Ricerca Progetti nazionali, regionali, internazionaliNAZIONALIPRIN 2022Unveiling the microbial impact on intestinal

Unveiling the microbial impact on intestinal fibrosis and the associated immune microenvironment: new insights for the pathogenesis and treatment of Crohn's disease-associated complications

The most investigated gut microbiota components are the bacteria, known to contribute to disease pathogenesis, including Crohn's disease (CD). Despite the enormous amount of metagenomic studies describing the intestinal microbiota composition in CD patients, no data define specific signatures across the different stages of fibrosis. In this regard, we profiled the microbiota composition of CD patients with different grades of fibrosis, and we pointed out 3 bacterial families, namely the Brevibacteriaceae, Sphingomonadaceae, and Caulobacteraceae to characterize CD fibrotic mucosal tissues. In particular, by searching for the bacterial protein-encoding transcripts, we pointed out the B1 fibrotic stage to be characterized by GUY30 (Brevibacteriaceae) and Tuf (Caulobacteraceae) proteins, the B2 by SWIT (Sphingomonadaceae), which, together with SPHME and NX02 (Sphingomonadaceae), featured the B3 stage. Functionally, these bacterial proteins are known to impact transcription and are likely to interfere with the host cellular apparatus. Thus, we hypothesized that specific bacterial proteins may promote the fibrotic process by impacting the intestinal mucosa functions and transcription and triggering specific pathways in different cellular compartments, whose inhibition may ameliorate experimental fibrosis both in vitro and in vivo. To test our hypothesis, we aim to address the following specific aims:

1) To identify the cellular subtypes and molecular pathways impacted by the specific bacterial factors during CD-associated fibrosis.

2) To unravel the cellular and molecular mechanisms and dynamics induced by the bacterial factors in 3D models of intestinal fibrosis

3) To evaluate the efficacy of nanomedicine-based therapy in inhibiting the deleterious processes induced by bacterial factors by exploiting in vivo models that recapitulate CD-associated fibrosis.

Conclusively, by exploiting a computational approach, we propose to define the bacteriome signatures associated with the different stages of CD-associated fibrosis and to unveil molecular and immune mechanisms lying beneath. Finally, we aim to validate nanomedicine-based protocols for the treatment of intestinal fibrosis. This project will ultimately offer new molecular targets for the development of tailored anti-fibrotic treatments, likely resulting as beneficial for healthcare soon, by facilitating the management of

stricturing CD, avoiding surgical intervention, and eventually cutting national health system costs.

 

Data di avvio 18 Ottobre 2023

Data di completamento 18 Ottobre 2025

Total cost  € 67019,00

 

Progetto 2022RKE4LK finanziato all’interno del Bando PRIN 2022 di cui al Decreto Direttoriale n. 104 del 02/02/2022 nell’ambito del Piano Nazionale di Ripresa e Resilienza, Missione 4 – Componente 2. Dalla Ricerca all’Impresa - Investimento 1.1 Fondo per il Programma Nazionale della Ricerca (PNR) e Progetti di Ricerca di Rilevante Interesse Nazionale (PRIN), finanziato dall’Unione europea – NextGenerationEU – CUP B53D23021900006