ECCO Grant Study Synopsis: Silvia Cerantola

Silvia Cerantola, ECCO Grant Awardee

Decoding the neuroimmune crosstalk in Inflammatory Bowel Diseases

Silvia Cerantola
© Silvia Cerantola

Background & aim of research

Inflammatory Bowel Disease (IBD) results from an anomalous interaction between genetic, environmental, immunoregulatory and microbial-derived factors. IBD- associated specific mutations include genes involved in microbial recognition, such as mutations in the Toll-like receptor 4 (TLR4). Beside controlling host defence responses, TLR4 modulates enteric nervous system (ENS) activity, gut motility and repair processes following an insult. TLR4 deficiency in mice leads to significant ENS alterations, characterised by modified gut motility and susceptibility to inflammation. The findings of decreased gut catecholamine levels in IBD patients and the onset of milder experimental colitis after sympathectomy highlight the role of the nervous system as a key regulator of immune responses. Therefore, our research project aims to decode the neuroimmune interactions between the catecholaminergic system and innate immune sensor TLR4 in dinitrobenzene sulphonic acid (DNBS)-induced ileitis.

Methodology/experiments that will be used

Wild type mice will be subjected to: peripheral catecholamine depletion with 6- hydroxydopamine, TLR4 signalling inhibition and DNBS-induced ileitis. In collaboration with our multidisciplinary team, the neuroimmune biomarkers affected by DNBS-induced ileitis will be identified in order to disclose potential correlations between functional data, protein expression levels and microbiota signature and possibly to define an algorithm of IBD severity.

Anticipated main impact

In the short term this project will offer the opportunity to define the catecholamine– TLR4 interaction in ENS, disclose the TLR4–catecholamine crosstalk during IBD and delineate IBD enteric neuroimmune signatures. In the longer term, the benefits of this research will be the identification/repurposing of catecholaminergic system modulators as potential diagnostic/therapeutic strategies to target specifically sympathetic pathways in neuroimmune cells, to increase diagnostic and therapeutic efficacy and possibly reduce adverse effects.

Proposed timeline

Months 1–9: Mouse models of experimental sympathectomy and TLR4 inhibition; structural and functional analysis of ENS. Months 7–12: Evaluation of catecholaminergic system and TLR4 inhibition during experimental ileitis; structural and functional analysis of ENS.

Posted in ECCO News, SciCom, Committee News, Volume 17, Issue 3, Fellowships & Grants Synopsis Reports