{"doi":"10.1002/advs.202512681","title":"Intestinal Neutral Ceramidase Deficiency Triggers Regulatory T Cell Response via Gd3 to Protect the Host from Intestinal Inflammation","abstract":"Abstract Sphingolipids play a crucial role in gut inflammation. Neutral ceramidase (NcDase) serves as a pivotal regulator of ceramide, the central intermediate in sphingolipid metabolism. The contribution of intestinal epithelial cells (IEC) NcDase to colitis is not well understood. Here, a protective mechanism by which IEC NcDase deficiency ( Asah2 ΔIEC ) and its‐related gangliosides prevent dextran sulfate sodium (DSS)‐induced colitis in mice is described. Asah2 ΔIEC mice display reduced susceptibility to DSS‐induced colitis and increase regulatory T (T reg ) cells compared to Asah2 fl/fl littermates. Deletion of IEC NcDase induces the upregulation of sialyltransferase ST8SIA1 and promotes the sialic‐acid‐containing ganglioside GD3 production. Siglec‐E is a sialic‐acid‐binding lectin expresses predominantly on myeloid cells. Mechanistically, it is identified that GD3 is a functional ligand for Siglec‐E on macrophages and found that GD3/Siglec‐E interaction induced a rapid metabolic rewiring of macrophages that involved the production of IL‐33, which contributes to the generation of ST2 + Foxp3 + T reg cells. Finally, deletion of ST8SIA1 or administration of dietary GD3 induces or reduces mucosal inflammation, respectively. This work defines a critical role for ganglioside GD3 in the induction of colonic T reg cells and identifies an activating pathway that follows engagement of Siglec‐E.","journal":"Advanced Science","year":2025,"id":535324,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9583,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":295146,"name":"Chao Lei","orcid":"0000-0002-5220-086X","position":1,"is_corresponding":false},{"id":295151,"name":"Mukesh K. Sriwastva","orcid":"0000-0003-4370-4625","position":2,"is_corresponding":false},{"id":1418921,"name":"Ting Wang","orcid":"0000-0003-2257-0699","position":3,"is_corresponding":false},{"id":1419421,"name":"Amanguli Tuohongerbieke","orcid":null,"position":4,"is_corresponding":false},{"id":1249761,"name":"Xiaotong Song","orcid":"0009-0001-3561-5852","position":5,"is_corresponding":false},{"id":1419422,"name":"Collin Noud","orcid":null,"position":6,"is_corresponding":false},{"id":1419423,"name":"Shannon Derkson","orcid":null,"position":7,"is_corresponding":false},{"id":293997,"name":"Yi Tan","orcid":"0000-0002-9798-6237","position":8,"is_corresponding":false},{"id":250786,"name":"Gerald W. Dryden","orcid":"0000-0001-9787-4537","position":9,"is_corresponding":false},{"id":295155,"name":"Craig J. McClain","orcid":"0000-0002-7219-8939","position":10,"is_corresponding":false},{"id":481172,"name":"Zhongbin Deng","orcid":"0000-0003-1409-5824","position":11,"is_corresponding":false},{"id":1083427,"name":"Zhishan Xu","orcid":"0009-0000-5519-9481","position":0,"is_corresponding":true}],"reference_count":40,"raw_metadata":null,"created_at":"2026-07-19T02:51:56.297114Z","pmid":"41201002","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}