Controlled colonization of the human gut with a genetically engineered microbial therapeutic

• 成果类型: Article
• 署名作者: Whitaker, Weston R.; Russ, Zachary N.; Stanley Shepherd, Elizabeth; Popov, Lauren M.; Louie, Alexander; Lam, Kathy; Zong, David M.; Gill, Clare C. C.; Gehrig, Jeanette L.; Rishi, Harneet S.; Tan, Jessica A.; Buness, Areta; Godoy, Janeth; Banta, Domenique; Jaidka, Sonia; Wilson, Katheryne; Flood, Jake; Bukshpun, Polina; Yocum, Richard; Cook, David N.; Warsi, Tariq; Mclean, Lachy; Sonnenburg, Justin L.; Deloache, William C.
• 署名单位: Stanford University; Chan Zuckerberg Initiative (CZI); Stanford University
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-10318
• DOI: 10.1126/science.adu8000
• 发表日期: 2025-07-17
• 页码: 303-308
• 关键词: bacteroides-thetaiotaomicron; lactococcus-lactis; expression; strain; polysaccharide; hyperoxaluria; carbohydrate; mobilization; engraftment; bacteria

摘要

Precision microbiome programming for therapeutic applications is limited by challenges in achieving reproducible colonic colonization. Previously, we created an exclusive niche that we used to engraft engineered bacteria into diverse microbiota in mice by using a porphyran prebiotic. Building on this approach, we have now engineered conditional attenuation into a porphyran-utilizing strain of Phocaeicola vulgatus by replacing native essential gene regulation with a porphyran-inducible promoter to allow reversible engraftment. Engineering a five-gene oxalate degradation pathway into the reversibly engrafting strain resulted in a therapeutic candidate that reduced hyperoxaluria, a cause of kidney stones, in preclinical models. Our phase 1/2a clinical trial demonstrated porphyran dose-dependent abundance and reversible engraftment in humans, reduction of oxalate in the urine, and characterized genetic stability challenges to achievinglong-term treatment.