Mechanisms involved to the protective effect of short-chain fatty acids during Clostridioides difficile-associated colitis

Author(s)

José Luís Fachi

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia
• Defense date: 2021-05-26

Examining board members

Marco Aurélio Ramirez Vinolo; Pedro Manoel Mendes de Moraes Vieira; Renata Sesti Costa; Kelly Grace Magalhães; Renato de Lima Santos

• Advisor: Marco Aurélio Ramirez Vinolo

Abstract

Under physiological conditions, intestinal colonization by pathogens is restricted by commensal bacteria. The use of antibiotics causes an imbalance in the composition of the microbiota and it is associated with the development of "Clostridioides difficile"-infection (CDI). Microbiota-derived metabolites, short-chain fatty acids (SCFAs), are known to have a beneficial effect on the maintenance of intestinal homeostasis. We found that the luminal content of these compounds is reduced during antibiotic therapy and that their oral administration improves acute "C. difficile" colitis in mice. However, it is not clear the molecular mechanisms behind this effect. Here, we aimed to investigate the signaling pathways activated by SCFAs during "C. difficile" infection (CDI). We found that butyrate treatment protected the intestinal epithelial cells from damage via stabilization of the transcription factor hypoxia-inducible factor (HIF-1), mitigating local inflammatory response and the systemic consequences of the infection. On the other hand, acetate improved innate immune responses through the FFAR2 receptor, coordinating neutrophils and type 3 innate lymphoid cells (ILC3) functions, which elicit antimicrobial and epithelial repair responses. We conclude that short-chain fatty acids play a fundamental role in maintaining the intestinal mucosa integrity and protecting against damage during "C. difficile" infection. These findings lead us to advance in understanding the microbiota and host interaction and to identify new molecular targets for therapeutic interventions (AU)

• FAPESP's process: 17/06577-9 - Mechanisms involved in the protective effect of short-chain fatty acids against Clostridium difficile-associated colitis
• Grantee: José Luís Fachi
• Support Opportunities: Scholarships in Brazil - Doctorate