Metabolomic networks connect host-microbiome processes to human Clostridioides difficile infections
John I. Robinson, … , Peter J. Mucha, Jeffrey P. Henderson
John I. Robinson, … , Peter J. Mucha, Jeffrey P. Henderson
Published August 12, 2019
Citation Information: J Clin Invest. 2019;129(9):3792-3806. https://doi.org/10.1172/JCI126905.
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Research Article Gastroenterology Infectious disease

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

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

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Figure 6

Bile acid transformations in the clinical cohort.

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Bile acid transformations in the clinical cohort. (A) A force-directed n...
(A) A force-directed network layout illustrates associations between bile acids in the study cohort. Each node represents a bile acid and each connecting line (edge) represents an association between 2 bile acids as 1 of the 5 highest correlations for at least 1 of the corresponding nodes. Edge lengths are determined by the level of correlation between connected bile acids. Nodes are colored by community assignment. (B) Scheme showing metabolic transformations producing bile acids in the network analysis. The central structure highlighted in gray represents a tri-hydroxylated primary bile acid (e.g., cholic acid). Taurine or glycine conjugation forms peptide bonds to the carboxylic acid group (right). Alcohol groups are removed from the bile acid nucleus (dehydroxylation, bottom right) or oxidized to a ketone (top left). Bile acid sulfation involves substitution of an alcohol group with a sulfate (R = SO4–) group (bottom left). Desulfation of bile acid sulfates yields unsaturated bile acids (left).