Acronimo: Gut-NeuroMuscle

Titolo: Gut and NeuroMuscular system: investigating the impact of microbiota on nerve regeneration and muscle reinnervation after peripheral nerve injury.

Codice Progetto: 20227YB93W

Responsabile scientifico per il DMM: Prof.ssa Matilde Cescon
Coordinatore: Università degli Studi di TORINO - Prof.ssa Giulia RICHI

Partner-Unità di ricerca: Università degli Studi di PADOVA

Bando: PRIN 2022 - Decreto Direttoriale n. 104 del 02-02-2022
Durata: 28/09/2023 - 27/09/2025 (24 mesi)

Finanziamento progetto: € 226.787,00 - CUP C53D23003030001

 

Abstract del progetto

Peripheral nerve injuries are very common and can cause sensory deficits, loss of motor function, or a combination of both. Despite research advancements, recovery of nerve and muscle functions after nerve repair are often suboptimal affecting patients’ functional ability and quality of life. A relevance for microbiota in modulating tissue healing has been recently emerging, but to date a direct link between microbiota and peripheral nervous system (PNS) is under-investigated. This is the gap the Gut-NeuroMuscle project aims to fill in, by exploring the impact of microbiota in the response to traumatic median nerve injury, defining histological and molecular details pointing at mechanisms underlying this crosstalk. Supporting this project, we here provide preliminary data evidencing a defective development of the neuromuscular system in the absence of gut microbiota. For the first time we show that germ-free mice develop hypermyelinated peripheral nerves and immature neuromuscular junctions together with atrophic skeletal muscle. Moreover, transcriptomic analysis on dorsal root ganglia and sciatic nerves evidenced in both tissues a downregulation of ATF3 (Activating Transcription Factor 3), a driving factor necessary for a successful nerve regeneration, triggering our interest in exploring the effects of microbiota depletion on nerve regeneration. Indeed, very recently, antibiotic treatments have been shown to impair functional recovery in a model of crushed sciatic nerve, albeit with no cellular or molecular insight, underlying the urgent need for further investigation. In the present project, mice will be treated with a cocktail of broad-spectrum antibiotics to create microbiota-deficient animals and will be subjected to median nerve injury. First, we will investigate the effect of microbiota depletion on Wallerian degeneration and denervation-induced skeletal muscle atrophy, then on nerve regeneration and muscle reinnervation. Finally, different approaches will be explored to find the best therapeutic strategy to restore gut dysbiosis and improve nerve regeneration and muscle reinnervation. Strategies include: i) microbiota metabolites, chosen after a high-throughput screening of microbiota-derived metabolites in vitro on different cells belonging to the neuromuscular system; ii) probiotics, enriched in strains producing the selected metabolites, iii) prebiotics. Outcomes of this study will open new research horizons in the crosstalk between microbiota and host tissue physiology and will pave the way for the development of innovative microbiota-based therapies to improve nerve regeneration and muscle reinnervation. Moreover, our results will represent the first seeds for a novel multi-disciplinary area of research, integrating microbiota/nutritional approaches and tissue engineering to further enhance nerve-injured patients’ recovery.