One in five individuals displays elevated lipoprotein (a) [Lp(a)], a highly atherogenic lipoprotein resembling low-density lipoproteins (LDL). Pathophysiological, epidemiological and genetic studies demonstrate that when circulating Lp(a) levels are high (above 125 nmol/L), cardiovascular event rates sharply increase. The major structural difference between Lp(a) and LDL is that Lp(a) contains a large signature protein, apolipoprotein (a) [apo(a)]. Apo(a) is extremely polymorphic in size as it contains 1 to more than 40 kringle-IV2 (KIV2) domains giving origin to more than 40 isoforms in humans. The size of apo(a) is inversely correlated with the circulating levels of Lp(a), but the exact molecular and metabolic pathways regulating Lp(a) plasma concentrations have not been clearly established yet. The goal of the present research project is to decipher these pathways. (1) For instance, the molecular mechanisms governing Lp(a) production are poorly understood. Short RNAs (miRs) control gene expression and have been shown to modulate lipoproteins homeostasis. miRs work by inducing RNA silencing and thereby reduce target genes expression. We will investigate the influence of these regulatory elements on the expression of the gene encoding apo(a). (2) In the population, Lp(a) levels can vary by up to 100-fold in carriers of identical apo(a) isoforms. We have recruited a large family in which several individuals present extremely high Lp(a) levels. We will determine the genetic causes on their apo(a) gene that are responsible for their extreme Lp(a) plasma concentrations leading to premature cardiovascular events. (3) Lp(a) levels are resistant to lifestyle changes and lipid lowering drugs such as statins, which poses a real challenge for clinical management. A novel class of lipid lowering agents, the PCSK9 inhibitors induce a 30% reduction in circulating Lp(a) levels. We will investigate the mechanisms by which PCSK9 inhibitors modulate Lp(a) plasma levels and the influence of the size of apo(a) on the response of patients to these novel therapies. (4) The gene encoding apolipoprotein E (apoE) is the only gene besides apo(a) and pcsk9 to have a significant association with circulating Lp(a) levels. Humans display three major apoE isoforms (e2/e3/e4) that differ by the presence of different amino acids at position 112 and 158. Carriers of the e2 allele display much lower Lp(a) than non-e2 carriers. We will study the pathway by which this particular apoE isoform lowers Lp(a) in humans. Taken together these studies have profound implications in terms of deciphering the genetic and metabolic pathways regulating plasma Lp(a) levels, and pave the way to enhanced diagnosis and therapeutics approaches for patients at high risk of Lp(a)-induced cardiovascular diseases.

Obesity is associated with increased severity of infectious diseases. There is an urgent need to provide adapted lifestyle recommendation to reduce that risk which could be due to low grade inflammation and increased immune checkpoint (ICP) overexpression such as the PD-1/PDL1 pathway that leads to exhaustion of T-cells. Nutrim_Check is a new translational research collaborative network involving 4 groups of investigators that is organized into 6 complementary work-packages. Combining expertise in nutrition, metabolism, immunology and large-scale data analysis, our aim is to assess the interaction between NUTRition, IMmune CHECKpoints, and immune and metabolic health. Thanks to access to databases and biobanks with blood and adipose tissue samples from existing cohorts of subjects with metabolic deterioration, we will characterize obesity-related and cell and tissue-specific T cell dysfunction (ICP expression) and explore the interaction between dietary patterns, nutrients, gut microbiota (GM), metabolites and ICP modification (WP1). We will evaluate if T cell dysfunction can be rescued after dietary intervention known to improve metabolism and inflammation in a pilot study (WP2, i.e. called the pro immune diet). Mechanistic insights linking changes of T cell ICP expression will be addressed using ex vivo and in vitro models from human cells and detailed immune cell characterization will be undertaken (WP3). The infectious model of investigation will be the COVID-19, but this project extends broadly to viral infection vulnerability. Of note, an holistic and standardized mass cytometry approach will be used to obtain a detailed phenotyping of the immune populations. Patients from the pilot nutritional intervention will also be phenotyped in depth at the molecular level (metagenomics and metabolomics, WP4) and large-scale data analysis will be undertaken thanks to local expertise in biostatistic and machine learning (WP5). We will explore a novel not yet explored idea that chronic inflammatory tone due to increased expression of ICP contributes to adaptive immune evasion and sustained viral infection in dietary-related diseases. We propose this phenomenon may be fixable by nutritional amelioration in vulnerable populations such as people with obesity and metabolic diseases. Thanks to precise coordination (WP6), the project will provide information of academic and industrial interest with new information on food compounds known to broaden their spectrum of consumption, with emphasis on the immune response. The communication and dissemination Strategy will address the various target groups including the public, food, pharma and healthcare sectors and policy makers

Given the continuous rise of diet-related chronic diseases worldwide, our timely translational project SINFONI, gathering international pluridisciplinary academic and industrial experts, develops a multifunctional anti-inflammatory dietary approach to improve cardiometabolic risk profile. Our novel concept will simultaneously target metabolic endotoxemia and inflammatory status balance, gastrointestinal barrier integrity and gut microbiota, food glycaemic response and cardiometabolic profile. Based on strong preliminary works from its partners, SINFONI proposes a highly innovative science-based approach for the industrial development of food products allowing 1) to investigate the synergistic impact of combining different bioactive food concepts (polyphenols, bioactive lipid, modified starch) to modulate low-grade inflammation and related cardiometabolic risk profile 2) to monitor early postprandial and low-grade inflammation multi-biomarkers signature by a specific dynamic experimental design, and 3) to develop and validate a range of novel multifunctional food products by selecting specific ingredients’ validated properties as effective synergistic tools to promote relevant changes in inflammatory status, gut microbiota and related cardiometabolic risk factors. SINFONI will explore most recent food technologies for targeted delivery of bioactive food components in order to design several food products that can be easily implemented in everyday diet to provide sufficient bioactive compounds, optimal matrix and ensure optimal taste.

Bariatric surgery (BS) is the most effective treatment to achieve durable weight loss, despite a large variability among individuals. BS has been associated with major gut brain axis modifications impacting eating behavior, food preferences and sensory perceptions. The gut microbiota (GM) is a key player into the gut-brain axis and is deeply remodeled after BS. The individual variability in changing food preferences following BS, in parallel to differential alteration of GM merits further investigation regarding the weight loss success and maintenance after BS. BARIA-gut-TASTE aims at understanding the interplay of BS-induced changes of GM and the evolution of eating behavior associated with success and maintenance of post BS-weight loss. Based on 6 workpackages, our project will combine clinical, epidemiological, and mechanistic tasks to: 1) To investigate via a prospective randomized controlled trial in patients with obesity whether incorporating a pro-microbiota diversity diet post BS leads to an improved eating behavior after 12 months, using a comprehensive phenotyping of eating behavior/reward/sensory alterations in ecological conditions, 2) To explore the potential mediating biological pathways to identify specific signatures of the relationship between modifications of GM and food preferences/reward, 3) To further explore at a larger representative cohort the longitudinal associations between GM with food preferences/ intake and the longer-term weight loss success and maintenance of BS. Multidisciplinary BARIA-gut-TASTE involves 4 partners and 2 collaborators, gathering complementary expertise in obesity and BS, food behavior and preferences, nutrition, gut health and microbiota, psychiatry, epidemiology and metabolomics. Being of major relevance for clinical practice, the knowledge developed in BARIA-gut-TASTE will allow to adapt nutritional care of patients undergoing BS on more individual approaches according to the concept of precision medicine.