Biology subjects

Hutchinson, N.

Publications and source records attributed to Hutchinson, N..

3 recordsLinked to original sources

bioRxiv2025

Programmable conjugative CRISPR interference targeting genotoxin in the gut

Among microbially derived metabolites that influence host disease, colibactin garners increasing attention for its roles in the rising incidence of early-onset colorectal cancer. Produced by pks Escherichia coli, colibactin is a potent genotoxin, yet no approved therapeutics directly suppress it. Here, we engineered a self-transmissible conjugative plasmid to deliver CRISPR interference (CRISPRi) into multiple pks strains. This system silences transcription of colibactin biosynthetic genes and abolishes pks E. coli genotoxicity without the resistance mutations associated with wild-type Cas9-mediated bacterial inhibition. In mice, conjugation-mediated CRISPRi reduces DNA damage and pks E. coli colonization while preserving commensal diversity. Importantly, the system also lowers tumorigenesis driven by pks E. coli and outperforms a pharmacologic inhibitor in a mouse colorectal cancer model. Finally, we extend this platform to silence a second pathogenic metabolite, establishing a translational strategy to neutralize diverse microbial metabolites and expanding the toolkit for programmable live biotherapeutics in the gut.

bioengineering↗

bioRxiv2024

The global fish and invertebrate abundance value of mangroves

Mangroves are a critical coastal habitat that provides a suite of ecosystem services and supports livelihoods. We undertake the first global analysis to estimate density and abundance of 37 commercially important fish and invertebrates that are known to extensively use mangroves. Geomorphic mangrove type, sea surface salinity and temperature, and length of mangrove forest edge were important in predicting the density of commercial fish and invertebrates, with deltaic systems supporting the highest densities. The model predicted high densities throughout parts of southeast Asia, the northern coast of South America, the Red Sea, and the Caribbean and Central America. Application of our model onto the global mangrove extent, estimates that mangroves support the annual abundance of nearly 800 billion young-of-year fish and invertebrates contained in our model. Our results confirm the critical role of mangroves globally in supporting fish and fisheries, and further builds the case for their conservation and restoration.

ecology↗

bioRxiv2023

Engineered Bacillus subtilis as oral probiotics to target circulating lactic acid

Elevated lactate concentrations are implicated in various acute and chronic diseases such as sepsis and mitochondrial dysfunction, respectively. Conversely, ineffective lactate clearance is associated with poor clinical prognoses and high mortality in these diseases. While several groups have proposed using small molecule inhibitors and enzyme replacement to reduce circulating lactate, there are few practical and effective ways to manage this condition. Recent evidence suggests that lactate is exchanged between systemic circulation and the gut, allowing bidirectional modulation between the gut microbiota and peripheral tissues. Inspired by these findings, this work seeks to engineer spore-forming probiotic B. subtilis strains to enable intestinal delivery of lactate oxidase as a therapeutic enzyme. After strain optimization, we showed that oral administration of engineered B. subtilis spores to the gut of mice reduced elevations in blood lactate in two different mouse models involving exogenous challenge or pharmacologic perturbation without disrupting gut microbiota composition, liver function, or immune homeostasis. Taken together, through the oral delivery of engineered probiotic spores to the gastrointestinal tract, our proof-of-concept study offers a practical strategy to aid in the management of disease states with elevated blood lactate and provides a new approach to knocking down circulating metabolites to help understand their roles in host physiological and pathological processes. Significance StatementThis study pioneers the use of engineered Bacillus subtilis spores as an oral probiotic therapy to enhance the clearance of elevated blood lactate, a condition linked to severe health issues like sepsis and metabolic disorders. By genetically modifying these spores to deliver therapeutic enzymes directly to the gut, we demonstrated a practical, effective method to modulate systemic lactate levels. This approach leverages the natural exchange between the gut microbiota and systemic circulation, offering a new strategy for managing diseases associated with lactate dysregulation. The safety and efficacy of this method were validated in mouse models, providing a foundation for future clinical applications.

bioengineering↗