Intestinal epithelial Syndecan-1 maintains mucosal homeostasis in inflammatory bowel disease by enhancing <i>Faecalibacterium prausnitzii</i> biofilm formation.
Syndecan-1 is crucial for maintaining intestinal barrier integrity and promoting beneficial gut bacteria, which may have implications for inflammatory bowel disease management.
Where it sits
this study against the rest of the dihexa corpusSummary and findings
This study investigated the role of Syndecan-1 (SDC1) in maintaining intestinal barrier integrity and its interaction with the gut microbiome in the context of inflammatory bowel disease (IBD). In DSS-induced colitis, Sdc1 knockout mice exhibited exacerbated inflammation and barrier impairment compared to wild-type mice. The study identified a significant depletion of Faecalibacterium prausnitzii in Sdc1 knockout models.
Abstract
Despite the rising global incidence of inflammatory bowel disease (IBD), curative therapies remain unavailable. While our previous work implicated the intestinal proteoglycan Syndecan-1 (SDC1) in IBD-associated barrier dysfunction and inflammation, the underlying mechanism was unclear. This study aimed to elucidate how SDC1 maintains intestinal barrier integrity through interactions with the gut microbiome. In DSS-induced colitis, global knockout of <i>Sdc1</i> (<i>Sdc1</i><sup><i>-/-</i></sup>) exhibited exacerbated inflammatory infiltration and greater impairment of barrier structure and function than wild-type (WT). Formation of intestinal organoids was independent of genotype, indicating that <i>Sdc1</i><sup><i>-/-</i></sup> does not impair barrier function via disrupting epithelial development. The heightened colitis susceptibility in <i>Sdc1</i><sup><i>-/-</i></sup> mice was abolished in the antibiotic-treated pseudo-germ-free models, and transmissible to WT mice via fecal microbiota transplantation. Similar results were reproduced in a germ-free mouse model. Metagenomic sequencing identified <i>Faecalibacterium prausnitzii</i> as the most significantly depleted species upon <i>Sdc1</i> knockout. <i>In vitro</i>, SDC1-attached glycosaminoglycans (heparan sulfate (HS) and chondroitin sulfate (CS)) but not the SDC1 core protein promoted <i>F. prausnitzii</i> growth. Prokaryotic transcriptome profiling indicated that HS/CS induces cobalamin biosynthesis in <i>F. prausnitzii</i>. The critical role of cobalamin as a mediator was confirmed, as its synthetic inhibition significantly diminished the growth-promoting effect of HS/CS. Mechanism studies showed that HS/CS enhanced biofilm formation in <i>F. prausnitzii</i>, thereby facilitating cobalamin biosynthesis. Oral administration of HS ameliorated DSS-induced colitis and promoted mucosal colonization of <i>F. prausnitzii</i>, independent of the host genotype. Finally, human IBD biopsies revealed a positive correlation between epithelial SDC1 and mucosal <i>F. prausnitzii,</i> as well as an inverse correlation with bacterial translocation and the number of LPS‑positive cells. Our study elucidates a novel mechanism in which the glycosaminoglycan chains of SDC1 promote <i>F. prausnitzii</i> colonization and growth through enhanced biofilm formation and cobalamin synthesis, thereby highlighting the therapeutic potential of HS for IBD and offering a new basis for host-directed microbiota regulation.
Background
This paper addresses the role of Syndecan-1 (SDC1) in inflammatory bowel disease (IBD) and its potential mechanisms in maintaining mucosal homeostasis. Previous research has linked SDC1 to barrier dysfunction and inflammation in IBD, but the specific mechanisms remain unclear. Understanding these mechanisms could provide insights into new therapeutic approaches for IBD.
Methods
The study utilized DSS-induced colitis in Sdc1 knockout and wild-type mice to assess inflammatory infiltration and barrier function. The population included genetically modified mice, and the primary outcomes measured were inflammatory infiltration and barrier integrity. The study also involved metagenomic sequencing and in vitro experiments to analyze the growth of Faecalibacterium prausnitzii.
Results
Sdc1 knockout mice exhibited exacerbated inflammatory infiltration and greater impairment of barrier structure and function compared to wild-type mice. The study found that antibiotic treatment abolished the heightened colitis susceptibility in Sdc1 knockout mice. Metagenomic sequencing revealed that Faecalibacterium prausnitzii was significantly depleted in Sdc1 knockout models.
Interpretation
The findings suggest that SDC1 plays a critical role in maintaining intestinal barrier integrity and promoting the growth of beneficial gut microbiota like Faecalibacterium prausnitzii. While the results are statistically significant, the clinical relevance remains uncertain due to the use of animal models and the potential for confounding factors. The implications for practice may include considering SDC1 and its glycosaminoglycan chains in future therapeutic strategies for IBD.
Key findings
- Sdc1 knockout mice exhibited exacerbated inflammatory infiltration and greater impairment of barrier structure and function than wild-type mice.
- The heightened colitis susceptibility in Sdc1 knockout mice was abolished in antibiotic-treated pseudo-germ-free models.
- Metagenomic sequencing identified Faecalibacterium prausnitzii as the most significantly depleted species upon Sdc1 knockout.
- Oral administration of heparan sulfate ameliorated DSS-induced colitis and promoted mucosal colonization of Faecalibacterium prausnitzii.
Limitations
- Primarily uses animal models, which may not fully translate to human conditions.
- Findings based on knockout models may introduce genetic confounding factors.
- Short-term study duration may not capture long-term effects.