A durably colonising engineered native symbiont enables sustained intestinal delivery for metabolic dysfunction and colitis.

BACKGROUND: Engineered bacterial therapeutics represent a promising strategy for sustained intestinal delivery of therapeutic molecules, but their efficacy is limited by inefficient colonisation, safety concerns and the need for repeated administration or auxiliary delivery systems. OBJECTIVE: To develop a safety-optimised native bacterial chassis capable of long-term gut colonisation and sustained therapeutic delivery for intestinal inflammatory and metabolic diseases. DESIGN: Native murine Escherichia coli isolates were screened for antibiotic susceptibility, genetic tractability and long-term intestinal colonisation. The selected strain, MEc30, was further optimised by deleting the putative virulence-associated clb and irp loci. MEc30 was then engineered to produce nicotinic acid (MEc30-NA) or deliver murine interleukin-10 (MEc30-mIL-10), and therapeutic efficacy was evaluated in a high-fat diet-induced metabolic dysfunction model as well as Il10 -/- and dextran sulphate sodium (DSS)-induced colitis models. RESULTS: MEc30 achieved stable lifelong colonisation of the murine intestine after a single oral administration, without antibiotic preconditioning or auxiliary delivery systems and did not detectably disturb host physiology or gut microbial ecology. Deletion of clb and irp abolished potential colibactin- and yersiniabactin-associated biosafety risks while preserving bacterial growth and colonisation capacity. MEc30-NA continuously produced nicotinic acid in the gut, activated epithelial GPR109a-associated barrier signalling, improved glucose and lipid metabolism, reduced systemic inflammation and avoided the sharp peak exposure associated with conventional nicotinic acid administration. MEc30-mIL-10 enabled sustained intestinal interleukin-10 delivery, suppressed inflammatory macrophage activation, improved barrier integrity and alleviated colitis in both Il10- / - and DSS-induced mouse models. CONCLUSION: This study identifies MEc30 as a durable and safety-optimised native E. coli chassis for sustained intestinal therapeutic delivery. Engineered native symbionts may provide a long-acting live biotherapeutic strategy for metabolic diseases and chronic intestinal inflammation.