{"doi":"10.1101/2025.11.08.687059","title":"Engineering butyrate-producing Lachnospiraceae to treat metabolic disease","abstract":"Abstract Engineering native gut bacteria offers a route to persistent, programmable therapeutics, yet many dominant taxa remain genetically intractable. Lachnospiraceae are a prevalent and abundant family in the human gut microbiome, possessing metabolic functions generally associated with health 1 . Despite their promise as engineered live biotherapeutics, genetic manipulation of Lachnospiraceae remains challenging. Here, we develop a modular toolkit for Lachnospiraceae engineering, including constitutive and inducible expression and chromosomal integration systems. Applying this toolkit to the native commensal Coprococcus comes , we program secretion of the mammalian cytokine interleukin-22 (IL-22) in the mouse intestinal tract where it elicits ileal transcriptional responses consistent with cytokine signaling. In a mouse model of metabolic associated steatotic liver disease, IL-22–secreting C. comes improves glucose homeostasis and attenuates hepatic steatosis. This work demonstrates that a native Lachnospiraceae chassis can be genetically programmed to modulate host metabolic and immune physiology. The toolkit provides a generalizable foundation for Lachnospiraceae-derived microbiome therapeutics and for probing causal links between Lachnospiraceae gene programs and host phenotypes.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":580731,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9473,"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":1213716,"name":"Sandra McClure","orcid":"0000-0001-8725-5871","position":1,"is_corresponding":false},{"id":583016,"name":"Joshua Glazier","orcid":null,"position":2,"is_corresponding":false},{"id":1491871,"name":"Recep Erdem Ahan","orcid":"0000-0002-6061-9062","position":3,"is_corresponding":false},{"id":1492186,"name":"Sadiksha Shakya","orcid":null,"position":4,"is_corresponding":false},{"id":1492187,"name":"D Castillo Villegas","orcid":null,"position":5,"is_corresponding":false},{"id":1492188,"name":"Tracy Leidan Chen","orcid":null,"position":6,"is_corresponding":false},{"id":1207872,"name":"Jay Fuerte-Stone","orcid":null,"position":7,"is_corresponding":false},{"id":1214213,"name":"Rory McGann","orcid":null,"position":8,"is_corresponding":false},{"id":1491872,"name":"Mark Mimee","orcid":"0000-0002-3083-2671","position":9,"is_corresponding":false},{"id":682311,"name":"Jack Arnold","orcid":"0000-0002-4840-1327","position":0,"is_corresponding":true}],"reference_count":70,"raw_metadata":null,"created_at":"2026-07-19T02:58:43.046112Z","pmid":"41279522","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":[]}