June 2024
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15 Reads
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5 Citations
Cell Host & Microbe
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June 2024
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15 Reads
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5 Citations
Cell Host & Microbe
February 2024
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75 Reads
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24 Citations
Cell
October 2023
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75 Reads
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7 Citations
Cell Reports
The increasing prevalence of food allergies has been linked to reduced commensal microbial diversity. In this article, we describe two features of allergy-protective Clostridia that contribute to their beneficial effects. Some Clostridial taxa bear flagella (a ligand for TLR5) and produce indole (a ligand for the aryl hydrocarbon receptor [AhR]). Lysates and flagella from a Clostridia consortium induced interleukin-22 (IL-22) secretion from ileal explants. IL-22 production is abrogated in explants from mice in which TLR5 or MyD88 signaling is deficient either globally or conditionally in CD11c⁺ antigen-presenting cells. AhR signaling in RORγt⁺ cells is necessary for the induction of IL-22. Mice deficient in AhR in RORγt⁺ cells exhibit increased intestinal permeability and are more susceptible to an anaphylactic response to food. Our findings implicate TLR5 and AhR signaling in a molecular mechanism by which commensal Clostridia protect against allergic responses to food.
June 2023
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86 Reads
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21 Citations
Techniques by which to genetically manipulate members of the microbiota enable both the evaluation of host-microbe interactions and an avenue by which to monitor and modulate human physiology. Genetic engineering applications have traditionally focused on model gut residents, such as Escherichia coli and lactic acid bacteria. However, emerging efforts by which to develop synthetic biology toolsets for "nonmodel" resident gut microbes could provide an improved foundation for microbiome engineering. As genome engineering tools come online, so too have novel applications for engineered gut microbes. Engineered resident gut bacteria facilitate investigations of the roles of microbes and their metabolites on host health and allow for potential live microbial biotherapeutics. Due to the rapid pace of discovery in this burgeoning field, this minireview highlights advancements in the genetic engineering of all resident gut microbes.
May 2023
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6 Reads
The Journal of Immunology
Perturbations to the commensal gut microbiota are associated with the increasing prevalence of food allergies. Our lab has reported that colonization of germ-free mice with feces from healthy, but not cow’s milk allergic, infants protects against anaphylaxis to a cow’s milk allergen. Protection was associated with higher levels of the secondary bile acid (SBA) isodeoxycholic acid (isoDCA) in the feces of healthy-colonized mice. IsoDCA has been reported to induce regulatory T cells (Tregs) which suppress inflammation. We hypothesize that isoDCA-driven induction of mucosal Tregs promotes non-responsiveness and protects against food allergy. To study this, we identified two Clostridiaspecies, Peptacetobacter hiranonisand Ruminococcus gnavus, that together produce isoDCA from taurocholic acid (TCA), an abundant host bile acid. Using a Group II intron-based system, we engineered R. gnavus Δrumgna_00694, a functional knock-out of a 3β-hydroxysteroid dehydrogenase required to produce isoDCA. In our system, P. hiranonisconverts TCA to deoxycholic acid (DCA) and R. gnavusWT, but not Δrumgna_00694, converts DCA to isoDCA. Ongoing experiments will compare isoDCA-dependent Treg induction in gut-associated lymphoid tissues of mice co-colonized with P. hiranonisand R. gnavusWT or Δrumgna_00694. Once optimized, this system can be used in our allergic sensitization model to investigate the role of SBA in protection against food allergy and maintenance of intestinal homeostasis.
May 2023
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19 Reads
The Journal of Immunology
It is well known that accumulated changes in microbiota composition over several decades have contributed to an increase in non-communicable chronic diseases. While much effort has been devoted toward achieving a consensus on the microbes, and their products, driving this increase, inconsistent results suggest more research is required to understand the disparity in observed outcomes. Previous work from our lab identified a consortium of commensal Clostridia that alone was sufficient to preserve intestinal barrier integrity and prevent sensitization to food allergens in mice by inducing IL-22. Further investigation determined that members of this consortium display flagella. When isolated, these commensal flagella (Fla-C) exhibited TLR5-dependent IL-22 induction at a magnitude comparable to flagellin from SalmonellaTyphimurium (Fla-ST). However, mice treated with Fla-C maintained intestinal barrier function significantly more effectively than Fla-ST or negative control PBS-treated mice as measured by a serum FITC-dextran permeability assay. This was accompanied by a striking difference in the expression of Reg3 antimicrobial peptides and IL-17; all of which were significantly increased by treatment with Fla-ST when compared to Fla-C. Sequencing of Clostridia consortium-derived flagellated isolates revealed flagellin genes with unique hypervariable regions when compared to fliC from S. Typhimurium. These results highlight the distinct impacts of commensal and pathogenic flagella and suggest an important role for flagellated commensal bacteria in the maintenance of intestinal epithelial barrier function. Supported by a grant from National Institutes of Health (RO1 AI06302)
March 2023
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273 Reads
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2 Citations
Plasmids are extrachromosomal genetic elements that often encode fitness enhancing features. However, many bacteria carry 'cryptic' plasmids that do not confer clear beneficial functions. We identified one such cryptic plasmid, pBI143, which is ubiquitous across industrialized gut microbiomes, and is 14 times as numerous as crAssphage, currently established as the most abundant genetic element in the human gut. The majority of mutations in pBI143 accumulate in specific positions across thousands of metagenomes, indicating strong purifying selection. pBI143 is monoclonal in most individuals, likely due to the priority effect of the version first acquired, often from one's mother. pBI143 can transfer between Bacteroidales and although it does not appear to impact bacterial host fitness in vivo, can transiently acquire additional genetic content. We identified important practical applications of pBI143, including its use in identifying human fecal contamination and its potential as an inexpensive alternative for detecting human colonic inflammatory states.
October 2022
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13 Reads
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2 Citations
Cell Host & Microbe
Bacteriophage therapy is a promising strategy to treat bacterial infections and sculpt the microbiome. In a recent Cell paper, Federici et al. (2022) demonstrate that a Klebsiella pneumoniae phage cocktail can specifically remove pathobionts from the mouse gut. Safety and persistence of therapeutic phages were shown in a Phase 1 trial.
February 2022
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190 Reads
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10 Citations
Transient molecules in the gastrointestinal (GI) tract, such as nitric oxide and hydrogen sulfide, are key signals and mediators of inflammatory bowel disease (IBD). Because these molecules are extremely short-lived in the body, they are difficult to detect. To track these reactive molecules in the GI tract, we have developed a miniaturized device that integrates genetically-engineered probiotic biosensors with a custom-designed photodetector and readout chip. Leveraging the molecular specificity of living sensors, we genetically encoded bacteria to respond to IBD-associated molecules by luminescing. Low-power electronic readout circuits (nanowatt power) integrated into the device convert the light from just 1 μL of bacterial culture into a wireless signal. We demonstrate biosensor monitoring in the GI tract of small and large animal models and integration of all components into a sub-1.4 cm3 ingestible form factor capable of supporting wireless communication. The wireless detection of short-lived, disease-associated molecules could support earlier diagnosis of disease than is currently possible, more accurate tracking of disease progression, and more timely communication between patient and their care team supporting remote personalized care.
June 2021
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18 Reads
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5 Citations
Nature Medicine
A yeast strain engineered to regulate levels of pathogenic metabolites in the gut provides protection against colitis in mouse models.
... In a USA study recruiting 141 children aged 3-16 months, children with egg allergy (n = 66) harbored abundant genera from the Lachnospiraceae and Streptococcaceae families, while controls without egg allergy (n = 75) harbored abundant Leuconostocaceae [117]. An animal study previously showed that Clostridia-containing microbiota protected against food allergen sensitization [116], and the anaerobe Anaerostipes caccae from the feces of a healthy infant was found to prevent food allergy in mice [121]. The association of non-food allergies with the gut microbiota was also observed [122]. ...
June 2024
Cell Host & Microbe
... Plasmids are extrachromosomal self-replicating genetic elements ubiquitous in bacteria. For example, a recent study has shown that a specific plasmid, namely the pBI143 plasmid, is one of the most prevalent and abundant genetic elements found in the gut microbiomes of industrialized human populations worldwide 1 . Moreover, studies involving a few thousand strains have shown that there are, on average, two to three different plasmids per strain of Escherichia coli, Klebsiella and Salmonella, and almost one plasmid per strain of Staphylococcus aureus 2,3 . ...
February 2024
Cell
... Similarly, activation of AhR signaling by indoles improved barrier function and prevented adverse reactions to food in mice. 118 Microbial factors can also affect intestinal barrier function and have been proposed as cofactors in CeD pathogenesis. Using an ex vivo approach, early studies found that E coli and Shigella led to tight junction alterations and increased translocation of gliadin peptides to the lamina propria. ...
October 2023
Cell Reports
... Multi-strain microbial consortia enable division of labor, which reduces the metabolic load on individual organisms and allows for the entire consortium to behave more efficiently (2)(3)(4). This benefit has led to advances in microbiome engineering (5)(6)(7)(8), bioremediation (9)(10)(11)(12)(13)(14), and bioproduction (2,3,(15)(16)(17)(18), making consortia engineering one of the fastest growing fields in synthetic biology. Most natural microbial communities are made of many species working together. ...
June 2023
... This suggests a possible mechanism for antibiotic-induced PCN increase in TPCN events, wherein plasmid dimerization generates tandem repeats of plasmids that can further amplify in a RecA-dependent manner 32 . Cryptic plasmids are abundant 33,34 , and the presence of Tn-encoding resistance genes on cryptic plasmids, or their anecdotal transposition on such plasmids, have been reported 35,36 . Our analysis identified that in 4 out of 56 bloodstream infections E. coli isolates, increased TZP resistance due to PCN events was associated with cryptic plasmids carrying a βlactamase in the parental susceptible isolate. ...
March 2023
... For the purposes of this review, "phage therapy" refers to the administration of phage viruses to selectively reduce populations of pathobionts known to promote MADs. Preclinical studies have demonstrated successful resolution of dysbiotic microbiomes and improvements in phenotype in alcoholic liver disease [95], intestinal inflammation and IBD [74,96], colorectal cancer, and others [74,[97][98][99][100]. ...
October 2022
Cell Host & Microbe
... Recent advances in flexible electronics, chemical sensors, and smart packaging have contributed to the emergence of ingestible capsule technologies capable of monitoring gaseous molecules in the gut. [21][22][23][24][25] In general, ingestible gas sensors must operate in both aerobic and anaerobic environments, withstand moisture and caustic conditions, and minimize interference from other electroactive molecules. [26] Kalantar-zadeh et al. and others have demonstrated wireless ingestible capsules equipped with metaloxide field effect transistor (FET) sensors capable of monitoring oxygen (O 2 ), H 2 , and CO 2 levels in the GI tract. ...
February 2022
... In recent years, engineered yeasts developed through biosynthetic techniques have also found novel applications in the regulation of purinergic signalling mediated by the gut microbiota [95,96]. Based on an inflammatory therapeutic strategy that regulates eATPadenosine homeostasis, Benjamin M. et al. developed a novel engineered yeast; this engineered yeast can secrete apyrase in response to the metabolite eATP produced in the inflamed gut, thereby depleting proinflammatory eATP and promoting the production of immunosuppressive adenosine [43]. ...
June 2021
Nature Medicine
... Recently engineered WCBs have been optimized by applying new synthetic biology tools to sense molecules within a clinically relevant range of concentrations (McNerney, et al., 2019a;Chang et al., 2021;Courbet et al., 2015;Watstein & Styczynski, 2018). Several labs also demonstrated the possibility of using bacteria for biomarker detection in vivo (Daeffler et al., 2017;Gurbatri et al., 2024;Inda et al., 2019;Riglar et al., 2017). ...
July 2019
Journal of Allergy and Clinical Immunology