The Chemistry of Microbiomes Proceedings of a Seminar Series (2017) / Chapter Skim
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10 Engineering the Microbiome for Human Health Applications - Timothy K. Lu, Mark Mimee, Robert J. Citorik, and Karen Pepper
10 Engineering the Microbiome for Human Health Applications - Timothy K. Lu, Mark Mimee, Robert J. Citorik, and Karen Pepper
Pages 65-76
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From page 65... ...
Beyond individual bacteria, increasing interest has been placed on the study of microbial consortia, interactions between host and microbe, the role of viruses, and the modulation of these processes for therapeutic applications. Despite significant progress in recombinant probiotics, therapeutic microbial consortia, and targeted antimicrobials, translation into clinical applications still faces numerous challenges and unknowns.
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From page 66... ...
Below, we discuss examples of microbes being used, either individually or as consortia, to treat disease. A major challenge in creating microbiotabased therapeutics is the identification and customization of bacterial communities to address complex human diseases, despite the diversity of human-associated microbiota.
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From page 67... ...
-- protected against colitis in mouse models of IBD. In addition to cytokines, the protease inhibitor Elafin, when produced by lactic acid bacteria, restored the proteolytic homeostasis disrupted in mouse colitis models and protected against inflammation (Motta et al., 2012)
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From page 68... ...
Antibiotics, a key example of subtractive therapies, often have the undesirable effect of killing a broad set of microbes outside of the desired target. This can result in severe side effects, such as increased susceptibility to bacterial pathogens, including Clostridium difficile.
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From page 69... ...
Many advances in microbiome therapeutics have been validated using rodent models, but the ability to generalize these findings to humans has yet to be comprehensively tested. In addition, the development of fully autonomous cellular therapies requires biosensors that are clinically relevant biosensors and genetic circuits that are robust.
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From page 70... ...
The localized production of medicines could also be set in motion by these sensors, as needed to treat disease on demand. Relevance, Robustness, and Stability of Genetic Circuits The genetic circuits needed to implement sense-and-respond bacterial therapeutics are usually prototyped in optimal in vitro growth conditions, but once inside the body, they may behave differently.
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From page 71... ...
Current additive and subtractive strategies to manipulate the human microbiome include engineering bacteria to produce therapeutic molecules, constituting natural or artificial consortia to modulate the host, and applying selective antimicrobials. Challenges in creating microbiome therapeutics include engineering microbial therapies that are well adapted to specific environments in the body or able to achieve stable colonization, discovering or constructing clinically relevant biosensors, engineering robust and effective synthetic gene circuits that can function in vivo, and establishing regulatory frameworks to account for safety and biocontainment concerns in addition to therapeutic efficacy.
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Proc Natl Acad Sci USA 107(25)
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Proc Natl Acad Sci USA 104(27)
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Proc Natl Acad Sci USA 110(50)
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Proc Natl Acad Sci USA 105(43)
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