Clostridium sporogenes-derived metabolites protect against colonic inflammation
The gut microbiota exerts a profound influence on intestinal immune homeostasis, primarily through the production of metabolites that regulate host immune responses. This doctoral thesis examines the role of the human commensal bacterium Clostridium sporogenes in producing specific metabolites, incl...
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| Format: | Doctoral Thesis |
| Language: | English |
| Published: |
Philipps-Universität Marburg
2025
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| Online Access: | PDF Full Text |
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| Summary: | The gut microbiota exerts a profound influence on intestinal immune homeostasis, primarily through the production of metabolites that regulate host immune responses. This doctoral thesis examines the role of the human commensal bacterium Clostridium sporogenes in producing specific metabolites, including indole-3-propionic acid, branched-chain fatty acids and short-chain fatty acids, and their effects on the immune system and colitis progression.
Using germ-free mice monocolonised with C. sporogenes, it was demonstrated that C. sporogenes produces significant amounts of the short-chain fatty acids acetate and propionate as well as the branched-chain fatty acids isobutyrate and isovalerate while significantly elevating indole-3-propionic acid levels in the colon and serum. These metabolites are known factors that contribute to gut health by shaping immune cell phenotypes. For instance, colonised mice exhibited enhanced levels of anti-inflammatory FoxP3+ regulatory T cells, and an increased production of IL-22 and IL-13, key cytokines that regulate mucosal barrier integrity and immune responses.
In a dextran sulfate sodium-induced colitis model, colonised mice showed significant resistance to colitis symptoms, including reduced weight loss with faster weight gain, preserved colonic crypt structure, limited immune cell infiltration and reduced inflammation. RNA-sequencing of colonic tissues revealed that inflammatory and Th17-related genes were highly upregulated in conventional mice compared to the monocolonised mice, indicating a protective immunological environment. Furthermore, C. sporogenes-derived indole-3-propionic acid was found to suppress the pro-inflammatory cytokines IL-17A and IL-17F, which play a key role in driving inflammation in Th17 cells. The suppression of IL-17A/F was found to be mechanistically linked to the downregulation of the mechanistic target of Rapamycin (mTOR) pathway and alterations in the ribosomal protein biosynthesis, but without affecting cell viability. This observation provides a new insight into how microbial metabolites can modulate T cell function.
This study also shows that C. sporogenes-colonisation significantly increased the number and activity of tuft cells in the colon, an essential cell type for epithelial repair and immune signalling. These tuft cells were found to express the free fatty acid receptors 2 and 3, which mediate responses to short-chain fatty acids and branched-chain fatty acids. Notably, the increased tuft cell activity was associated with an elevated IL-22 and IL-13 production, further contributing to the protective phenotype observed in C. sporogenes-colonised mice.
While C. sporogenes-colonisation improved colitis outcomes in germ-free mice, the probiotic administration of C. sporogenes to conventional mice with an established microbiome did not yield the same protective effects, likely due to the competitive microbial environment. However, oral administration of C. sporogenes-derived metabolites to conventional mice significantly reduced colitis severity, pointing to its potential for future clinical applications.
This thesis identifies C. sporogenes as a key producer of beneficial gut-derived metabolites that modulate immune responses and protect against colitis. Its unique metabolic profile, including indole-3-propionic acid, branched-chain fatty acids and short-chain fatty acids underscores its potential as a therapeutic agent for inflammatory bowel diseases. The mechanistic insights provided by this research offer a foundation for developing novel probiotic strategies to treat intestinal inflammation. |
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| Physical Description: | 122 Pages |
| DOI: | 10.17192/z2025.0146 |