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 7

The bile acid distribution in patients with CDI resembles that of a characteristic subgroup of uninfected, hospitalized patients.

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The bile acid distribution in patients with CDI resembles that of a char...
(A) Depicted here is a PCA plot of uninfected patients’ bile acid profiles (green, n = 62). Onto this space, we projected the bile acid metabolome of patients with CDI (red, n = 62). Data ellipses are drawn around each group of samples (95% level). Clustering of CDI specimens at high PC1 values is consistent with a favored bile acid distribution among patients with CDI. (B) Dot plot of PC1 scores for each patient sample (n = 62 in each group). Gray dashed line represents optimal PC1 threshold for distinguishing Cx–/EIA– from Cx+/EIA+ samples. This threshold was chosen by maximizing the sum of percent sensitivity and specificity. (C) ROC plot evaluating the ability of PC1 to distinguish CDI patients from controls. The gray region represents the bootstrapped 95% confidence interval for the true-positive rate at each false-positive rate. An asterisk marks the point corresponding to the optimal PC1 threshold depicted in B. (D) PCA loading plot depicting the relative contributions of each bile acid to the distribution of Cx–/EIA– samples in A. Abbreviations are indicated in Table 3.