To date, globally one out of four children is stunted and the current best- of -practice treatments are not able to correct for more than a third of the observed growth delays. The development of complementary, innovative interventions are therefore of utmost importance. In the Afribiota study we showed that stunting was associated with small intestinal bacterial overgrowth dominated by bacteria that normally reside in the oropharyngeal cavity and are associated with small intestinal inflammation and decrease lipid absorption. The oral-hygienic approach emerges as an entirely new preventive approach to tackle stunting. Therefore, our primary objective is to demonstrate by a specifically-designed clinical trial among 720 infants and their families in Bangui (Central-African Republic (CAR), that educating children and their families to implement strict and sustained rules of oral and nasopharyngeal hygiene will significantly prevent or reverse stunting; Our second objective is to investigate the oral cavity as a microbiological hub whose qualitative and quantitative alterations may impact on the future of child’s health. This will encompass fine description and monitoring of the oral microbiome assembly by and dynamics from birth, including key parameters influencing its ecological successions, like maternal and child hygiene, antibiotic use, and nutrition (including breastfeeding); Our third objective is to nucleate the conditions for the development of a global program of education to oral health in the CAR. Beyond the crucial question on how oral microbial communities expand to the gut resulting in the establishment of dysbiosis and stunting, this study will thus have a direct clinical benefit regarding both oral health and the treatment of undernutrition in Africa. The planned intervention on oral health will also allow us to assess the role of oral hygiene on other comorbidities, an area of much interest, as there are no data available on oral health in Africa.

In the context of improving food sustainability, while ensuring food safety and security, the search for innovative foods is crucial for the future. The French macroalgae sector is of interest because of the nutritional potential of this naturally available marine resource. Whole macroalgae are indeed little exploited as food source while they are nutritionally dense and contains relatively high levels of bioactive compounds with demonstrated potential health benefits. The multidisciplinary collaborative project ALGOMENU “Potential of macroalgae as a new sustainable food source” aims to assess the potential of whole macroalgae on the French market as a new safe food source contributing to a healthy diet through gut ecosystem modulation. We propose to 1) select macroalgae species of potential interest by biochemical composition characterisation of nutritional and bioactive profiles and test eco-friendly processes to reduce contaminants and increase bioactive compound biodisponibility ; 2) assess in vivo tolerance and impact of the selected macroalgae consumption on diet-nutrient handling as well as impact on digestive ecosystem and systemic metabolic repercussions (in particular metabolism of metals) in animals fed balanced diet vs high calorie diet, representative of the Western population; and 3) assess consumer’s acceptability of edible macroalgae and formulated products containing macroalgae into diet by sociologic, food testing and perception approaches. The results of the project will help to determine whether whole marine macroalgae are good candidate for food transition with nutritional and/or nutraceutical benefits.

Acute mesenteric ischemia or intestinal infarction is an absolute medical emergency, as can be myocardial infarction. However, if there are ways to diagnose myocardial infarction (electrocardiograms, blood biomarkers), there is currently no way to diagnose digestive infarction early. This lack of early diagnosis is responsible for a mortality rate of 60 to 80% of patients who are victims of bowel infarction. In the rare cases where the patient survives, he then presents heavy intestinal sequelae. It is interesting to note that the highly unfavorable prognosis of this pathology is directly linked to this delay in diagnosis. It is therefore essential to be able to recognize early mesenteric ischemia in order not to see it evolve into late mesenteric ischemia associated with the death of the patient. To date, there is no biomarker allowing physicians and surgeons an early diagnosis allowing rapid management of patients with mesenteric ischemia. We have recently identified and provided the proof of concept that Glucagon Like Peptide 1 (GLP-1), a hormone secreted by the intestine, could be this much sought-after biomarker which would allow an early diagnosis of intestinal infarction.This project consists in validating the biological relevance of this biomarker in the clinic with patients who have been hospitalized and diagnosed for mesenteric ischemia. Finally, this project also aims to understand the role of GLP-1 during its early secretion when the barrier function of the intestine is disturbed by combining complementary approaches ranging from in vitro to in vivo via the ex-vivo.

A common feature of metabolic diseases, including obesity, associated insulin resistance and subsequent T2D, is their association with chronic inflammatory processes in various tissues, as well as an increased general risk of infection. While the mechanistic bases of this metaflammation state have been partly uncovered, recent evidences have shed light on the intestinal contribution to this feature. Under physiological conditions, the intestinal mucosa indeed forms a selective barrier, which ingeniously allows an efficient transcellular transport of nutrients while rigorously excluding the paracellular flow of immune-stimulatory bacterial products across the epithelium. By contrast, an early increase of intestinal permeability and subsequent translocation of bacterial endotoxins in the systemic circulation have been suggested to pave the road to the subclinical inflammatory state that accompanies the diabesity cascade. While a comprehensive mapping of the molecular mechanisms that elicit or sustain such defective epithelial integrity has long remained poorly understood, microbial imbalance, food composition and hyperglycemia have been lately proposed to be at play. Because hyperglycemia and loss of insulin action are often two sides of the same coin, we hypothesize that, beyond hyperglycemia, defective intestinal insulin signaling could directly impair epithelial integrity upon diabetic conditions. Preliminary results from the GutBarrIR consortium indeed reveal that intestinal insulin sensitivity, which is decreased upon obesity, controls two essential components of the epithelial gut barrier: bactericidal and renewal capacities. This pinpoints blunted local insulin action per se (independently of hyperglycemia or adiposity) as a prime candidate in the potential triggers of gut leakiness, metabolic endotoxemia and metaflammation observed during the metabolic syndrome. Therefore, our proposal aims at investigating the role of intestinal epithelial insulin receptor as a gatekeeper of the gut barrier, by deciphering its contribution to antimicrobial defenses and epithelium renewal capacities. More precisely, we will: (i) evaluate the molecular mechanisms underlying functional defects of anti-microbial producing Paneth cells upon gut insulin resistance, (ii) determine whether altered gut microbiota and associated immune response contribute to impaired intestinal permeability following blunted intestinal IR signaling, and (iii) assess whether insulin signaling represents an intestinal stem cell intrinsic mechanism for gut barrier integrity maintenance in mouse and human. The success of this proposal relies on the development, through pharmacological and genetic approaches, of original mouse models of either global or gut specific insulin action deficiency that do not display parallel hyperglycemia or obesity. Our project also implies the use of human gut organoids, which represent an excellent alternative for animal models to pre-screen selective pharmacological targeting of insulin receptor downstream pathways and will help to translate our results into clinic. This will allow the specific exploration of the molecular and cellular mechanisms mediating gut barrier impairment upon local insulin signaling loss, which is central to the design of preventive and therapeutic strategies. Rather than a triggering factor, we assume that loss of insulin action might aggravate the chronic low-grade inflammation during progressive weight gain. Moreover, we anticipate that while insulin signaling could represent a mechanism to coordinate food ingestion and epithelial protection under physiological conditions, loss of insulin action selectively in the gut could weaken host defense and represent a risk factor for intestinal inflammatory or infectious injuries under diabetic conditions. Moreover, outcomes of the GurBarrIR program might also open up promising perspectives in the context of inflammatory bowel diseases therapies.

STEP’s primary objective is to collect all necessary preclinical data on the efficacy and safety of synchrotron-generated microbeams to make possible a First-in-man clinical trial in patients with refractory mesio-temporal lobe epilepsy in the aftermath. STEP represents the transition between 20 years of basic research on Microbeam Radiation Therapy (MRT) and the clinical development of an innovative radiosurgery approach of brain diseases. During the last twenty years, the extremely high flux of photons generated by 3rd generation synchrotrons, has enabled the development of novel irradiation strategies holding great promises for innovative radiotherapy. In particular, the possibility to split weakly diverging synchrotron-generated X-rays into arrays of 50-µm wide microbeams, separated by 200-800 µm, has allowed the emergence of the MRT. Several pre-clinical studies performed by STEP partners and other groups have shown that MRT offers a particularly safe procedure to transect or lesion specific brain regions without the usual tissular, vascular or behavioral side effects of conventional radiotherapy. The collaboration between engineers, researchers and clinicians of the Biomedical Beamline (ID17) at the European Synchrotron Radiation Facility (ESRF), INSERM, and University Hospital of Grenoble-Alpes has shown the efficacy of MRT in animal models of Epilepsy to suppress seizures and neuronal synchronization over several months, without histological or functional deleterious side effects. Therefore, MRT has the potential to become a disruptive technology for treating diseases where the target is closely surrounded by tissues whose function should be preserved, as in focal epilepsies and several other neurological diseases. Our preclinical expertise and the recent experience of patient irradiation at the ESRF, as well as the close collaboration with the Grenoble University Hospital should make the First-in-man clinical trial of MRT possible in 2025. To reach this ambitious goal, STEP will determinate the optimal MRT procedures for an efficient seizure suppression in a rat model of mesiotemporal lobe epilepsy (WP1) and will correlate this information with toxicity thresholds determined in normal rats and minipigs (WP2). These data will help to prepare the documentation required by regulatory and safety French agencies and to design an adapted protocol for the first safety clinical trial in epileptic patients (WP3). The choice to first consider mesiotemporal lobe epilepsy (MTLE) is motivated by several aspects: (i) it is a typical and well described drug-resistant focal epilepsy; (ii) surgical resection of the epileptic zone following craniotomy, is the current gold-standard therapeutic option for this form of epilepsy, is effective in 50 to 80% of cases, but remains risky and has a significant cost for the Health Systems; (iii) the Grenoble University Hospital epilepsy surgery program has accumulated a strong expertise of MTLE patients so that obtaining a significant cohort for the clinical trials should be straightforward; (iv) animal models of MTLE have been well described and members of the consortium already have the expertise to use such models. All members of the consortium have the complementary expertise to conduct this project and have been working together for more than 5 years. The strengths of STEP relies on high-level and robust preclinical studies, which pave the way for a smooth translation towards Phase I clinical trials. We believe that STEP will provide a disruptive therapeutic approach, potentially applicable outside the epilepsy field.