Programming a Human Commensal Bacterium, Bacteroides thetaiotaomicron, to Sense and Respond to Stimuli in the Murine Gut Microbiota

Mimee, Mark; Tucker, Alex C.; Voigt, Christopher A.; Lu, Timothy K.

doi:10.1016/j.cels.2016.03.007

Cited by 64 publications

(80 citation statements)

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“…Metabolic modeling could, in particular, help explore the contributions of different carbohydrate degradation genes and processes to microbiome recovery 44 , especially for many anaerobic bacteria that are hard to culture or genetically modify 45 . Such investigations could also be informative in understanding the contributions of core and accessory genomes within a species and whether strain-level differences could cause variability in microbiome recovery across individuals.…”

Section: Discussionmentioning

confidence: 99%

Gut microbiome recovery after antibiotic usage is mediated by specific bacterial species

Nandi

Lee

Ghosh

et al. 2018

Preprint

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Dysbiosis in the gut microbiome due to antibiotic usage can persist for extended periods of time, impacting host health and increasing the risk for pathogen colonization. The specific factors associated with variability in gut microbiome recovery remain unknown.Using data from 4 different cohorts in 3 continents comprising >500 microbiome profiles from 117 subjects, we identified 20 bacterial species exhibiting robust association with gut microbiome recovery post antibiotic therapy. Functional and growth analysis showed that microbiome recovery is supported by enrichment in carbohydrate degradation and energy production capabilities. Association rule mining on 782 microbiome profiles from the MEDUSA database enabled reconstruction of the gut microbial 'food-web', identifying many recovery-associated bacteria (RABs) as primary colonizing species, with the ability to use both host and diet-derived energy sources, and to break down complex carbohydrates to support the growth of other bacteria. Experiments in a mouse model recapitulated the ability of RABs (Bacteroides thetaiotamicron and Bifidobacterium adolescentis) to promote microbiome recovery with synergistic effects, providing a two orders of magnitude boost to microbial abundance in early time-points and faster maturation of microbial diversity. The identification of specific microbial factors promoting microbiome recovery opens up opportunities for rationally fine-tuning pre-and probiotic formulations that prevent pathogen colonization and promote gut health.

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Section: Discussionmentioning

confidence: 99%

Gut microbiome recovery after antibiotic usage is mediated by specific bacterial species

Nandi

Lee

Ghosh

et al. 2018

Preprint

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“…These insights will continue to deepen our understanding of microbial enzyme systems in human and animal nutrition and health, as well as their involvement in driving fundamental environmental processes such as global carbon cycling. Successively, these basic research initiatives have lasting impacts on a variety of industries, serving to inform a wave of novel technologies with applications in industrial enzyme discovery (140,141) and engineered microbial therapeutics (142)(143)(144)(145)(146)(147)(148).…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Polysaccharide Utilization Loci: Fueling Microbial Communities

et al. 2017

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The complex carbohydrates of terrestrial and marine biomass represent a rich nutrient source for free-living and mutualistic microbes alike. The enzymatic saccharification of these diverse substrates is of critical importance for fueling a variety of complex microbial communities, including marine, soil, ruminant, and monogastric microbiota. Consequently, highly specific carbohydrate-active enzymes, recognition proteins, and transporters are enriched in the genomes of certain species and are of critical importance in competitive environments. In Bacteroidetes bacteria, these systems are organized as polysaccharide utilization loci (PULs), which are strictly regulated, colocalized gene clusters that encode enzyme and protein ensembles required for the saccharification of complex carbohydrates. This review provides historical perspectives and summarizes key findings in the study of these systems, highlighting a critical shift from sequence-based PUL discovery to systems-based analyses combining reverse genetics, biochemistry, enzymology, and structural biology to precisely illuminate the molecular mechanisms underpinning PUL function. The ecological implications of dynamic PUL deployment by key species in the human gastrointestinal tract are explored, as well as the wider distribution of these systems in other gut, terrestrial, and marine environments.

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“…This engineered strain can be administered as spores that selectively germinate in the colon to bypass key challenges associated with oral delivery, including survival upon exposure to stomach acids, bile salts, and digestive enzymes. Other groups have focused on organisms that are able to colonize the gastrointestinal tract, including Bacteroides spp 43 . This genus of bacteria is known for harboring a diverse repertoire of enzymes for the breakdown of host-and diet-derived carbohydrates [44][45][46][47] .…”

Section: Design Of Engineered Therapeutic Strains For the Human Gutmentioning

confidence: 99%

Developing a new class of engineered live bacterial therapeutics to treat human diseases

et al. 2020

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A complex interplay of metabolic and immunological mechanisms underlies many diseases that represent a substantial unmet medical need. There is an increasing appreciation of the role microbes play in human health and disease, and evidence is accumulating that a new class of live biotherapeutics comprised of engineered microbes could address specific mechanisms of disease. Using the tools of synthetic biology, nonpathogenic bacteria can be designed to sense and respond to environmental signals in order to consume harmful compounds and deliver therapeutic effectors. In this perspective, we describe considerations for the design and development of engineered live biotherapeutics to achieve regulatory and patient acceptance. Regulatory considerations for live biotherapeutic products Live biotherapeutic products (LBPs) are defined as live organisms designed and developed to treat, cure, or prevent a disease or condition in humans 10. Notably, LBPs exclude vaccines, filterable viruses, oncolytic viruses, and organisms used as vectors for transferring genes into the host. LBPs are distinguished from probiotic supplements on the basis of their labeling claims, as

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Programming a Human Commensal Bacterium, Bacteroides thetaiotaomicron, to Sense and Respond to Stimuli in the Murine Gut Microbiota

Cited by 64 publications

References 0 publications

Gut microbiome recovery after antibiotic usage is mediated by specific bacterial species

Gut microbiome recovery after antibiotic usage is mediated by specific bacterial species

Polysaccharide Utilization Loci: Fueling Microbial Communities

Developing a new class of engineered live bacterial therapeutics to treat human diseases

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