Madeline Graham, BA

She/Her/Hers
Technical Research Assistant II
Pathology
Infectious Diseases
Commensal modulation of Clostridioides difficile infection in vivo

Principal Investigator: Lynn Bry, M.D., Ph.D.

Authors: Graham M, DiBenedetto N, Delaney M, Lavin R, Pavao A, Yeliseyev V, Bry L
Lay Abstract

Clostridioides difficile, commonly referred to as C. diff, is a bacterium that can cause severe illness in patients with disturbances in the healthy, normally present (commensal) bacteria in their colon, often resulting from antibiotic treatment. C. difficile is common in hospital settings and places a substantial burden on healthcare systems. Due to the nature of C. difficile and its spores, it can be very difficult to cure, and many people experience recurrent infections.

Using pre-clinical models, we investigated the effects of three different commensals on C. difficile’s behaviors as a pathogen, including on patient outcomes from infection: Paraclostridium bifermentans (PBI), Clostridium sardiniense (CSAR), and Clostridium scindens (CSCI).

We found that CSAR, which produces compounds that C. difficile metabolizes, exacerbated the infection. PBI and CSCI both compete with C. difficile metabolically and reduced the severity of the infection early on. Only PBI, which exerts metabolic competition via more pathways, promoted recovery from C. difficile infection and resulting colonic damage long-term. These findings support PBI as a potential therapeutic against C. difficile infection.

Scientific Abstract

Background: Clostridioides difficile infection (CDI) places a substantial burden on healthcare systems. Commensal microbiota alter the course and severity of CDI. The present study aims to assess the effects of select commensals on CDI to define how they modulate disease. In particular, Clostridium scindens (CSCI) has shown promise as a CDI bacteriotherapeutic.

Methods: Using a germfree mouse model, we previously studied the effects of other commensal Clostridia on CDI: Paraclostridium bifermentans (PBI), Clostridium sardiniense (CSAR). Cecal contents were analyzed for C. difficile vegetative and spore biomass, toxin B content, tissue damage, and short-chain fatty acid profiles.

Results: Germfree Swiss-Webster mice mono-associated with PBI, which readily ferments amino acids through all three Stickland pathways, had the greatest protection from CDI. Mice with CSCI, which is moderately proteolytic and only ferments through two Stickland pathways, also survived infection, but with higher toxin B content long-term and chronic colonic damage. Mice with non-proteolytic and butyrate-producing CSAR declined rapidly.

Conclusions: The present findings support PBI as a superior bacteriotherapeutic against CDI to CSCI.

Clinical Implications
This research aims to identify bacteria in the human gut that have protective effects against Clostridioides difficile infection and to understand the mechanisms of this protection. These findings reveal new approaches to treat and prevent C. difficile disease.

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