Abstract
The balance between gut microbiota and host is critical for maintaining host health. Although dysregulation of the gut microbiota triggers the development of various inflammatory diseases, including colitis, the molecular mechanism of microbiota-driven colitis development is largely unknown. Here, we found that gasdermin D (GSDMD) was activated during acute colitis. In the dextran sulfate sodium (DSS)-induced colitis model, compared to wild-type mice, Gsdmd-deficient mice had less colitis severity. Mechanistically, GSDMD expression in intestinal epithelial cells (IECs), but not infiltrating immune cells, was critical for GSDMD-mediated colitis progression. Moreover, commensal Escherichia coli (E. coli) largely overgrew during colitis, and then the dysregulated commensal E. coli mediated GSDMD activation. Furthermore, the activated GSDMD promoted the release of interleukin-18 (IL-18), but not the transcript or maturation level of IL-18, which in turn mediated goblet cell loss to induce colitis development. Thus, GSDMD promotes colitis development by mediating IL-18 release, and the microbiota can mediate colitis pathogenesis through regulation of GSDMD activation. Our results provide a potential molecular mechanism by which the microbiota-driven GSDMD activation contributes to colitis pathogenesis.
Highlights
The gut microbiota constantly affects host nutrient absorption and immune system development [1, 2]
We isolated intestinal epithelial cells (IECs) and lamina propria lymphocytes (LPLs) from mouse colon tissues, and we found that both the mRNA and protein levels of gasdermin D (GSDMD) in IECs were much higher than those of GSDMD in LPLs (Figures 1B, C), suggesting that GSDMD is mainly expressed in IECs
We found that the expression of Caspase 1 or Caspase 11 was dramatically induced on Day 3 in the dextran sulfate sodium (DSS)-induced colitis model (Figure 1E and Supplementary Figure 1)
Summary
The gut microbiota constantly affects host nutrient absorption and immune system development [1, 2]. The mutual relationship between the gut microbiota and host is crucial for maintaining intestinal homeostasis [3,4,5]. When this homeostatic balance is compromised, excessive immune responses are triggered and contribute to various inflammatory diseases, including. Various reports have shown that the dysregulation of gut microbiota and the host immune system is critical for IBD development [3, 4, 9]. It is still largely unknown how the dysregulated microbiota promotes IBD development. Controversial roles of some of these genes in colitis have been observed by different studies [14,15,16,17,18,19,20,21,22,23,24,25,26,27]
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