Alcoholic hepatitis (AH) is the most severe form of alcohol-associated liver disease (ALD). The pathogenesis of this life-threatening disease is complex and poorly understood due to the lack of animal models, while translational studies suffer from limited access to human liver samples. Despite its undeniable economical and health burden affecting both women and men, ALD has received very limited attention from health policy makers, pharmaceutical companies, and funding agencies. The major consequence is the very limited therapeutic arsenal, particularly for AH where the tools for the patient’s management have not evolved substantially over the last decades. Based on unique liver samples collected by our group, we have demonstrated a profound alteration of hepatocyte regeneration in AH liver. The proposed project is a translational study aiming at dissecting the cellular and molecular mechanisms implicated in the altered liver regeneration of patients with AH, in order to develop innovative therapeutic strategies.

Breast milk is a unique source of nutritional and bioactive substances essential to the development of immune and digestive systems of the newborn. Its beneficial effects on development and health are especially important in preterm newborns for whom many studies have demonstrated that breast milk significantly reduces the risk of several diseases including digestive intolerance, ulcerative necrotizing enterocolitis (NEC), sepsis, and food allergy. In addition, breast milk has shown long-term positive effects on cognitive development and metabolism and cardiovascular health in adult. During their hospital stay, preterm infants receive pooled human milk (HM) from different donors provided by human milk bank (HMB). However, HM needs to be treated in order to limit the development of potentially pathogenic agents, whilst retaining its nutritional and immunomodulatory properties. The most common practice performed in HMBs worldwide to treat HM is a low-temperature (62°C) long-time (30 minutes) pasteurization known as “Holder” pasteurization. However, Holder pasteurization performed in HMB completely destroys important milk factors such as the bile salt-stimulated lipase (BSSL), alters milk fat globules structures and reduces both the nutritional value and immunological properties of HM. High hydrostatic pressure (HHP) processing is a recent technology in the food industry that applies a non-thermal high pressure treatment to the product. This new process is one of the most promising methods for food treatment and preservation at room temperature. For HM, HHP is a promising alternative method to Holder pasteurization as several studies have demonstrated that HHP preserves milk nutritional and immunological properties and inactivate microorganisms. Our objectives will be divided into 3 points: 1/ to determine if HHP process improve milk quality in term of sensitive bioactive factors (growth factors, hormones, microRNAs and bacteriostatic properties) compared to Holder pasteurization; 2/ to study experimentally if HHP-treated HM possesses more potent intestinotropic properties than pasteurized HM; 3/ to study in preterm infants, if HHP-treated HM improve the neonatal health, gut microbiome and the early postnatal growth of these infants compared to infants fed with pasteurized HM during 21 days. Our strong consortium implicate recognized scientists (INSERM, Universities, Hospital) specialized in the field of neonatal physiology, a private French partner HPBioTech (AP) that has an international patent for HHP-treated human milk, recognized clinical experts in infant nutrition and recognized experts in the field of gut microbiota. All of these partners have complementary skills to carry out the various tasks to support the present project and have national and international recognition in their respective fields. The clinical study will be performed in the Jeanne de Flandre hospital of the CHRU of Lille. To conclude, providing an alternative to Holder pasteurization with better performance in regard of microbiological safety, nutritional and biological components would be a major step forward including but not limited to the French population of preterm and low birth weight infants. Moreover, our project may have a good economic impact for HMBs as HPP may improve the safety of human milk (microorganism), reduce losses (pasteurization failure) and improve storage and transportation of treated-HM (4°C instead of -20°C). It may also permit to better understand the establishement of gut microbiota associated with breastmilk components.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease caused by genetic and environmental factors. The latter act firstly as neonatal primers: their exposure during the perinatal period disturbs early maturation of gut microbiota and immune system and induces an increased susceptibility to colitis, called pathological imprinting. Environmental factors act secondly as colitis triggers, causing or worsening colitis development in patients with genetic susceptibility or pathological imprinting. Our hypothesis is that gut luminal microplastics (MPs), which are increasingly present because of expanding human oral MP exposure, belong to environmental UC primers and/or triggers. Indeed, pilot studies detected MPs in neonatal and adult feces, and accumulating data show that ingestion of MPs promote gut inflammation and dysbiosis in mice. Our main aims are:1) To identify in human feces the MPs with pro-inflammatory and pro-dysbiotic properties. Nano-and microplastics will be characterized in control and UC patient feces and correlated with inflammatory calprotectin level and dysbiosis parameters. Combined analyzes will identify a cocktail of MPs with pro-inflammatory and pro-dysbiotic properties thereafter called pro-UC MP cocktail. 2) To assess MP effects on UC pathogenesis either as neonatal primer of UC susceptibility and/or as promoting UC trigger. Pregnant mice will be exposed to the pro-UC MP cocktail and the effects on gut immune response, permeability, microbiota, nano-and microplastic presence in feces, and susceptibility to experimental colitis will be assessed in male and female offspring. These parameters as well as fecal metabolome will be also assessed in response to the pro-UC MP cocktail exposure in gnotobiotic mice colonized with humanized microbiota from control or UC patients. This multidisciplinary project will provide new essential knowledge on human exposure to MPs and their impact on gut homeostasis, particularly in the UC pathophysiology.

The nose is the main entrance for respiratory viruses. These viruses are present there in an early stage and affect its function in terms of breathing and air humidification. The high percentage of COVID-19 patients diagnosed with anosmia highlight the primordial role of the nasal cavity in the physiopathology of respiratory viral infections. Mucus is the primary defense against viral infections. This physical barrier crucial in viral clearance is well known in the lung, unlike the nasal cavity where it has been little studied. The aim of our study is to elucidate the role of nasal mucociliary clearance in experimental mouse models of infection with the human syncytial virus and the SARS-CoV-2. We will use mice deficient for the two gel-forming mucins Muc5b and Muc5ac. We will study the diffusion of viruses in the nasal cavity, anosmia, cell damage, inflammation, localization of viral mimetics and the molecular mechanisms involved by molecular methods routinely performed completed by RNA-Fish and single-cell RNAseq.

Fatty liver diseases among which alcoholic and non-alcoholic steatohepatitis [(N)ASH] have become a major health issue worldwide as they represent a major cause of liver failure and cancer. This is due to liver insult leading to fibrosis, a detrimental excess of extracellular matrix (ECM) deposition. The main contributors to this process are hepatic stellate cells (HSCs) which undergo myofibroblastic activation during (N)ASH development acquiring an uncontrolled ECM protein production phenotype. Despite being of central clinical importance regarding (N)ASH, how HSC activation is orchestrated at the molecular level has remained poorly defined. Bioinformatics analyses have allowed us to identify an unforeseen transcription factor, which drives HSC profibrotic activation. By combining functional genomics, in-vivo mouse models as well as the study of human liver biopsies, our project will allow to define clinically relevant novel molecular mechanisms involved in HSC-driven liver fibrosis.