Emerging strategies for engineering E. coli Nissle 1917-based therapeutics Original paper

What was reviewed?

This review on engineering Escherichia coli Nissle 1917 therapeutics surveyed how the long-used probiotic EcN is being redesigned as a live biotherapeutic to sense disease signals and deliver drugs directly in the gut or tumours. It grouped recent work into antimicrobial enhancement, mucosal repair, metabolic detoxification, and cancer immunotherapy, and tied these functions to EcN traits such as safe human use, facultative anaerobiosis, tumour tropism, and genetic tractability. It also highlighted the safety tension created by the EcN pks island, whose colibactin output is genotoxic and discussed editing strategies that silence colibactin while retaining microcin- and siderophore-linked benefits.

Who was reviewed?

Evidence came from engineered EcN strains tested in DSS colitis mice, Salmonella and VRE infection models, PKU and hyperammonemia models, and several murine solid tumours that permit high intratumoural EcN growth, alongside early human studies of auxotrophic, chromosomally integrated EcN derivatives to confirm biocontainment and metabolite delivery. The review compared how these hosts, which all feature inflamed or nutrient-restricted niches, select for EcN circuits that exploit iron competition, microcin production or local lysis to release payloads, and it set these findings against decades of clinical use of unmodified Mutaflor to frame risk.

Most important findings

Key advances demonstrated that EcN can be engineered with inflammation- or pathogen-inducible promoters to secrete microcins or heterologous bacteriocins, thereby extending its natural activity against Enterobacteriaceae to precisely the inflamed, iron-poor settings where these blooms occur. Curli-based PATCH systems proved EcN can display mucosal-healing molecules and modestly improve colitis. Metabolic strains such as SYNB1618 and SYNB1020 have demonstrated in vivo conversion of phenylalanine or ammonia under auxotrophic biocontainment; however, clinical benefit will require higher flux or longer residence times. Tumour-colonising EcN carrying lytic or STING-agonist circuits converted “cold” tumours into inflamed lesions and synergised with checkpoint blockade. A central message was that simple deletion of the pks island may remove desirable iron and microcin functions, so finer edits in clbP or circuit-level containment are preferable.

Key implications

For clinicians and translational teams, EcN is emerging as a modular live drug that can be matched to microbiome-defined problems such as Enterobacteriaceae overgrowth, ulcerated colitis, toxin accumulation or poorly immunogenic tumours. However, once EcN is engineered, historical safety cannot be assumed; future clinical products must combine chromosomal integration, auxotrophic or kill-switch containment, and colibactin-silencing edits while keeping the adhesion, microcin and iron-uptake traits that underpin efficacy. Microbiome-signature resources should therefore annotate engineered EcN not just by indication but also by sensor, payload and pks status to support precision use.