especially in the postprandial state. In the non-stimulated (basal, fasting) state, GLUT4 is efficiently retained within intracellular compartments. The nature of this retention mechanism is currently largely unknown. Upon insulin stimulation during the postprandial state, GLUT4 translocates to the cell surface via increased exocytosis and/or diminished retention, allowing the cell to take up glucose.

Our team has two research goals. First, we aim to unravel in vitro the cellular trafficking pathways of GLUT4. We determine how these are altered in insulin resistance, a condition that is closely associated with T2D, and their sensitivity to micronutrients, especially those derived from food during the postprandial phase. To this aim, we study various GLUT4 trafficking parameters in insulin responsive and insulin resistant cells, such as intracellular retention, insulin signaling, and the dynamics of GLUT4 between the different organelles. In addition, we study the role of reactive oxygen species (ROS), also sensitive to (phyto)micronutrients, in intracellular GLUT4 traffic, under both physiological and pathophysiological conditions.

In a more translational research line, multiple methodologies are exploited in order to find novel ways to modulate GLUT4 traffic in vitro and in vivo. In particular, we focus on enhancing the appearance of GLUT4 at the cell surface via interference with either insulin signaling or the intracellular GLUT4 retention machinery. This research line includes the analysis of the effects of food components, such as (phyto)micronutrients. The final goal of this research line is to be able to ameliorate glucose homeostasis in diabetes in vivo using GLUT4 as target molecule.

These studies will allow to better understand how (phyto)micronutrients from food affect certain aspects of intracellular GLUT4 traffic and of the complications that are associated with the dysregulated postprandial glucose homeostasis associated with T2D.

Main publications of recent years:
 KEYWORDS: GLUT4, adipocyte