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Chapter 14 : Engineering Diagnostic and Therapeutic Gut Bacteria

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Abstract:

Genetically engineered bacteria have the potential to diagnose and treat a wide range of diseases linked to the gastrointestinal tract, or gut. Such engineered microbes will be less expensive and invasive than current diagnostics and more effective and safe than current therapeutics. Recent advances in synthetic biology have dramatically improved the reliability with which bacteria can be engineered with the sensors, genetic circuits, and output (actuator) genes necessary for diagnostic and therapeutic functions. However, to deploy such bacteria , researchers must identify appropriate gut-adapted strains and consider performance metrics such as sensor detection thresholds, circuit computation speed, growth rate effects, and the evolutionary stability of engineered genetic systems. Other recent reviews have focused on engineering bacteria to target cancer ( ) or genetically modifying the endogenous gut microbiota ( ). Here, we develop a standard approach for engineering “smart probiotics,” which both diagnose and treat disease, as well as “diagnostic gut bacteria” and “drug factory probiotics,” which perform only the former and latter function, respectively. We focus on the use of cutting-edge synthetic biology tools, gut-specific design considerations, and current and future engineering challenges.

Citation: Landry B, Tabor J. 2018. Engineering Diagnostic and Therapeutic Gut Bacteria, p 333-361. In Britton R, Cani P (ed), Bugs as Drugs. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.BAD-0020-2017
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Figure 1

The three classes of engineered gut bacteria. Smart probiotics sense one or more biomarkers, compute that those biomarkers are present in a combination indicative of disease, and respond by delivering a precise dose of one or more appropriate therapeutics at the diseased tissue. Diagnostic gut bacteria sense one or more biomarkers, compute that those biomarkers are present in a combination indicative of disease, and produce a reporter which can be externally measured by a clinician. Drug factory probiotics constitutively produce a therapeutic within the body.

Citation: Landry B, Tabor J. 2018. Engineering Diagnostic and Therapeutic Gut Bacteria, p 333-361. In Britton R, Cani P (ed), Bugs as Drugs. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.BAD-0020-2017
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Figure 2

A comparison of the development process for natural and engineered probiotics. (A) Natural probiotics are isolated and then tested for efficacy without an ability to methodically improve their capabilities. (B) In contrast, engineered probiotics undergo a design-build-test-learn cycle which allows for continual probiotic improvement and knowledge gain with each iteration.

Citation: Landry B, Tabor J. 2018. Engineering Diagnostic and Therapeutic Gut Bacteria, p 333-361. In Britton R, Cani P (ed), Bugs as Drugs. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.BAD-0020-2017
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Figure 3

Examples of current engineered gut bacteria. (A) A drug factory probiotic was made by engineering to constitutively produce IL-10. IL-10 is secreted by the bacteria and then bound by the IL-10 receptor in the gut, resulting in downregulation of host inflammation. (B) DSS was used to induce inflammation in mice, and disease pathology was measured with histological scores. Treatment with the IL-10 drug factory probiotic was found to decrease symptoms by 50% compared to untreated mice or mice administered the natural probiotic . (C) A diagnostic gut bacterium was created by engineering Nissle to sense thiosulfate, which is produced in the gut during inflammation. The thiosulfate is sensed by the ttrSR TCS, which activates expression of the fluorescent protein sfGFP. (D) sfGFP fluorescence of bacteria isolated from the feces and distal and proximal colon was measured and found to be significantly increased in mice experiencing inflammation in each location. Panel adapted from ( ) with permission of the publisher. (E) NGF-1 was modified to express the ATC sensor TetR, which controlled expression of the cro TF. The cro TF is one component of the lambda phage cro/cI toggle switch. ATC altered the start of the switch to become cro-dominant, and therefore produce LacZ protein, which produces a blue pigment. (F) The ATC-sensing diagnostic gut bacteria were administered to mice which were administered ATC via drinking water. Temporary administration of ATC was found to activate LacZ production, and the memory was retained for up to 1 week. Panel adapted from ( ) with permission of the publisher. (G) The native RhaR rhamnose sensor in was used to control expression of the Int12 recombinase, which permanently inverts a barcode segment of DNA in the genome. (H) The rhamnose diagnostic gut bacteria switched the state of the barcode as detected via qPCR when administered rhamnose in drinking water. However, even without administration of rhamnose, the sensor toggled states, due to either leaky recombination or residual rhamnose in the plant-based chow. Panel reprinted from ( ) with permission of the publisher.

Citation: Landry B, Tabor J. 2018. Engineering Diagnostic and Therapeutic Gut Bacteria, p 333-361. In Britton R, Cani P (ed), Bugs as Drugs. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.BAD-0020-2017
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Figure 4

An outline of the types of sense, compute, and respond behavior an engineered gut bacterium can exhibit. Chemicals from a variety of sources within the gut may be of interest to a smart bacterium, including the host diet, compounds produced locally by the host in the bacterium’s microenvironment, signals from other components of the microbiome, and general biomarkers of host disease. Computation is performed with a variety of logic gates and memory elements. The bacterium actuates a response with a therapeutic molecule in the case of a smart probiotic, or by producing a nucleotide or protein-based reporter for a diagnostic gut bacterium.

Citation: Landry B, Tabor J. 2018. Engineering Diagnostic and Therapeutic Gut Bacteria, p 333-361. In Britton R, Cani P (ed), Bugs as Drugs. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.BAD-0020-2017
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Figure 5

The different components used to construct an engineered gut bacterium. The pros and cons of each component are listed in green and red text, respectively. (A) Sensors can be selected from OCSs or TCSs. (B) Logic circuits can be constructed using TFs, CRISPR/Cas repressors, RNA-based sRNA transcriptional activators, or serine recombinases. (C) Genetic memory can take the form of a toggle switch or recombined DNA. (D) The state of a circuit can be assayed using colorimetric, luminescent, fluorescent, or nucleotide reporters.

Citation: Landry B, Tabor J. 2018. Engineering Diagnostic and Therapeutic Gut Bacteria, p 333-361. In Britton R, Cani P (ed), Bugs as Drugs. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.BAD-0020-2017
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References

/content/book/10.1128/9781555819705.chap14
1. Hosseinidoust Z,, Mostaghaci B,, Yasa O,, Park B-W,, Singh AV,, Sitti M . 2016. Bioengineered and biohybrid bacteria-based systems for drug delivery. Adv Drug Deliv Rev 106( Pt A) : 27 44.[CrossRef] [PubMed]
2. Chien T,, Doshi A,, Danino T . 2017. Advances in bacteria cancer therapies using synthetic biology. Curr Opin Syst Biol 5 : 1 8.[CrossRef]
3. Sheth RU,, Cabral V,, Chen SP,, Wang HH . 2016. Manipulating bacterial communities by in situ microbiome engineering. Trends Genet 32 : 189 200.[CrossRef] [PubMed]
4. Mimee M,, Citorik RJ,, Lu TK . 2016. Microbiome therapeutics: advances and challenges. Adv Drug Deliv Rev 105( Pt A) : 44 54.[CrossRef] [PubMed]
5. WHO . 2006. Probiotics in Food: Health and Nutritional Properties and Guidelines for Evaluation. Food and Agriculture Organization of the UN, London, Ontario, Canada. http://www.fao.org/food/food-safety-quality/a-z-index/probiotics/en/
6. Wang H,, Lee I-S,, Braun C,, Enck P . 2016. Effect of probiotics on central nervous system functions in animals and humans: a systematic review. J Neurogastroenterol Motil 22 : 589 605.[CrossRef] [PubMed]
7. Choi HH,, Cho Y-S . 2016. Fecal microbiota transplantation: current applications, effectiveness, and future perspectives. Clin Endosc 49 : 257 265.[CrossRef] [PubMed]
8. Bron PA,, Kleerebezem M,, Brummer R-J,, Cani PD,, Mercenier A,, MacDonald TT,, Garcia-Ródenas CL,, Wells JM . 2017. Can probiotics modulate human disease by impacting intestinal barrier function? Br J Nutr 117 : 93 107.[CrossRef]
9. Bermudez-Brito M,, Plaza-Díaz J,, Muñoz-Quezada S,, Gómez-Llorente C,, Gil A . 2012. Probiotic mechanisms of action. Ann Nutr Metab 61 : 160 174.[CrossRef] [PubMed]
10. Sarkar A,, Mandal S . 2016. Bifidobacteria: insight into clinical outcomes and mechanisms of its probiotic action. Microbiol Res 192 : 159 171.[CrossRef] [PubMed]
11. Rogers NJ,, Mousa SA . 2012. The shortcomings of clinical trials assessing the efficacy of probiotics in irritable bowel syndrome. J Altern Complement Med 18 : 112 119.[CrossRef] [PubMed]
12. Holmes E,, Kinross J,, Gibson GR,, Burcelin R,, Jia W,, Pettersson S,, Nicholson JK . 2012. Therapeutic modulation of microbiota-host metabolic interactions. Sci Transl Med 4 : 137rv6.[CrossRef] [PubMed]
13. Claesen J,, Fischbach MA . 2015. Synthetic microbes as drug delivery systems. ACS Synth Biol 4 : 358 364.[CrossRef] [PubMed]
14. Brophy JAN,, Voigt CA . 2014. Principles of genetic circuit design. Nat Methods 11 : 508 520.[CrossRef] [PubMed]
15. Steidler L,, Hans W,, Schotte L,, Neirynck S,, Obermeier F,, Falk W,, Fiers W,, Remaut E . 2000. Treatment of murine colitis by Lactococcus lactis secreting interleukin-10. Science 289 : 1352 1355.[PubMed]
16. Steidler L,, Neirynck S,, Huyghebaert N,, Snoeck V,, Vermeire A,, Goddeeris B,, Cox E,, Remon JP,, Remaut E . 2003. Biological containment of genetically modified Lactococcus lactis for intestinal delivery of human interleukin 10. Nat Biotechnol 21 : 785 789.[CrossRef] [PubMed]
17. Braat H,, Rottiers P,, Hommes DW,, Huyghebaert N,, Remaut E,, Remon JP,, van Deventer SJH,, Neirynck S,, Peppelenbosch MP,, Steidler L . 2006. A phase I trial with transgenic bacteria expressing interleukin-10 in Crohn’s disease. Clin Gastroenterol Hepatol 4 : 754 759.[CrossRef]
18. Bermúdez-Humarán LG,, Aubry C,, Motta J-PP,, Deraison C,, Steidler L,, Vergnolle N,, Chatel J-MM,, Langella P . 2013. Engineering lactococci and lactobacilli for human health. Curr Opin Microbiol 16 : 278 283.[CrossRef] [PubMed]
19. Vandenbroucke K,, de Haard H,, Beirnaert E,, Dreier T,, Lauwereys M,, Huyck L,, Van Huysse J,, Demetter P,, Steidler L,, Remaut E,, Cuvelier C,, Rottiers P . 2010. Orally administered L. lactis secreting an anti-TNF nanobody demonstrate efficacy in chronic colitis. Mucosal Immunol 3 : 49 56.[CrossRef] [PubMed]
20. Intrexon Corporation . 2016. ActoBiotics® platform: a novel class of oral biotherapeutics. https://www.dna.com/.
21. Vandenbroucke K,, Hans W,, Van Huysse J,, Neirynck S,, Demetter P,, Remaut E,, Rottiers P,, Steidler L . 2004. Active delivery of trefoil factors by genetically modified Lactococcus lactis prevents and heals acute colitis in mice. Gastroenterology 127 : 502 513.[CrossRef] [PubMed]
22. Han W,, Mercenier A,, Ait-Belgnaoui A,, Pavan S,, Lamine F,, van Swam II,, Kleerebezem M,, Salvador-Cartier C,, Hisbergues M,, Bueno L,, Theodorou V,, Fioramonti J . 2006. Improvement of an experimental colitis in rats by lactic acid bacteria producing superoxide dismutase. Inflamm Bowel Dis 12 : 1044 1052.[CrossRef] [PubMed]
23. Rochat T,, Bermúdez-Humarán L,, Gratadoux J-J,, Fourage C,, Hoebler C,, Corthier G,, Langella P . 2007. Anti-inflammatory effects of Lactobacillus casei BL23 producing or not a manganese-dependant catalase on DSS-induced colitis in mice. Microb Cell Fact 6 : 22.[CrossRef] [PubMed]
24. Carroll IM,, Andrus JM,, Bruno-Bárcena JM,, Klaenhammer TR,, Hassan HM,, Threadgill DS . 2007. Anti-inflammatory properties of Lactobacillus gasseri expressing manganese superoxide dismutase using the interleukin 10-deficient mouse model of colitis. Am J Physiol Gastrointest Liver Physiol 293 : G729 G738.[CrossRef]
25. Foligne B,, Dessein R,, Marceau M,, Poiret S,, Chamaillard M,, Pot B,, Simonet M,, Daniel C . 2007. Prevention and treatment of colitis with Lactococcus lactis secreting the immunomodulatory Yersinia LcrV protein. Gastroenterology 133 : 862 874.[CrossRef] [PubMed]
26. Watterlot L,, Rochat T,, Sokol H,, Cherbuy C,, Bouloufa I,, Lefèvre F,, Gratadoux JJ,, Honvo-Hueto E,, Chilmonczyk S,, Blugeon S,, Corthier G,, Langella P,, Bermúdez-Humarán LG . 2010. Intragastric administration of a superoxide dismutase-producing recombinant Lactobacillus casei BL23 strain attenuates DSS colitis in mice. Int J Food Microbiol 144 : 35 41.[CrossRef] [PubMed]
27. LeBlanc JG,, del Carmen S,, Miyoshi A,, Azevedo V,, Sesma F,, Langella P,, Bermúdez-Humarán LG,, Watterlot L,, Perdigon G,, de Moreno de LeBlanc A . 2011. Use of superoxide dismutase and catalase producing lactic acid bacteria in TNBS induced Crohn’s disease in mice. J Biotechnol 151 : 287 293.[CrossRef]
28. Motta J-P,, Bermúdez-Humarán LG,, Deraison C,, Martin L,, Rolland C,, Rousset P,, Boue J,, Dietrich G,, Chapman K,, Kharrat P,, Vinel J-P,, Alric L,, Mas E,, Sallenave J-M,, Langella P,, Vergnolle N . 2012. Food-grade bacteria expressing elafin protect against inflammation and restore colon homeostasis. Sci Transl Med 4 : 158ra144.[CrossRef] [PubMed]
29. Takiishi T,, Korf H,, Van Belle TL,, Robert S,, Grieco FA,, Caluwaerts S,, Galleri L,, Spagnuolo I,, Steidler L,, Van Huynegem K,, Demetter P,, Wasserfall C,, Atkinson MA,, Dotta F,, Rottiers P,, Gysemans C,, Mathieu C . 2012. Reversal of autoimmune diabetes by restoration of antigen-specific tolerance using genetically modified Lactococcus lactis in mice. J Clin Invest 122 : 1717 1725.[CrossRef]
30. Chen Z,, Guo L,, Zhang Y,, Walzem RL,, Pendergast JS,, Printz RL,, Morris LC,, Matafonova E,, Stien X,, Kang L,, Coulon D,, McGuinness OP,, Niswender KD,, Davies SS . 2014. Incorporation of therapeutically modified bacteria into gut microbiota inhibits obesity. J Clin Invest 124 : 3391 3406.[CrossRef] [PubMed]
31. Robert S,, Gysemans C,, Takiishi T,, Korf H,, Spagnuolo I,, Sebastiani G,, Van Huynegem K,, Steidler L,, Caluwaerts S,, Demetter P,, Wasserfall CH,, Atkinson MA,, Dotta F,, Rottiers P,, Van Belle TL,, Mathieu C . 2014. Oral delivery of glutamic acid decarboxylase (GAD)-65 and IL10 by Lactococcus lactis reverses diabetes in recent-onset NOD mice. Diabetes 63 : 2876 2887.[CrossRef]
32. Duan FF,, Liu JH,, March JC . 2015. Engineered commensal bacteria reprogram intestinal cells into glucose-responsive insulin-secreting cells for the treatment of diabetes. Diabetes 64 : 1794 1803.[CrossRef] [PubMed]
33. Rosberg-Cody E,, Stanton C,, O’Mahony L,, Wall R,, Shanahan F,, Quigley EM,, Fitzgerald GF,, Ross RP . 2011. Recombinant lactobacilli expressing linoleic acid isomerase can modulate the fatty acid composition of host adipose tissue in mice. Microbiology 157 : 609 615.[CrossRef] [PubMed]
34. Chen H-L,, Lai Y-W,, Chen C-S,, Chu T-W,, Lin W,, Yen C-C,, Lin M-F,, Tu M-Y,, Chen C-M . 2010. Probiotic Lactobacillus casei expressing human lactoferrin elevates antibacterial activity in the gastrointestinal tract. Biometals 23 : 543 554.[CrossRef] [PubMed]
35. Paton AW,, Jennings MP,, Morona R,, Wang H,, Focareta A,, Roddam LF,, Paton JC . 2005. Recombinant probiotics for treatment and prevention of enterotoxigenic Escherichia coli diarrhea. Gastroenterology 128 : 1219 1228.[CrossRef] [PubMed]
36. Koo OK,, Amalaradjou MAR,, Bhunia AK . 2012. Recombinant probiotic expressing Listeria adhesion protein attenuates Listeria monocytogenes virulence in vitro . PLoS One 7 : e29277.[CrossRef] [PubMed]
37. Focareta A,, Paton JC,, Morona R,, Cook J,, Paton AW . 2006. A recombinant probiotic for treatment and prevention of cholera. Gastroenterology 130 : 1688 1695.[CrossRef] [PubMed]
38. Duan F,, March JC . 2010. Engineered bacterial communication prevents Vibrio cholerae virulence in an infant mouse model. Proc Natl Acad Sci USA 107 : 11260 11264.[CrossRef]
39. Gordley RM,, Bugaj LJ,, Lim WA . 2016. Modular engineering of cellular signaling proteins and networks. Curr Opin Struct Biol 39 : 106 114.[CrossRef] [PubMed]
40. Smanski MJ,, Zhou H,, Claesen J,, Shen B,, Fischbach MA,, Voigt CA . 2016. Synthetic biology to access and expand nature’s chemical diversity. Nat Rev Microbiol 14 : 135 149.[CrossRef] [PubMed]
41. Dobrin A,, Saxena P,, Fussenegger M . 2016. Synthetic biology: applying biological circuits beyond novel therapies. Integr Biol 8 : 409 430.[CrossRef] [PubMed]
42. Tabor JJ,, Groban ES,, Voigt CA, . 2009. Performance characteristics for sensors and circuits used to program E. coli , p 401 439. In Lee SY (ed), Systems Biology and Biotechnology of Escherichia coli . Springer, Dordrecht, The Netherlands.[CrossRef]
43. Olson EJ,, Hartsough LA,, Landry BP,, Shroff R,, Tabor JJ . 2014. Characterizing bacterial gene circuit dynamics with optically programmed gene expression signals. Nat Methods 11 : 449 455.[CrossRef] [PubMed]
44. Castillo-Hair SM,, Igoshin OA,, Tabor JJ . 2015. How to train your microbe: methods for dynamically characterizing gene networks. Curr Opin Microbiol 24 : 113 123.[CrossRef] [PubMed]
45. Ulrich LE,, Koonin EV,, Zhulin IB . 2005. One-component systems dominate signal transduction in prokaryotes. Trends Microbiol 13 : 52 56.[CrossRef] [PubMed]
46. Gupta S,, Bram EE,, Weiss R . 2013. Genetically programmable pathogen sense and destroy. ACS Synth Biol 2 : 715 723.[CrossRef] [PubMed]
47. Saeidi N,, Wong CK,, Lo T-MT-M,, Nguyen HX,, Ling H,, Leong SSJ,, Poh CL,, Chang MW . 2011. Engineering microbes to sense and eradicate Pseudomonas aeruginosa, a human pathogen. Mol Syst Biol 7 : 521.[CrossRef] [PubMed]
48. Archer EJ,, Robinson AB,, Süel GM . 2012. Engineered E. coli that detect and respond to gut inflammation through nitric oxide sensing. ACS Synth Biol 1 : 451 457.[CrossRef] [PubMed]
49. Drouault S,, Anba J,, Corthier G . 2002. Streptococcus thermophilus is able to produce a β-galactosidase active during its transit in the digestive tract of germ-free mice. Appl Environ Microbiol 68 : 938 941.[CrossRef] [PubMed]
50. Hamady ZZR,, Scott N,, Farrar MD,, Lodge JPA,, Holland KT,, Whitehead T,, Carding SR . 2010. Xylan-regulated delivery of human keratinocyte growth factor-2 to the inflamed colon by the human anaerobic commensal bacterium Bacteroides ovatus . Gut 59 : 461 469.[CrossRef] [PubMed]
51. Mimee M,, Tucker AC,, Voigt CA,, Lu TK . 2015. Programming a human commensal bacterium, Bacteroides thetaiotaomicron, to sense and respond to stimuli in the murine gut microbiota. Cell Syst 1 : 62 71. (Erratum, https://doi.org/10.1016/J.CELS.2016.03.007.)[CrossRef] [PubMed]
52. Pickard JM,, Maurice CF,, Kinnebrew MA,, Abt MC,, Schenten D,, Golovkina TV,, Bogatyrev SR,, Ismagilov RF,, Pamer EG,, Turnbaugh PJ,, Chervonsky AV . 2014. Rapid fucosylation of intestinal epithelium sustains host-commensal symbiosis in sickness. Nature 514 : 638 641.[CrossRef] [PubMed]
53. Gao R,, Stock AM . 2009. Biological insights from structures of two-component proteins. Annu Rev Microbiol 63 : 133 154.[CrossRef] [PubMed]
54. Galperin MY . 2010. Diversity of structure and function of response regulator output domains. Curr Opin Microbiol 13 : 150 159.[CrossRef] [PubMed]
55. Daeffler KN-M,, Galley JD,, Sheth RU,, Ortiz-Velez LC,, Bibb CO,, Shroyer NF,, Britton RA,, Tabor JJ . 2017. Engineering bacterial thiosulfate and tetrathionate sensors for detecting gut inflammation. Mol Syst Biol 13 : 923.[CrossRef] [PubMed]
56. Kotula JW,, Kerns SJ,, Shaket LA,, Siraj L,, Collins JJ,, Way JC,, Silver PA . 2014. Programmable bacteria detect and record an environmental signal in the mammalian gut. Proc Natl Acad Sci USA 111 : 4838 4843.[CrossRef] [PubMed]
57. Winter SE,, Thiennimitr P,, Winter MG,, Butler BP,, Huseby DL,, Crawford RW,, Russell JM,, Bevins CL,, Adams LG,, Tsolis RM,, Roth JR,, Bäumler AJ . 2010. Gut inflammation provides a respiratory electron acceptor for Salmonella . Nature 467 : 426 429.[CrossRef] [PubMed]
58. Winter SE,, Lopez CA,, Bäumler AJ . 2013. The dynamics of gut-associated microbial communities during inflammation. EMBO Rep 14 : 319 327.[CrossRef] [PubMed]
59. Hensel M,, Hinsley AP,, Nikolaus T,, Sawers G,, Berks BC . 1999. The genetic basis of tetrathionate respiration in Salmonella typhimurium . Mol Microbiol 32 : 275 287.[CrossRef] [PubMed]
60. Riglar DT,, Giessen TW,, Baym M,, Kerns SJ,, Niederhuber MJ,, Bronson RT,, Kotula JW,, Gerber GK,, Way JC,, Silver PA . 2017. Engineered bacteria can function in the mammalian gut long-term as live diagnostics of inflammation. Nat Biotechnol 35 : 653 658.[CrossRef] [PubMed]
61. Siuti P,, Yazbek J,, Lu TK . 2013. Synthetic circuits integrating logic and memory in living cells. Nat Biotechnol 31 : 448 452.[CrossRef] [PubMed]
62. Yang L,, Nielsen AAK,, Fernandez-Rodriguez J,, McClune CJ,, Laub MT,, Lu TK,, Voigt CA . 2014. Permanent genetic memory with >1-byte capacity. Nat Methods 11 : 1261 1266.[CrossRef] [PubMed]
63. Duan F,, Curtis KL,, March JC . 2008. Secretion of insulinotropic proteins by commensal bacteria: rewiring the gut to treat diabetes. Appl Environ Microbiol 74 : 7437 7438.[CrossRef] [PubMed]
64. Castagliuolo I,, Beggiao E,, Brun P,, Barzon L,, Goussard S,, Manganelli R,, Grillot-Courvalin C,, Palù G . 2005. Engineered E. coli delivers therapeutic genes to the colonic mucosa. Gene Ther 12 : 1070 1078.[CrossRef] [PubMed]
65. Myhrvold C,, Kotula JW,, Hicks WM,, Conway NJ,, Silver PA . 2015. A distributed cell division counter reveals growth dynamics in the gut microbiota. Nat Commun 6 : 10039.[CrossRef] [PubMed]
66. Huttenhower C , , et al, Human Microbiome Project Consortium . 2012. Structure, function and diversity of the healthy human microbiome. Nature 486 : 207 214.[CrossRef] [PubMed]
67. Huibregtse IL,, Snoeck V,, de Creus A,, Braat H,, De Jong EC,, Van Deventer SJH,, Rottiers P . 2007. Induction of ovalbumin-specific tolerance by oral administration of Lactococcus lactis secreting ovalbumin. Gastroenterology 133 : 517 528.[CrossRef]
68. Huibregtse IL,, Marietta EV,, Rashtak S,, Koning F,, Rottiers P,, David CS,, van Deventer SJH,, Murray JA . 2009. Induction of antigen-specific tolerance by oral administration of Lactococcus lactis delivered immunodominant DQ8-restricted gliadin peptide in sensitized nonobese diabetic Abo Dq8 transgenic mice. J Immunol 183 : 2390 2396.[CrossRef] [PubMed]
69. Caluwaerts S,, Vandenbroucke K,, Steidler L,, Neirynck S,, Vanhoenacker P,, Corveleyn S,, Watkins B,, Sonis S,, Coulie B,, Rottiers P . 2010. AG013, a mouth rinse formulation of Lactococcus lactis secreting human trefoil factor 1, provides a safe and efficacious therapeutic tool for treating oral mucositis. Oral Oncol 46 : 564 570.[CrossRef] [PubMed]
70. Pontes DS,, de Azevedo MSP,, Chatel J-M,, Langella P,, Azevedo V,, Miyoshi A . 2011. Lactococcus lactis as a live vector: heterologous protein production and DNA delivery systems. Protein Expr Purif 79 : 165 175.[CrossRef] [PubMed]
71. Conrad K,, Roggenbuck D,, Laass MW . 2014. Diagnosis and classification of ulcerative colitis. Autoimmun Rev 13 : 463 466.[CrossRef] [PubMed]
72. Donaldson GP,, Lee SM,, Mazmanian SK . 2016. Gut biogeography of the bacterial microbiota. Nat Rev Microbiol 14 : 20 32.[CrossRef] [PubMed]
73. Schultz M,, Watzl S,, Oelschlaeger TA,, Rath HC,, Göttl C,, Lehn N,, Schölmerich J,, Linde HJ . 2005. Green fluorescent protein for detection of the probiotic microorganism Escherichia coli strain Nissle 1917 (EcN) in vivo . J Microbiol Methods 61 : 389 398.[CrossRef] [PubMed]
74. Spees AM,, Wangdi T,, Lopez CA,, Kingsbury DD,, Xavier MN,, Winter SE,, Tsolis RM,, Bäumler AJ . 2013. Streptomycin-induced inflammation enhances Escherichia coli gut colonization through nitrate respiration. MBio 4 : e00430-13.[CrossRef] [PubMed]
75. Kamada N,, Chen GY,, Inohara N,, Núñez G . 2013. Control of pathogens and pathobionts by the gut microbiota. Nat Immunol 14 : 685 690.[CrossRef] [PubMed]
76. Shetty RP,, Endy D,, Knight TF Jr . 2008. Engineering BioBrick vectors from BioBrick parts. J Biol Eng 2 : 5.[CrossRef] [PubMed]
77. St-Pierre F,, Cui L,, Priest DG,, Endy D,, Dodd IB,, Shearwin KE . 2013. One-step cloning and chromosomal integration of DNA. ACS Synth Biol 2 : 537 541.[CrossRef] [PubMed]
78. Kelly JR,, Rubin AJ,, Davis JH,, Ajo-Franklin CM,, Cumbers J,, Czar MJ,, de Mora K,, Glieberman AL,, Monie DD,, Endy D . 2009. Measuring the activity of BioBrick promoters using an in vivo reference standard. J Biol Eng 3 : 4.[CrossRef]
79. Mutalik VK,, Guimaraes JC,, Cambray G,, Lam C,, Christoffersen MJ,, Mai Q-A,, Tran AB,, Paull M,, Keasling JD,, Arkin AP,, Endy D . 2013. Precise and reliable gene expression via standard transcription and translation initiation elements. Nat Methods 10 : 354 360.[CrossRef] [PubMed]
80. Lutz R,, Bujard H . 1997. Independent and tight regulation of transcriptional units in Escherichia coli via the LacR/O, the TetR/O and AraC/I1-I2 regulatory elements. Nucleic Acids Res 25 : 1203 1210.[CrossRef] [PubMed]
81. Cox RS III,, Surette MG,, Elowitz MB . 2007. Programming gene expression with combinatorial promoters. Mol Syst Biol 3 : 145.[CrossRef] [PubMed]
82. Chen Y-J,, Liu P,, Nielsen AAK,, Brophy JAN,, Clancy K,, Peterson T,, Voigt CA . 2013. Characterization of 582 natural and synthetic terminators and quantification of their design constraints. Nat Methods 10 : 659 664.[CrossRef]
83. Cambray G,, Guimaraes JC,, Mutalik VK,, Lam C,, Mai Q-A,, Thimmaiah T,, Carothers JM,, Arkin AP,, Endy D . 2013. Measurement and modeling of intrinsic transcription terminators. Nucleic Acids Res 41 : 5139 5148.[CrossRef] [PubMed]
84. Salis HM,, Mirsky EA,, Voigt CA . 2009. Automated design of synthetic ribosome binding sites to control protein expression. Nat Biotechnol 27 : 946 950.[CrossRef] [PubMed]
85. Espah Borujeni A,, Channarasappa AS,, Salis HM . 2014. Translation rate is controlled by coupled trade-offs between site accessibility, selective RNA unfolding and sliding at upstream standby sites. Nucleic Acids Res 42 : 2646 2659.[CrossRef] [PubMed]
86. Farasat I,, Kushwaha M,, Collens J,, Easterbrook M,, Guido M,, Salis HM . 2014. Efficient search, mapping, and optimization of multi-protein genetic systems in diverse bacteria. Mol Syst Biol 10 : 731.[CrossRef] [PubMed]
87. Yoon SH,, Kim SK,, Kim JF . 2010. Secretory production of recombinant proteins in Escherichia coli . Recent Pat Biotechnol 4 : 23 29.[CrossRef] [PubMed]
88. Andersen JB,, Sternberg C,, Poulsen LK,, Bjørn SP,, Givskov M,, Molin S . 1998. New unstable variants of green fluorescent protein for studies of transient gene expression in bacteria. Appl Environ Microbiol 64 : 2240 2246.[PubMed]
89. Wang J,, Shoemaker NB,, Wang GR,, Salyers AA . 2000. Characterization of a Bacteroides mobilizable transposon, NBU2, which carries a functional lincomycin resistance gene. J Bacteriol 182 : 3559 3571.[CrossRef] [PubMed]
90. Bosma EF,, Forster J,, Nielsen AT . 2017. Lactobacilli and pediococci as versatile cell factories: evaluation of strain properties and genetic tools. Biotechnol Adv 35 : 419 442.[CrossRef] [PubMed]
91. Mierau I,, Kleerebezem M . 2005. 10 years of the nisin-controlled gene expression system (NICE) in Lactococcus lactis . Appl Microbiol Biotechnol 68 : 705 717.[PubMed]
92. Karlskås IL,, Maudal K,, Axelsson L,, Rud I,, Eijsink VGH,, Mathiesen G . 2014. Heterologous protein secretion in lactobacilli with modified pSIP vectors. PLoS One 9 : e91125.[CrossRef] [PubMed]
93. Heiss S,, Hörmann A,, Tauer C,, Sonnleitner M,, Egger E,, Grabherr R,, Heinl S . 2016. Evaluation of novel inducible promoter/repressor systems for recombinant protein expression in Lactobacillus plantarum . Microb Cell Fact 15 : 50.[CrossRef]
94. Rud I,, Jensen PR,, Naterstad K,, Axelsson L . 2006. A synthetic promoter library for constitutive gene expression in Lactobacillus plantarum . Microbiology 152 : 1011 1019.[CrossRef] [PubMed]
95. van Pijkeren JP,, Britton RA . 2014. Precision genome engineering in lactic acid bacteria. Microb Cell Fact 13( Suppl 1) : S10.[CrossRef] [PubMed]
96. Oh JH,, van Pijkeren JP . 2014. CRISPR-Cas9-assisted recombineering in Lactobacillus reuteri . Nucleic Acids Res 42 : e131.[CrossRef] [PubMed]
97. Chan LY,, Kosuri S,, Endy D . 2005. Refactoring bacteriophage T7. Mol Syst Biol 1 : 2005.0018.[CrossRef] [PubMed]
98. Temme K,, Zhao D,, Voigt CA . 2012. Refactoring the nitrogen fixation gene cluster from Klebsiella oxytoca . Proc Natl Acad Sci USA 109 : 7085 7090.[CrossRef] [PubMed]
99. Zhou H,, Vonk B,, Roubos JA,, Bovenberg RAL,, Voigt CA . 2015. Algorithmic co-optimization of genetic constructs and growth conditions: application to 6-ACA, a potential nylon-6 precursor. Nucleic Acids Res 43 : 10560 10570.
100. Burén S,, Young EM,, Sweeny EA,, Lopez-Torrejón G,, Veldhuizen M,, Voigt CA,, Rubio LM . 2017. Formation of nitrogenase NifDK tetramers in the mitochondria of Saccharomyces cerevisiae . ACS Synth Biol 6 : 1043 1055.[CrossRef] [PubMed]
101. Tabor JJ,, Levskaya A,, Voigt CA . 2011. Multichromatic control of gene expression in Escherichia coli . J Mol Biol 405 : 315 324.[CrossRef] [PubMed]
102. Ramakrishnan P,, Tabor JJ . 2016. Repurposing synechocystis PCC6803 UirS-UirR as a UV-violet/green photoreversible transcriptional regulatory tool in E. coli . ACS Synth Biol 5 : 733 740.[CrossRef] [PubMed]
103. Schmidl SR,, Sheth RU,, Wu A,, Tabor JJ . 2014. Refactoring and optimization of light-switchable Escherichia coli two-component systems. ACS Synth Biol 3 : 820 831.[CrossRef] [PubMed]
104. Stanton BC,, Nielsen AAK,, Tamsir A,, Clancy K,, Peterson T,, Voigt CA . 2014. Genomic mining of prokaryotic repressors for orthogonal logic gates. Nat Chem Biol 10 : 99 105.[CrossRef] [PubMed]
105. Stanton BC,, Siciliano V,, Ghodasara A,, Wroblewska L,, Clancy K,, Trefzer AC,, Chesnut JD,, Weiss R,, Voigt CA . 2014. Systematic transfer of prokaryotic sensors and circuits to mammalian cells. ACS Synth Biol 3 : 880 891.[CrossRef] [PubMed]
106. Beal J . 2015. Signal-to-noise ratio measures efficacy of biological computing devices and circuits. Front Bioeng Biotechnol 3 : 93.[CrossRef] [PubMed]
107. Shinar G,, Milo R,, Martínez MR,, Alon U . 2007. Input output robustness in simple bacterial signaling systems. Proc Natl Acad Sci USA 104 : 19931 19935.[CrossRef] [PubMed]
108. Rubens JR,, Selvaggio G,, Lu TK . 2016. Synthetic mixed-signal computation in living cells. Nat Commun 7 : 11658.[CrossRef] [PubMed]
109. Daniel R,, Rubens JR,, Sarpeshkar R,, Lu TK . 2013. Synthetic analog computation in living cells. Nature 497 : 619 623.[CrossRef] [PubMed]
110. Rockwell NC,, Martin SS,, Lagarias JC . 2012. Red/green cyanobacteriochromes: sensors of color and power. Biochemistry 51 : 9667 9677.[CrossRef] [PubMed]
111. Rockwell NC,, Martin SS,, Lagarias JC . 2016. Identification of cyanobacteriochromes detecting far-red light. Biochemistry 55 : 3907 3919.[CrossRef] [PubMed]
112. Hermsen R,, Erickson DW,, Hwa T . 2011. Speed, sensitivity, and bistability in auto-activating signaling circuits. PLOS Comput Biol 7 : e1002265.[CrossRef] [PubMed]
113. Lundberg JO,, Govoni M . 2004. Inorganic nitrate is a possible source for systemic generation of nitric oxide. Free Radic Biol Med 37 : 395 400.[CrossRef] [PubMed]
114. Winter SE,, Winter MG,, Xavier MN,, Thiennimitr P,, Poon V,, Keestra AM,, Laughlin RC,, Gomez G,, Wu J,, Lawhon SD,, Popova IE,, Parikh SJ,, Adams LG,, Tsolis RM,, Stewart VJ,, Bäumler AJ . 2013. Host-derived nitrate boosts growth of E. coli in the inflamed gut. Science 339 : 708 711.[PubMed]
115. Nielsen AAK,, Der BS,, Shin J,, Vaidyanathan P,, Paralanov V,, Strychalski EA,, Ross D,, Densmore D,, Voigt CA . 2016. Genetic circuit design automation. Science 352 : aac7341.[PubMed]
116. Lou C,, Stanton B,, Chen Y-J,, Munsky B,, Voigt CA . 2012. Ribozyme-based insulator parts buffer synthetic circuits from genetic context. Nat Biotechnol 30 : 1137 1142.[CrossRef] [PubMed]
117. Qi LS,, Larson MH,, Gilbert LA,, Doudna JA,, Weissman JS,, Arkin AP,, Lim WA . 2013. Repurposing CRISPR as an RNA-guided platform for sequence-specific control of gene expression. Cell 152 : 1173 1183.[CrossRef] [PubMed]
118. Nielsen AA,, Voigt CA . 2014. Multi-input CRISPR/Cas genetic circuits that interface host regulatory networks. Mol Syst Biol 10 : 763.[CrossRef] [PubMed]
119. Gander MW,, Vrana JD,, Voje WE,, Carothers JM,, Klavins E . 2017. Digital logic circuits in yeast with CRISPR-dCas9 NOR gates. Nat Commun 8 : 15459.[CrossRef] [PubMed]
120. Del Vecchio D . 2015. Modularity, context-dependence, and insulation in engineered biological circuits. Trends Biotechnol 33 : 111 119.[CrossRef] [PubMed]
121. Bradley RW,, Buck M,, Wang B . 2016. Recognizing and engineering digital-like logic gates and switches in gene regulatory networks. Curr Opin Microbiol 33 : 74 82.[CrossRef] [PubMed]
122. Lucks JB,, Qi L,, Mutalik VK,, Wang D,, Arkin AP . 2011. Versatile RNA-sensing transcriptional regulators for engineering genetic networks. Proc Natl Acad Sci USA 108 : 8617 8622.[CrossRef] [PubMed]
123. Chappell J,, Takahashi MK,, Lucks JB . 2015. Creating small transcription activating RNAs. Nat Chem Biol 11 : 214 220.[CrossRef] [PubMed]
124. Westbrook AM,, Lucks JB . 2017. Achieving large dynamic range control of gene expression with a compact RNA transcription-translation regulator. Nucleic Acids Res 45 : 5614 5624.[CrossRef] [PubMed]
125. Argos P , , et al . 1986. The integrase family of site-specific recombinases: regional similarities and global diversity. EMBO J 5 : 433 440.[PubMed]
126. Friedland AE,, Lu TK,, Wang X,, Shi D,, Church G,, Collins JJ . 2009. Synthetic gene networks that count. Science 324 : 1199 1202.[PubMed]
127. Bonnet J,, Yin P,, Ortiz ME,, Subsoontorn P,, Endy D . 2013. Amplifying genetic logic gates. Science 340 : 599 603.[PubMed]
128. Roquet N,, Soleimany AP,, Ferris AC,, Aaronson S,, Lu TK . 2016. Synthetic recombinase-based state machines in living cells. Science 353 : aad8559.[PubMed]
129. Bonnet J,, Subsoontorn P,, Endy D . 2012. Rewritable digital data storage in live cells via engineered control of recombination directionality. Proc Natl Acad Sci USA 109 : 8884 8889.[CrossRef] [PubMed]
130. Daniel C,, Poiret S,, Dennin V,, Boutillier D,, Pot B . 2013. Bioluminescence imaging study of spatial and temporal persistence of Lactobacillus plantarum and Lactococcus lactis in living mice. Appl Environ Microbiol 79 : 1086 1094.[CrossRef] [PubMed]
131. Alon U . 2006. An Introduction to Systems Biology: Design Principles of Biological Circuits. CRC Press, Boca Raton, FL.
132. Moon TS,, Lou C,, Tamsir A,, Stanton BC,, Voigt CA . 2012. Genetic programs constructed from layered logic gates in single cells. Nature 491 : 249 253.[CrossRef] [PubMed]
133. Prindle A,, Selimkhanov J,, Li H,, Razinkov I,, Tsimring LS,, Hasty J . 2014. Rapid and tunable post-translational coupling of genetic circuits. Nature 508 : 387 391.[CrossRef] [PubMed]
134. Cookson NA,, Mather WH,, Danino T,, Mondragón-Palomino O,, Williams RJ,, Tsimring LS,, Hasty J . 2011. Queueing up for enzymatic processing: correlated signaling through coupled degradation. Mol Syst Biol 7 : 561.[CrossRef]
135. Cameron DE,, Collins JJ . 2014. Tunable protein degradation in bacteria. Nat Biotechnol 32 : 1276 1281.[CrossRef] [PubMed]
136. Takahashi MK,, Chappell J,, Hayes CA,, Sun ZZ,, Kim J,, Singhal V,, Spring KJ,, Al-Khabouri S,, Fall CP,, Noireaux V,, Murray RM,, Lucks JB . 2015. Rapidly characterizing the fast dynamics of RNA genetic circuitry with cell-free transcription-translation (TX-TL) systems. ACS Synth Biol 4 : 503 515.[CrossRef] [PubMed]
137. Moser F,, Broers NJ,, Hartmans S,, Tamsir A,, Kerkman R,, Roubos JA,, Bovenberg R,, Voigt CA . 2012. Genetic circuit performance under conditions relevant for industrial bioreactors. ACS Synth Biol 1 : 555 564.[CrossRef] [PubMed]
138. Tropini C,, Earle KA,, Huang KC,, Sonnenburg JL . 2017. The gut microbiome: connecting spatial organization to function. Cell Host Microbe 21 : 433 442.[CrossRef] [PubMed]
139. Klumpp S,, Hwa T . 2014. Bacterial growth: global effects on gene expression, growth feedback and proteome partition. Curr Opin Biotechnol 28 : 96 102.[CrossRef] [PubMed]
140. Shopera T,, He L,, Oyetunde T,, Tang YJ,, Moon TS . 2017. Decoupling resource-coupled gene expression in living cells. ACS Synth Biol 6 : 1596 1604.[CrossRef] [PubMed]
141. Salvado B,, Vilaprinyo E,, Sorribas A,, Alves R . 2015. A survey of HK, HPt, and RR domains and their organization in two-component systems and phosphorelay proteins of organisms with fully sequenced genomes. PeerJ 3 : e1183.[CrossRef] [PubMed]
142. Long T,, Tu KC,, Wang Y,, Mehta P,, Ong NP,, Bassler BL,, Wingreen NS . 2009. Quantifying the integration of quorum-sensing signals with single-cell resolution. PLoS Biol 7 : e1000068.[CrossRef] [PubMed]
143. Walthers D,, Tran VK,, Kenney LJ . 2003. Interdomain linkers of homologous response regulators determine their mechanism of action. J Bacteriol 185 : 317 324.[CrossRef] [PubMed]
144. Nakajima M,, Ferri S,, Rögner M,, Sode K . 2016. Construction of a miniaturized chromatic acclimation sensor from cyanobacteria with reversed response to a light signal. Sci Rep 6 : 37595.[CrossRef] [PubMed]
145. Gardner TS,, Cantor CR,, Collins JJ . 2000. Construction of a genetic toggle switch in Escherichia coli . Nature 403 : 339 342.[CrossRef] [PubMed]
146. Kobayashi H,, Kaern M,, Araki M,, Chung K,, Gardner TS,, Cantor CR,, Collins JJ . 2004. Programmable cells: interfacing natural and engineered gene networks. Proc Natl Acad Sci USA 101 : 8414 8419.[CrossRef] [PubMed]
147. Ptashne M . 2004. A Genetic Switch Phage Lambda Revisited. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY.
148. Junjua M,, Galia W,, Gaci N,, Uriot O,, Genay M,, Bachmann H,, Kleerebezem M,, Dary A,, Roussel Y . 2014. Development of the recombinase-based in vivo expression technology in Streptococcus thermophilus and validation using the lactose operon promoter. J Appl Microbiol 116 : 620 631.[CrossRef]
149. Farzadfard F,, Lu TK . 2014. Genomically encoded analog memory with precise in vivo DNA writing in living cell populations. Science 346 : 1256272.[PubMed]
150. Horwitz JP,, Chua J,, Curby RJ,, Tomson AJ,, Darooge MA,, Fisher BE,, Mauricio J,, Klundt I . 1964. Substrates for cytochemical demonstration of enzyme activity. I. Some substituted 3-indolyl-β-D-glycopyranosides. J Med Chem 7 : 574 575.[CrossRef] [PubMed]
151. Corthier G,, Delorme C,, Ehrlich SD,, Renault P . 1998. Use of luciferase genes as biosensors to study bacterial physiology in the digestive tract. Appl Environ Microbiol 64 : 2721 2722.[PubMed]
152. Kosuri S,, Goodman DB,, Cambray G,, Mutalik VK,, Gao Y,, Arkin AP,, Endy D,, Church GM . 2013. Composability of regulatory sequences controlling transcription and translation in Escherichia coli . Proc Natl Acad Sci USA 110 : 14024 14029.[CrossRef] [PubMed]
153. Auchtung JM,, Robinson CD,, Farrell K,, Britton RA . 2016. Minibioreactor arrays (MBRAs) as a tool for studying C. difficile physiology in the presence of a complex community. Methods Mol Biol 1476 : 235 258.[CrossRef] [PubMed]
154. Chassaing B,, Aitken JD,, Malleshappa M,, Vijay-Kumar M . 2014. Dextran sulfate sodium (DSS)-induced colitis in mice. Curr Protoc Immunol 104 : Unit 15.25.[PubMed]
155. Bucci V,, Tzen B,, Li N,, Simmons M,, Tanoue T,, Bogart E,, Deng L,, Yeliseyev V,, Delaney ML,, Liu Q,, Olle B,, Stein RR,, Honda K,, Bry L,, Gerber GK . 2016. MDSINE: Microbial Dynamical Systems INference Engine for microbiome time-series analyses. Genome Biol 17 : 121.[CrossRef] [PubMed]
156. Farrar MD,, Whitehead TR,, Lan J,, Dilger P,, Thorpe R,, Holland KT,, Carding SR . 2005. Engineering of the gut commensal bacterium Bacteroides ovatus to produce and secrete biologically active murine interleukin-2 in response to xylan. J Appl Microbiol 98 : 1191 1197.[CrossRef] [PubMed]
157. Hamady ZZR,, Scott N,, Farrar MD,, Wadhwa M,, Dilger P,, Whitehead TR,, Thorpe R,, Holland KT,, Lodge JPA,, Carding SR . 2011. Treatment of colitis with a commensal gut bacterium engineered to secrete human TGF-β1 under the control of dietary xylan 1. Inflamm Bowel Dis 17 : 1925 1935.[CrossRef] [PubMed]
158. Ng DTW,, Sarkar CA . 2011. Nisin-inducible secretion of a biologically active single-chain insulin analog by Lactococcus lactis NZ9000. Biotechnol Bioeng 108 : 1987 1996.[CrossRef] [PubMed]

Tables

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TABLE 1

Examples of engineered gut bacteria

Citation: Landry B, Tabor J. 2018. Engineering Diagnostic and Therapeutic Gut Bacteria, p 333-361. In Britton R, Cani P (ed), Bugs as Drugs. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.BAD-0020-2017

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