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Woodworth, M. H.

Publications and source records attributed to Woodworth, M. H..

5 recordsLinked to original sources
bioRxiv2026

Anti-psychotic therapeutics modify gut microbial metabolism and modulate susceptibility to gastrointestinal infection in mice

Antipsychotic medications are widely prescribed and associated with increased infection risk, but underlying mechanisms remain unclear. We examined if antipsychotic-induced microbiome and metabolome alterations impair colonization resistance. Using a murine model, we evaluated haloperidol, olanzapine, risperidone, and quetiapine through longitudinal microbiome profiling, untargeted metabolomic fingerprinting, behavioral testing, and enteric infection challenge. Antipsychotic exposure induced persistent behavioral changes and increased susceptibility to Citrobacter rodentium, with quetiapine and olanzapine producing the greatest weight loss. Microbiome sequencing revealed treatment-specific shifts in beta diversity without consistent alpha diversity changes, while untargeted metabolomic analysis demonstrated robust, drug-specific metabolic reprogramming, particularly in lipid and sterol pathways. Although microbial compositional changes did not fully account for functional outcomes, their integration with metabolomics data revealed disrupted bacterial taxa-metabolite networks and loss of homeostatic metabolic modules. These results provide a potential mechanistic link between the disruptive effects of antipsychotics on the microbiome and impaired colonization resistance.

microbiology↗
bioRxiv2026

Bacteriophage Heteroresistance as a Cause of Treatment Failure in Urinary Tract Infections

With the rise of antimicrobial resistance, urinary tract infections (UTIs) have become increasingly more difficult to treat, prompting renewed interest in bacteriophage (phage) therapy as an alternative or adjunct to antibiotics. UTIs are an attractive target for phage therapy because they generate a high density of actively replicating bacteria that supports phage propagation, and because the urinary tract is readily accessible for administration and monitoring. Yet studies of phage therapy for UTIs report mixed outcomes, including failures to meet clinical and microbiological endpoints. Here we follow the population dynamics of a clinical Escherichia coli UTI strain and two phages, HP3 and ES19, to which the strain appears susceptible by standard testing. Despite this apparent susceptibilty, both phages fail to suppress the strain, with resistance emerging almost immediately. Using the measured mutation rate, our mathematical model shows that traditional resistance cannot account for these dynamics. We instead demonstrate, including by a phage-specific population analysis profile assay we developed, that heteroresistance drives this rapid failure, offering a plausible explanation for treatment failures in UTI phage therapy.

evolutionary biology↗
bioRxiv2025

A theoretical exploration of protocols for treating prosthetic joint infections with combinations of antibiotics and bacteriophage (phage)

With the increase in the placement of prosthetic joints and other hardware in the body has come an increase in associated infections. These infections are particularly difficult to treat due to the underlying bacteria generating matrices which resist clearance by immune system effectors or antibiotics. These matrices, biofilms, have two primary ways of being eradicated, either by physical removal by debridement or by killing the underlying bacteria. The viruses which kill bacteria, bacteriophage, are readily capable of entering into biofilms and eradicating the bacteria therein. Therefore, bacteriophage have therapeutic potential as a supplement to antibiotics for the treatment of prosthetic joint infections. In this investigation, we generate a mathematical-computer simulation model to explore the contributions of the innate immune system with antibiotics, bacteriophage, and the joint action thereof in the control of biofilm-associated infections. Our results question the proposition that bacteriophage are an effective addition in the treatment of prosthetic joint infections.

microbiology↗
bioRxiv2023

Enteric Populations of Escherichia coli are Likely to be Resistant to Phages Due to O Antigen Production

Metagenomic data provide evidence that bacteriophage (phage) abound in the enteric microbiomes of humans. However, the contribution of these viruses in shaping the bacterial composition of the gut microbiome and how these phages are maintained remains unclear. We performed experiments with 751 combinations of 54 Escherichia coli and 9 phage isolates from four fecal microbiota transplantation (FMT) doses and 5 laboratory phages as samples of non-dysbiotic human enteric microbiota. We also developed a mathematical model of the population and evolutionary dynamics of bacteria and phage. Our experiments predict that as a consequence of the production of the O-antigen, most of the E. coli in the human enteric microbiome will be resistant to infections with the array of co-occurring phages. Our modeling suggests that phages are maintained in these enteric communities due to the high rates of transition between the resistant and sensitive states resulting from O-antigen production or spontaneous O-antigen loss, respectively. Based on our observations and predictions from this theory, we postulate that the phage found in the human gut are likely to play little role shaping the strain composition of E. coli of healthy individuals. Although we only investigated E. coli, the mechanism of resistance described here is shared among most of the Gram-negative bacteria. Extended AbstractEvidence is provided that as a consequence of O-antigen-mediated resistance, the genetically diverse array of bacteriophage in the gut microbiome of humans play little or no role in determining the densities and distribution of genetically diverse strain E. coli in this habitat. Our mathematical model predicts, and our experiments support the hypothesis that the phage present in the gut microbiome are maintained by replication on the minority of sensitive bacteria generated by the leakiness of O-antigen-mediated resistance.

microbiology↗