@article{reed_fletcher_huang_thanissery_rivera_parsons_stewart_kountz_shen_balskus_et al._2022, title={The Stickland Reaction Precursor trans-4-Hydroxy-l-Proline Differentially Impacts the Metabolism of Clostridioides difficile and Commensal Clostridia}, volume={7}, ISSN={["2379-5042"]}, DOI={10.1128/msphere.00926-21}, abstractNote={
            Proline is an essential environmental amino acid that
            C. difficile
            uses to support growth and cause significant disease. A posttranslationally modified form, hydroxyproline, is highly abundant in collagen, which is degraded by host proteases in response to
            C. difficile
            toxin activity.
          }, number={2}, journal={MSPHERE}, author={Reed, A. D. and Fletcher, J. R. and Huang, Y. Y. and Thanissery, R. and Rivera, A. J. and Parsons, R. J. and Stewart, A. K. and Kountz, D. J. and Shen, A. and Balskus, E. P. and et al.}, year={2022}, month={Apr} }
 @article{fletcher_pike_parsons_rivera_foley_mclaren_montgomery_theriot_2021, title={Clostridioides difficile exploits toxin-mediated inflammation to alter the host nutritional landscape and exclude competitors from the gut microbiota}, volume={12}, ISSN={["2041-1723"]}, url={https://doi.org/10.1038/s41467-020-20746-4}, DOI={10.1038/s41467-020-20746-4}, abstractNote={AbstractClostridioides difficile is a bacterial pathogen that causes a range of clinical disease from mild to moderate diarrhea, pseudomembranous colitis, and toxic megacolon. Typically, C. difficile infections (CDIs) occur after antibiotic treatment, which alters the gut microbiota, decreasing colonization resistance against C. difficile. Disease is mediated by two large toxins and the expression of their genes is induced upon nutrient depletion via the alternative sigma factor TcdR. Here, we use tcdR mutants in two strains of C. difficile and omics to investigate how toxin-induced inflammation alters C. difficile metabolism, tissue gene expression and the gut microbiota, and to determine how inflammation by the host may be beneficial to C. difficile. We show that C. difficile metabolism is significantly different in the face of inflammation, with changes in many carbohydrate and amino acid uptake and utilization pathways. Host gene expression signatures suggest that degradation of collagen and other components of the extracellular matrix by matrix metalloproteinases is a major source of peptides and amino acids that supports C. difficile growth in vivo. Lastly, the inflammation induced by C. difficile toxin activity alters the gut microbiota, excluding members from the genus Bacteroides that are able to utilize the same essential nutrients released from collagen degradation.}, number={1}, journal={NATURE COMMUNICATIONS}, author={Fletcher, Joshua R. and Pike, Colleen M. and Parsons, Ruth J. and Rivera, Alissa J. and Foley, Matthew H. and McLaren, Michael R. and Montgomery, Stephanie A. and Theriot, Casey M.}, year={2021}, month={Jan} }
 @article{theriot_fletcher_2019, title={Human fecal metabolomic profiling could inform Clostridioides difficile infection diagnosis and treatment}, volume={129}, ISSN={["1558-8238"]}, DOI={10.1172/JCI130008}, abstractNote={Clostridioides difficile is a significant public health threat, and diagnosis of this infection is challenging due to a lack of sensitivity in current diagnostic testing. In this issue of the JCI, Robinson et al. use a logistic regression model based on the fecal metabolome that is able to distinguish between patients with non-C. difficile diarrhea and C. difficile infection, and to some degree, patients who are asymptomatically colonized with C. difficile. The authors construct a metabolic definition of human C. difficile infection, which could improve diagnostic accuracy and aid in the development of targeted therapeutics against this pathogen.}, number={9}, journal={JOURNAL OF CLINICAL INVESTIGATION}, author={Theriot, Casey M. and Fletcher, Joshua R.}, year={2019}, month={Sep}, pages={3539–3541} }
 @article{fletcher_erwin_lanzas_theriot_2018, title={Shifts in the Gut Metabolome and Clostridium difficile Transcriptome throughout Colonization and Infection in a Mouse Model}, volume={3}, ISSN={["2379-5042"]}, url={http://europepmc.org/articles/PMC5874438}, DOI={10.1128/msphere.00089-18}, abstractNote={
            Clostridium difficile
            is a bacterial pathogen of global significance that is a major cause of antibiotic-associated diarrhea. Antibiotics deplete the indigenous gut microbiota and change the metabolic environment in the gut to one favoring
            C. difficile
            growth. Here we used metabolomics and transcriptomics to define the gut environment after antibiotics and during the initial stages of
            C. difficile
            colonization and infection. We show that amino acids, in particular, proline and branched-chain amino acids, and carbohydrates decrease in abundance over time and that
            C. difficile
            gene expression is consistent with their utilization by the bacterium
            in vivo
            . We employed an integrated approach to analyze the metabolome and transcriptome to identify associations between metabolites and transcripts. This highlighted the importance of key nutrients in the early stages of colonization, and the data provide a rationale for the development of therapies based on the use of bacteria that specifically compete for nutrients that are essential for
            C. difficile
            colonization and disease.
          }, number={2}, journal={MSPHERE}, author={Fletcher, Joshua R. and Erwin, Samantha and Lanzas, Cristina and Theriot, Casey M.}, year={2018} }
 @article{kinkead_whitmore_mccracken_fletcher_ketelsen_kaufman_jones_weiss_barker_allen_2018, title={Bacterial lipoproteins and other factors released by Francisella tularensis modulate human neutrophil lifespan: Effects of a TLR1 SNP on apoptosis inhibition}, volume={20}, ISSN={["1462-5822"]}, DOI={10.1111/cmi.12795}, abstractNote={Francisella tularensis infects several cell types including neutrophils, and aberrant neutrophil accumulation contributes to tissue destruction during tularaemia. We demonstrated previously that F. tularensis strains Schu S4 and live vaccine strain markedly delay human neutrophil apoptosis and thereby prolong cell lifespan, but the bacterial factors that mediate this aspect of virulence are undefined. Herein, we demonstrate that bacterial conditioned medium (CM) can delay apoptosis in the absence of direct infection. Biochemical analyses show that CM contained F. tularensis surface factors as well as outer membrane components. Our previous studies excluded roles for lipopolysaccharide and capsule in apoptosis inhibition, and current studies of [14C] acetate‐labelled bacteria argue against a role for other bacterial lipids in this process. At the same time, studies of isogenic mutants indicate that TolC and virulence factors whose expression requires FevR or MglA were also dispensable, demonstrating that apoptosis inhibition does not require Type I or Type VI secretion. Instead, we identified bacterial lipoproteins (BLPs) as active factors in CM. Additional studies of isolated BLPs demonstrated dose‐dependent neutrophil apoptosis inhibition via a TLR2‐dependent mechanism that is significantly influenced by a common polymorphism, rs5743618, in human TLR1. These data provide fundamental new insight into pathogen manipulation of neutrophil lifespan and BLP function.}, number={2}, journal={CELLULAR MICROBIOLOGY}, author={Kinkead, Lauren C. and Whitmore, Laura C. and McCracken, Jenna M. and Fletcher, Joshua R. and Ketelsen, Brandi B. and Kaufman, Justin W. and Jones, Bradley D. and Weiss, David S. and Barker, Jason H. and Allen, Lee-Ann H.}, year={2018}, month={Feb} }