Descripción del proyecto
Poner a prueba los metabolitos de las bacterias intestinales
El microbioma del intestino humano desempeña una función fundamental en la salud, y las alteraciones en su composición causan diversas enfermedades. Los grupos de genes biosintéticos podrían estar implicados en la estructura del microbioma, pero muy pocos han sido experimentalmente validados por su impacto metabólico perjudicial en el hospedador humano. El objetivo del proyecto SMs-Gut, financiado con fondos europeos, es ampliar estos descubrimientos e identificar metabolitos especializados en el intestino con una función esencial en el desarrollo de la enfermedad inflamatoria intestinal y el cáncer colorrectal. Los científicos utilizarán una combinación de bioinformática, biología sintética y tecnologías analíticas para descifrar las funciones biológicas de los compuestos descubiertos.
Objetivo
Composition changes of the human gut microbiome has been associated with a series of diseases. However, little is known about the mechanism of this microbiome alteration. Recent in silico studies revealed thousands of biosynthetic gene clusters (BGCs) that encode diverse types of specialized metabolites from human microbiomes. Many of these molecules are potentially involved in shaping microbiome structure or directly affect host cell and contribute to disease development. To date, only colibactin, a hybrid polyketide/non-ribosomal peptide produced by Escherichia coli in human gut, has been experimentally validated for its deleterious metabolic impact on human host and linked to the development of colorectal cancer (CRC). Thus, this project aims to expand the knowledge of specialized metabolites produced by gut microbiome and unravel their role in development of inflammatory bowel disease (IBD) and CRC. State-of-the-art bioinformatic, synthetic biology and chemical-analytic technologies will be used to tackle this challenge. In silico identification of BGCs will be facilitated by sequence homology search and the occurrence of function-related resistant makers. The cloning process will be realized by either capturing native BGCs, adopting polymerase amplification or using synthetic DNA, followed by HiFi DNA assembly, Red/ET recombineering based DNA integration method or combining of both strategies. The chemical diversity of these specialized metabolites will be unlocked by heterologous expression of the cloned BGCs and structure elucidation of the produced molecules. The biological functions of the discovered compounds will be established by probing their genotoxicity and cytotoxicity in vitro with human intestinal cell lines.
Ámbito científico
- natural sciencesbiological sciencessynthetic biology
- natural sciencesbiological sciencesgeneticsDNA
- medical and health sciencesclinical medicinegastroenterologyinflammatory bowel disease
- medical and health sciencesclinical medicineoncologycolorectal cancer
- natural sciencesbiological sciencesmicrobiology
Palabras clave
Programa(s)
Régimen de financiación
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinador
01069 Dresden
Alemania