Hydrogen sulfide promotes the pathogenicity of TH17 cells via modulating their metabolic capacities

• Applicant: Dr. Francesco Siracusa
• Subject Area: Gastroenterology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 572412435

Effector CD4+ T cells and the intestinal microbiota with its secreted metabolites create an intricate network of interactions that is fundamental in promoting mucosal homeostasis and ultimately the host’s health. Perturbation of one of the three components of this network - i.e. effector CD4+ T cells/microbiota/metabolites - can disrupt homeostasis leading to intestinal inflammation and eventually to the onset of chronic immune-mediated inflammatory diseases (IMIDs), such as inflammatory bowel diseases (IBD), and inflammation-associated colorectal cancer (CRC). An environmental trigger that can simultaneously perturb each single component of this network is the diet. Effector CD4+ T cells, and in particular TH17 cells (a cell type found enriched in the mucosa of patients suffering from IMIDs and CRC) quickly react to diet changes and need to re-wire their metabolism in order to adapt to the diet-modulated microenvironment and ultimately survive. At mucosal sites, diet-derived microbial metabolites play a crucial role in modulating this metabolic re-wiring and their absence or over-abundance can promote anti- or pro-inflammatory immune responses. Yet, little is still known about the vast majority of the microbial metabolites and their potential role as modulators of CD4+ T cell function, especially with regards to those secreted in gaseous form such as hydrogen sulfide (H2S) secreted by sulfate-reducing bacteria (SRBs), bacteria that have been long associated with intestinal inflammation. This project aims at investigating whether diet-derived microbial H2S can modulate metabolism and function of intestinal TH17 cells, ultimately rendering them able to induce intestinal inflammation and eventually leading to the onset of CRC. This will be tested in three work programmes (WPs). In WP1, the role of H2S in promoting hyper TH17 cell metabolism will be dissected. WP2 aims at revealing the molecular mechanism by which H2S promotes pathogenicity via using IBD mouse models. In WP3, the role of H2S in promoting inflammation-associated CRC will be investigated. This study could significantly improve our understanding of the connection between diet-derived microbial metabolites and immune T cell metabolism and what the consequences of their modulation is for the development of intestinal inflammation. Furthermore, this study will provide the scientific and clinical communities with new molecular targets that can potentially be used to develop novel therapies to treat IBD and ideally prevent CRC.

• DFG Programme: Research Grants