Project description
Antibiotic treatment and intestinal immune responses
Beta-lactam antibiotics account for roughly half of all clinical antibiotic use and work by disrupting the bacterial cell wall. This process releases cell wall fragments that can cross the intestinal lining and activate immune signalling pathways, potentially driving inflammation. However, the scale of this response and whether it differs between drug-resistant and susceptible bacteria remains poorly understood. With the support of the Marie Skłodowska-Curie Actions programme, the PG-BIR project will employ intestinal organoids and organ-on-chip models to quantify cell wall fragment release and measure the resulting immune responses. The comparison between resistant and susceptible bacterial strains will pave the way towards safer antibiotic regimens and advanced antimicrobial stewardship strategies.
Objective
β-Lactam antibiotics constitute roughly half of clinical use and act by inhibiting peptidoglycan (PG) biosynthesis, causing lysis. The resulting PG fragments can traverse the small-intestinal epithelium and activate NOD1/NOD2–NF-κB signalling, yet the scale and consequences of β-lactam–induced PG release—particularly in multidrug-resistant (MDR) versus susceptible bacteria—remain poorly defined. PG-βIR will delineate how clinically used β-lactams modulate PG-fragment outputs and host responses. I will deploy small-intestinal apical-out organoids and a small-intestine organ-on-chip to quantify transepithelial PG flux by LC–MS/MS muropeptidomics, epithelial signalling (NF-κB readouts, cytokines) and barrier function, and we will test mechanistic requirements using organoids from knockout lines in epithelial transport and innate recognition (SLC15A1, SLC46A2, RNF43, NOD1, NOD2, IL-1Ra). Comparative panels will include resistant and susceptible Escherichia coli and Enterococcus faecalis; the most pro-inflammatory resistant E. coli identified ex vivo will progress to in-vivo validation. In-vivo confirmation will use gnotobiotic mice under β-lactam exposure, with compartment-resolved PG profiles (lumen, tissue, serum), NF-κB activation and cytokines analysed under a pre-specified plan. The programme is organoid-first to minimise animal use; in-vivo work confirms key mechanisms.
Expected outputs are a comparative atlas of β-lactam-induced PG outputs in MDR versus susceptible backgrounds, a mechanistic map of epithelial transport/sensing for PG translocation, and an inflammatory signature linking PG species to NOD1/NOD2 responses. These decision-grade results will inform antimicrobial stewardship (integrating inflammatory risk) and guide safer β-lactam regimens and next-generation dual-action prodrugs; data and protocols will follow FAIR, with open LC–MS/MS datasets and organoid/organ-on-chip methods.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- medical and health sciences basic medicine pharmacology and pharmacy pharmaceutical drugs antibiotics
- engineering and technology other engineering and technologies microtechnology organ on a chip
- medical and health sciences basic medicine pharmacology and pharmacy drug resistance multidrug resistance
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Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA)
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships
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(opens in new window) HORIZON-MSCA-2025-PF
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75724 Paris
France
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