Irritable Bowel Syndrome (IBS) touches up to 10% of the population and is characterized by recurrent abdominal pain and disturbed bowel habits. We have established that Trypsin-3 is the most active protease in tissues from IBS patients. It augments epithelial permeability, causes pain reproducing IBS symptoms. Our aim is to identify key compounds for IBS drug development, based on Trypsin-3 inhibition. We propose 1/ to establish screening assays for specific Trypsin-3 inhibitors 2/ to screen two libraries, and 3/ to develop an ELISA kit as a companion tool for biomarker studies and possible patient stratification. With these approaches, we believe that we would establish the necessary conditions for Trypsin-3 inhibitors drug discovery. Our tools would not only definitively confirm the therapeutic potential of Trypsin-3 inhibition, but they will also constitute the basis for Trypsin-3 drug development.

Mycotoxins are frequent contaminants of cereals, found in more than 25 % of samples worldwide. They are of high concern due to their potential health risks for humans and/or livestock. When ingested at low to moderate doses, their impact on human health is likely to be significant as they can induce stunting, immune dysfunction and contribute to cancers. In livestock, they can induce acute poisoning, but also various metabolic disturbances resulting in poor animal productivity following a chronic exposure. In France as well as in Europe, the climate conditions favor the contamination by Fusarium fungi. The main Fusarium toxins, ie deoxynivalenol (DON), fumonisins (FB) and zearalenone (ZEN) are regulated in food and feed. Fusarium fungi produce other toxins such as beauvericin, enniatins, apicidin and aurofusarin, less described and called “emerging” mycotoxins (EM). They are neither routinely determined, nor legislatively regulated. Little is known on their occurrence even if preliminary results suggest a high prevalence. In vitro, beauvericin and enniatins induce cytotoxicity, oxidative stress and apoptosis. In vivo, no conclusion can be drawn on chronic exposure due to the lack of relevant data. Aurofusarin and apicidin have been poorly investigated with less than 30 publications on their toxic effects. On the intestine, the first barrier against food contaminants, DON, FB and ZEN alter cell proliferation and differentiation, nutrient absorption, immunity and barrier function while the effects of EM are unknown. Mycotoxins, as well as antibiotics, are secondary metabolites of fungi. While the effects of the latter are well described on the gut microbiome, the impact of Fusarium toxin on intestinal microbiota are limited and the impact of EM totally unknown. This project aims to fill gaps in the knowledge of EM. It will covers both occurrence and toxicity of EM and more precisely proposes (i) to perform a large-scale survey on the occurrence of EM in French cereals and to determine the relation between the concentration of EM and agricultural practices and (ii) to assess the impact of EM alone or combined with regulated mycotoxins in human and pigs. We will focus on intestinal functions (barrier, nutrients absorption, immunity) and use in parallel in vitro, ex vivo and in vivo models. Omics approaches (transcriptomics, proteomics, and metabolomics) will allow obtaining a global view of the toxicological effects of pigs orally exposed to EM. Intestinal and fecal samples will be used to assess by 16S gene sequencing and metatranscriptomic the effects of EM on the gut microbiota. The modified forms of EM produced by metabolization will be identified by mass spectrometry. These animal studies also aim to establish, a tolerable daily intake (TDI) To the best of our knowledge, this project which compares in a one health approach human and pig, is unique in its strategy. The complementarity of the approaches (from field survey and to omics methods) will allow performing a global study on occurrence and toxicity of four-selected EM. This innovative project relies on the involvement of 6 partners with complementary expertise, from agronomy to toxicology. It will benefit from the well-established relations between them.

While the primary role of metabolism is chemical conversions, can it also serve as an information processing device? To answer this question, we propose to encode various microbial metabolic models into Artificial Metabolic Networks (AMNs), which can be trained on experimental data or model simulations. Unlike “black box” artificial neural networks, our AMNs will be sparse and will reflect faithfully the structure and dynamics of metabolic networks. Our AMNs will be benchmarked on classical machine learning problems to assess what level of computational sophistication metabolism is able to handle. In the context of biotechnology, our AMNs will be applied to the design of experiments to (i) optimize the productivity of an added-value chemical (lycopene) E. coli producing strain defining nutrient compositions and gene deletions and (ii) classify infectious disease severity by engineering an E. coli biosensing strain detecting metabolic biomarkers in COVID-19 clinical samples.