Intestinal transgene delivery with native E. coli chassis allows persistent physiological changes
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Abstract
Live bacterial therapeutics (LBTs) could reverse diseases by engrafting in the gut and providing persistent beneficial functions in the host. However, attempts to functionally manipulate the gut microbiome of conventionally raised (CR) hosts have been unsuccessful because engineered microbial organisms (i.e., chassis) have difficulty in colonizing the hostile luminal environment. In this proof-of-concept study, we use native bacteria as chassis for transgene delivery to impact CR host physiology. Native Escherichia coli bacteria isolated from the stool cultures of CR mice were modified to express functional genes. The reintroduction of these strains induces perpetual engraftment in the intestine. In addition, engineered native E. coli can induce functional changes that affect physiology of and reverse pathology in CR hosts months after administration. Thus, using native bacteria as chassis to "knock in" specific functions allows mechanistic studies of specific microbial activities in the microbiome of CR hosts and enables LBT with curative intent.
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Deconjugation of taurine-conjugated BAs impacts colonization resistance against Klebsiella pneumoniae, colorectal cancer development, and metabolic disease.
“For example, deconjugation of taurine-conjugated BAs has been shown to impact the establishment of colonization resistance against Klebsiella pneumoniae, the development of colorectal cancer and more recently metabolic disease43–45.”
From Bile salt hydrolases shape the bile acid landscape and restrict Clostridioides difficile growth in the murine gut (2023) · cites this paper as [43]
The Results (‘Engineered native E. coli bacteria affect host physiology’; page unavailable) report that BSH-expressing bacteria altered bile acids and improved insulin sensitivity in a mouse model of type 2 diabetes, supporting the metabolic-disease part of the sentence. The cited paper does not establish effects on colonization resistance against Klebsiella pneumoniae or colorectal cancer development. (LLM, conf=0.87)
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Foley, M. H., Walker, M. E., Stewart, A. K., O’Flaherty, S., Gentry, E. C., Patel, S., Beaty, V. V., Allen, G., Pan, M., Simpson, J. B., et al. (2023) · Nature Microbiology · doi:10.1038/s41564-023-01337-7 · Cited by 181 · see citing works
The Gut Microbial Bile Acid Modulation and Its Relevance to Digestive Health and Diseases
Fogelson, K. A., Dorrestein, P. C., Zarrinpar, A., & Knight, R. (2023) · Gastroenterology · doi:10.1053/j.gastro.2023.02.022 · Cited by 177 · see citing works
Self-citationNative microbiome dominates over host factors in shaping the probiotic genetic evolution in the gut
Jiang, S., Zhang, C., Han, Z., Ma, W., Wang, S., Huo, D., Cui, W., Zhai, Q., Huang, S., & Zhang, J. (2023) · npj Biofilms and Microbiomes · doi:10.1038/s41522-023-00447-8 · Cited by 25 · see citing works
Gut microbiota drives structural variation of exogenous probiotics to enhance colonization
Jiang, S., Huang, S., Zhang, Z., Ma, W., Han, Z., Song, Y., Huo, D., Cui, W., & Zhang, J. (2025) · Gut Microbes · doi:10.1080/19490976.2025.2503371 · Cited by 15 · see citing works
The role of the microbiome in liver disease
Schöler, D., & Schnabl, B. (2024) · Current Opinion in Gastroenterology · doi:10.1097/mog.0000000000001013 · Cited by 16 · see citing works
- Authors
- Russell, B. J., Brown, S. D., Siguenza, N., Mai, I., Saran, A. R., Lingaraju, A., Maissy, E. S., Dantas Machado, A. C., Pinto, A. F. M., Sanchez, C., Rossitto, L.-A., Miyamoto, Y., Richter, R. A., Ho, S. B., Eckmann, L., Hasty, J., Gonzalez, D. J., Saghatelian, A., Knight, R., & Zarrinpar, A.
- Affiliations
- University of California San Diego (US)
- Salk Institute for Biological Studies (US)
- Corresponding author
- Zarrinpar, Amir
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2022-08
- Volume
- 185
- Issue
- 17
- Pages
- 3263-3277.e15
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC9464905
- OpenAlex
- W4289780991
- Cited by
- 151
- References
- 81
- Citations by year
- 2026: 29 · 2025: 37 · 2024: 35 · 2023: 37 · 2022: 13
- FWCI
- 14.60
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion, cc-by)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- U.S. Department of Veterans Affairs (I01 BX005707, UL1TR001442, P30DK120515, R01 HL148801, P30 CA014195, P50 AA011999, R01 EB030134, BX005707, P30 DK063491, U01 CA265719)
- American Heart Association (16BGIA27760160, P30 DK063491, DK063491)
- Glenn Foundation for Medical Research (P30 CA014195)
- American Association for the Study of Liver Diseases (P30 DK120515, P50 AA011999)
- Fondation pour la Recherche Médicale
- National Institutes of Health (5f31hd106762-02, UL1TR001442, CA014195, DK-063491, AA011999, DK120515)
- University of California, San Diego (T32 GM007752, T32 AR064194, P30DK063491, DK063491)
- National Institute on Alcohol Abuse and Alcoholism (P50AA011999)
- National Heart, Lung, and Blood Institute (R01HL148801, R01HL157445)
- National Institute of Mental Health (R21MH117780)
- National Cancer Institute (R21CA259921, U01CA265719, P30CA014195)
- National Institute of General Medical Sciences (T32GM007752)
- National Institute of Diabetes and Digestive and Kidney Diseases (R03DK114536, F32DK113721, K08DK102902, P30DK120515, P30DK063491)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (T32AR064194)
- National Institute of Biomedical Imaging and Bioengineering (R01EB030134)
- National Center for Advancing Translational Sciences
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (F31 HD106762)
- Eurostars
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Cancer Research and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Agricultural and Biological Sciences › Food Science › Probiotics and Fermented Foods
- Keywords
- transgene delivery, intestinal colonization
- MeSH terms
- Gastrointestinal Microbiome, Animals, Bacteria, Escherichia coli, Transgenes, Mice, Microbiota
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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