Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Clinical innovation and scientific progress in GLP-1 medicine (Nov 2025)
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Metabolomic networks connect host-microbiome processes to human Clostridioides difficile infections
John I. Robinson, William H. Weir, Jan R. Crowley, Tiffany Hink, Kimberly A. Reske, Jennie H. Kwon, Carey-Ann D. Burnham, Erik R. Dubberke, Peter J. Mucha, Jeffrey P. Henderson
John I. Robinson, William H. Weir, Jan R. Crowley, Tiffany Hink, Kimberly A. Reske, Jennie H. Kwon, Carey-Ann D. Burnham, Erik R. Dubberke, Peter J. Mucha, Jeffrey P. Henderson
View: Text | PDF
Research Article Gastroenterology Infectious disease

Metabolomic networks connect host-microbiome processes to human Clostridioides difficile infections

  • Text
  • PDF
Abstract

Clostridioides difficile infection (CDI) accounts for a substantial proportion of deaths attributable to antibiotic-resistant bacteria in the United States. Although C. difficile can be an asymptomatic colonizer, its pathogenic potential is most commonly manifested in patients with antibiotic-modified intestinal microbiomes. In a cohort of 186 hospitalized patients, we showed that host and microbe-associated shifts in fecal metabolomes had the potential to distinguish patients with CDI from those with non–C. difficile diarrhea and C. difficile colonization. Patients with CDI exhibited a chemical signature of Stickland amino acid fermentation that was distinct from those of uncolonized controls. This signature suggested that C. difficile preferentially catabolizes branched chain amino acids during CDI. Unexpectedly, we also identified a series of noncanonical, unsaturated bile acids that were depleted in patients with CDI. These bile acids may derive from an extended host-microbiome dehydroxylation network in uninfected patients. Bile acid composition and leucine fermentation defined a prototype metabolomic model with potential to distinguish clinical CDI from asymptomatic C. difficile colonization.

Authors

John I. Robinson, William H. Weir, Jan R. Crowley, Tiffany Hink, Kimberly A. Reske, Jennie H. Kwon, Carey-Ann D. Burnham, Erik R. Dubberke, Peter J. Mucha, Jeffrey P. Henderson

×

Figure 3

Amino acid metabolism in C. difficile.

Options: View larger image (or click on image) Download as PowerPoint
Amino acid metabolism in C. difficile.

(A) Stickland metabolism consist...
(A) Stickland metabolism consists of anaerobic amino acid fermentation through coupled oxidation and reduction pathways. In the reductive pathway, amino acids are first deaminated to form 2-hydroxy acids and then reduced to carboxylic acids. In the oxidative pathway, amino acids are deaminated and oxidized with loss of CO2 to yield a distinct set of carboxylic acids. Depicted here are established Stickland substrates and products identified within patient fecal metabolomes. Stickland substrates include the nonproteinogenic amino acid ornithine. ND, not determined. (B) Heatmap of Stickland precursor and product abundances corresponding to patient fecal metabolomes from the 3 diagnostic groups. Metabolites were organized using unsupervised hierarchical clustering. Metabolites differing significantly (Mann-Whitney U test; *P < 0.05, ***P < 0.001) between Cx–/EIA– and Cx+/EIA+ groups are labeled, along with the direction of the difference relative to the Cx–/EIA– control group. Stickland products are labeled according to the color scheme in A. (C) Adjusted and unadjusted (crude) CDI odds ratios and confidence intervals (95%) for Stickland precursors and products. Odds ratios were estimate by fitting logistic regression models to each of 2000 bootstrap samples stratified on Cx/EIA status (Cx–/EIA– vs. Cx+/EIA+). Logistic models containing a single metabolite were fit to obtain crude odds ratios (red). A single logistic model including all metabolites was fit to obtain the adjusted odds ratios (green). Bars represent 95% bootstrap percentile confidence intervals and black dots represent median odds ratios across all bootstrap samples. Stickland products are labeled according to the color scheme in A.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts