Design, construction, and in vivo augmentation of a complex gut microbiome

Cheng, Alice G.; Ho, Po-Yi; Aranda-Díaz, Andrés; Jain, Sunit; Yu, Feiqiao Brian; Meng, Xiangru; Wang, Min; Iakiviak, Mikhail; Nagashima, Kazuki; Zhao, Aishan; Murugkar, Pallavi; Patil, Advait; Atabakhsh, Katayoon; Weakley, Allison M.; Jia, Yan; Brumbaugh, Ariel R.; Higginbottom, Steven K.; Dimas, Alejandra; Shiver, Anthony L.; Deutschbauer, Adam M.; Neff, Norma; Sonnenburg, Justin L.; Huang, Kerwyn Casey; Fischbach, Michael A.

doi:10.1016/j.cell.2022.08.003

Cited by 140 publications

(102 citation statements)

References 94 publications

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“…Each of these studies, some explicitly and some implicitly, are searching for what has been termed the “minimal microbial community”, that is, the minimal set of organisms required to accurately reproduce natural community functions ( 16 ). The number of microbial strains in constructed communities ranged from under 10 ( 21 , 28 ) to between 20 and 100 ( 27 , 29 – 32 ), although some studies starting with a large number of microbes reported that only a small number of organisms consistently colonized plant sites ( 21 , 30 ). In addition to the loss of starting organisms, in vitro microbial communities commonly lose α-diversity over time, compared to their starting communities ( 33 – 35 ).…”

Section: Introductionmentioning

confidence: 99%

A Reproducible and Tunable Synthetic Soil Microbial Community Provides New Insights into Microbial Ecology

et al. 2022

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Section: Introductionmentioning

confidence: 99%

A Reproducible and Tunable Synthetic Soil Microbial Community Provides New Insights into Microbial Ecology

et al. 2022

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“…Future studies will test microbiome-resident rMETaseproducing E. coli for multiple cancer types. Recent advances in the manipulation of the gut microbiome indicate the future potential of treating disease as shown in the present report with E. coli JM109-rMETase (69,70).…”

Section: Photographs Of Tumors Excised From Mice Treated With Phospha...mentioning

confidence: 59%

Oral Installation of Recombinant Methioninase-producingEscherichia coliinto the Microbiome Inhibits Colon-cancer Growth in a Syngeneic Mouse Model

Kubota

Han

Hamada

et al. 2022

Cancer Genomics Proteomics

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Background/Aim: All cancer types so far tested are methionine-addicted. Targeting the methionine addiction of cancer with recombinant methioninase (rMETase) has shown great progress in vitro, in mouse models, and in the clinic. However, administration of rMETase requires multiple doses per day. In the present study, we determined if rMETase-producing Escherichia coli JM109 (E. coli JM109-rMETase) might be an effective anticancer agent when installed into the microbiome. Materials and Methods: E. coli JM109-rMETase was administered to a syngeneic model of MC38 colon cancer growing subcutaneously in C57BL/6 mice. JM109-rMETase was administered orally by gavage to the mice twice per day. Tumor size was measured with calipers. Results: The administration of E. coli JM109-rMETase twice a day significantly inhibited MC38 coloncancer growth. E. coli JM109-rMETase was found in the stool of treated mice, indicating it had entered the microbiome. Conclusion: The present study indicates the potential of microbiome-based treatment of cancer targeting methionine addiction.

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“…There are multiple limitations of our study. E. lenta -mediated P-gp inhibition was tested in GF and CONV-R mice using the P-gp substrate digoxin; synthetic communities (Cheng et al 2022) or humanized mice (Turnbaugh et al 2009) could be used to test how E. lenta affects P-gp function in the context of other members of the human gut microbiota. Although digoxin is a sensitive and physiologically-relevant P-gp probe, additional P-gp substrates could be used to assess generalizability.…”

Section: Discussionmentioning

confidence: 99%

Human gut Actinobacteria boost drug absorption by secreting P-glycoprotein ATPase inhibitors

Kyaw

Sandy

Trepka

et al. 2022

Preprint

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Drug efflux transporters are a major determinant of drug efficacy and toxicity. A canonical example is P-glycoprotein (P-gp), an efflux transporter that controls the intestinal absorption of diverse compounds. Despite reports that P-gp expression depends on the microbiome, the mechanisms responsible and their physiological relevance remain unclear. Surprisingly, we found that the cardiac drug-metabolizing gut ActinobacteriumEggerthella lentaincreases drug absorption in mice through post-translational inhibition of P-gp ATPase efflux activity. P-gp inhibition is conserved in theEggerthellaceaefamily but absent in other Actinobacteria. Comparative genomics identified genes associated with P-gp inhibition. Finally, activity-guided biochemical fractionation coupled to metabolomics identified a cluster of isoflavonoids produced byE. lentarelated to plant-derived P-gp inhibitors. These results highlight the unexpected overlap between diet- and microbiome-derived compounds, and the importance of considering the broader relevance of the gut microbiome for drug disposition beyond first-pass metabolism.

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Design, construction, and in vivo augmentation of a complex gut microbiome

Cited by 140 publications

References 94 publications

A Reproducible and Tunable Synthetic Soil Microbial Community Provides New Insights into Microbial Ecology

A Reproducible and Tunable Synthetic Soil Microbial Community Provides New Insights into Microbial Ecology

Oral Installation of Recombinant Methioninase-producingEscherichia coliinto the Microbiome Inhibits Colon-cancer Growth in a Syngeneic Mouse Model

Human gut Actinobacteria boost drug absorption by secreting P-glycoprotein ATPase inhibitors

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