Gasdermin D promotes development of intestinal tumors through regulating IL-1β release and gut microbiota composition.

Publisher: BioMed Central Country of Publication: England NLM ID: 101170464 Publication Model: Electronic Cited Medium: Internet ISSN: 1478-811X (Electronic) Linking ISSN: 1478811X NLM ISO Abbreviation: Cell Commun Signal Subsets: MEDLINE

Original Publication: [London] : BioMed Central, c2003-

Gastrointestinal Microbiome* ; Phosphate-Binding Proteins*/metabolism ; Phosphate-Binding Proteins*/genetics ; Interleukin-1beta*/metabolism ; Intracellular Signaling Peptides and Proteins*/metabolism ; Intracellular Signaling Peptides and Proteins*/genetics; Animals ; Humans ; Mice ; Intestinal Neoplasms/microbiology ; Intestinal Neoplasms/metabolism ; Intestinal Neoplasms/pathology ; Intestinal Neoplasms/genetics ; Mice, Inbred C57BL ; Mice, Knockout ; Colorectal Neoplasms/microbiology ; Colorectal Neoplasms/metabolism ; Colorectal Neoplasms/pathology ; Colorectal Neoplasms/genetics ; Gasdermins

The interplay between gut microbiota and host is crucial for maintaining host health. When this balance is broken, various diseases can arise, including colorectal cancer (CRC). However, the mechanism by which gut microbiota and host interactions mediate CRC development remains unclear. Here, we found that Gasdermin D (GSDMD), an inflammasome effector responsible for forming membrane pores to mediate cell pyroptosis, was upregulated in both human and mouse intestinal tumor samples. GSDMD deficiency significantly suppressed intestinal tumor development in Apc ^min/+ mice, a spontaneous CRC mouse model. Apc ^min/+ Gsdmd ^-/- mice exhibited reduced IL-1β release in the intestine, and the administration of recombinant mouse IL-1β partially restored intestinal tumor development in Apc ^min/+ Gsdmd ^-/- mice. Moreover, 16s rRNA sequencing showed a substantial increase in Lactobacillus abundance in the feces of Apc ^min/+ Gsdmd ^-/- mice compared to Apc ^min/+ mice. Concurrently, Kynurenine (Kyn), a metabolite derived from host tryptophan (Trp) metabolism, was significantly decreased in the feces of Apc ^min/+ Gsdmd ^-/- mice, as shown by metabolite analysis. Additionally, Kyn levels were inversely correlated with Lactobacillus abundance. Furthermore, the administration of exogenous Kyn also promoted intestinal tumor development in Apc ^min/+ Gsdmd ^-/- mice. Thus, GSDMD promotes spontaneous CRC development through increasing IL-1β release and Kyn production. Our data suggest an association between GSDMD, gut microbiota, the host Trp/Kyn pathway, and CRC development.
(© 2024. The Author(s).)

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11501A20220923BF59236, 11501A20220923BE5B6B3, 11501A20220923BD5F291 Shenzhen Longhua District Science and Technology Innovation Special Fund Project; 2024A1515030207 Basic and Applied Basic Research Foundation of Guangdong Province; JCYJ20220531092614032, JCYJ20220531092617039 Shenzhen Foundation of Science and Technology

Keywords: Colon cancer; GSDMD; Gut microbiota; Metabolite

0 (Phosphate-Binding Proteins)
0 (Interleukin-1beta)
0 (Gsdmd protein, mouse)
0 (Intracellular Signaling Peptides and Proteins)
0 (GSDMD protein, human)
0 (Gasdermins)

Date Created: 20241021 Date Completed: 20241022 Latest Revision: 20241030

20241031

PMC11492562

10.1186/s12964-024-01890-6

39434144