Characterization of intestinal microbiota and metabolite-sensing GPCRS in Inflammatory Bowel Diseases: Relevance of GPR91 and GPR109A

• Autores: Cristina Bauset Pastor
• Directores de la Tesis: María Dolores Barrachina Sancho (dir. tes.), Jesús Cosin Roger (codir. tes.)
• Lectura: En la Universitat de València ( España ) en 2024
• Idioma: inglés
• Número de páginas: 281
• Tribunal Calificador de la Tesis: Sara Calatayud Romero (presid.), Esther Caparrós Cayuela (secret.), Marianne Rebeca Spalinger (voc.)
• Programa de doctorado: Programa de Doctorado en Biomedicina y Farmacia por la Universitat de València (Estudi General)
• Menciones:
  • Internacional
• Calificación: Sobresaliente Cum Laude
• Materias:
  • Sociología
    • Problemas sociales
      • Enfermedad
• Enlaces
  • Tesis en acceso abierto en: webges.uv.es (pdf)
• Resumen

  • Inflammatory Bowel Diseases (IBD), which comprise Ulcerative Colitis (UC) and Crohns Disease (CD), are disorders of the gastrointestinal tract characterized by chronic inflammation and abnormal immune response. It is considered a multifactorial disease with interplay of genetics, environment, gut microbiota and immune response. As a result, complications such as fibrosis or fistulas can arise. Nowadays, there are not effective treatments which reverse the disease or prevent complications. In this context, gut microbiota plays a crucial role in maintaining gut health. Changes on its composition and function that occur in IBD contribute to the progression of the disease and result in metabolomic profile alterations. Metabolite-sensing G-protein coupled receptors (GPCRs), which are membrane receptors involved in signalling pathways including immune cells recruitment, or cytokines production, have emerged as pivotal players in the pathophysiology of IBD. Dysregulation of their functions may contribute to exacerbation of inflammation.

    In this study, intestinal microbiota population, metabolites, and metabolite-sensing GPCRs in intestinal resections from IBD patients were analysed. First, we detected lower microbiota richness and load in UC patients with higher proportion of Cellulosimicrobium. In addition, alterations in the levels of energy metabolism compounds, fatty acids, and amino acids were reported. Finally, an upregulation of most of the metabolite-sensing GPCRs analysed, associated with enhanced expression of pro-inflammatory and/or pro-fibrotic markers was observed. Then, the role of GPR91 and GPR109A in IBD pathogenesis was analysed in depth.

    First, GPR91 expression was higher in B3-CD. In addition, epithelial-to-mesenchymal transition (EMT) markers were upregulated and positively correlated with GPR91. The absence of the receptor prevented the EMT induced by a murine model of fibrosis, and in intestinal epithelial cells (IECs) treated with TGF-beta and stimulation with succinate. On the other hand, GPR91 expression was higher in UC and positively correlated with inflammasome components expression. Moreover, the deletion of the receptor impaired the increase in pro-inflammatory, pro-fibrotic, and inflammasome markers in a chronic colitis model and the inflammasome priming in IECs. Next, expression of GPR109A was higher in UC and CD and detected in epithelial cells and lamina propria. The treatment with its agonist beta-hydroxybutyrate increased gene expression of GPR109A, CD86, IL1B and NOS2 in M0 macrophages. Moreover, increased mRNA expression and secretion of IL-1beta, IL-6 and TNF-alpha was impaired in M1 macrophages when GPR109A was silenced. Finally, the secretome from M1 macrophages lacking GPR109A reduced the expression of collagens in intestinal fibroblasts.

    To conclude, GPR91 and GPR109A appear to play a role in complications associated with IBD and be therapeutic target candidates for IBD.