Dietary carbohydrates regulate intestinal colonization and dissemination of Klebsiella pneumoniae
Aaron L. Hecht, … , Mark Goulian, Gary D. Wu
Aaron L. Hecht, … , Mark Goulian, Gary D. Wu
Published March 21, 2024
Citation Information: J Clin Invest. 2024;134(9):e174726. https://doi.org/10.1172/JCI174726.
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Research Article Gastroenterology

Dietary carbohydrates regulate intestinal colonization and dissemination of Klebsiella pneumoniae

Abstract

Bacterial translocation from the gut microbiota is a source of sepsis in susceptible patients. Previous work suggests that overgrowth of gut pathobionts, including Klebsiella pneumoniae, increases the risk of disseminated infection. Our data from a human dietary intervention study found that, in the absence of fiber, K. pneumoniae bloomed during microbiota recovery from antibiotic treatment. We thus hypothesized that dietary nutrients directly support or suppress colonization of this gut pathobiont in the microbiota. Consistent with our study in humans, complex carbohydrates in dietary fiber suppressed the colonization of K. pneumoniae and allowed for recovery of competing commensals in mouse models. In contrast, through ex vivo and in vivo modeling, we identified simple carbohydrates as a limiting resource for K. pneumoniae in the gut. As proof of principle, supplementation with lactulose, a nonabsorbed simple carbohydrate and an FDA-approved therapy, increased colonization of K. pneumoniae. Disruption of the intestinal epithelium led to dissemination of K. pneumoniae into the bloodstream and liver, which was prevented by dietary fiber. Our results show that dietary simple and complex carbohydrates were critical not only in the regulation of pathobiont colonization but also disseminated infection, suggesting that targeted dietary interventions may offer a preventative strategy in high-risk patients.

Authors

Aaron L. Hecht, Lisa C. Harling, Elliot S. Friedman, Ceylan Tanes, Junhee Lee, Jenni Firrman, Fuhua Hao, Vincent Tu, LinShu Liu, Andrew D. Patterson, Kyle Bittinger, Mark Goulian, Gary D. Wu

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Figure 3

Complex carbohydrates increase microbiome diversity and reduce K. pneumoniae colonization after antibiotic depletion.

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Complex carbohydrates increase microbiome diversity and reduce K. pneumo...
(A–F) Mice were provided a FF or a HF diet starting on day –7, treated with oral antibiotics on day –3 to day 0 (gray shading), and gavaged with K. pneumoniae (day 0). Serial stool samples were subjected to analysis as follows: (A) Shannon α diversity of stool microbiome from mice provided a FF or HF diet including the antibiotic treatment period (gray shading) and recovery, as determined by shotgun metagenomic sequencing. (B) GH genes with significantly different abundances between FF and FH diets 4 weeks after gavage with K. pneumoniae grouped by substrate type. Open circles represent genes with higher levels in mice on the FF diet, and closed circles represent genes with higher levels in mice on the HF diet. (C) K. pneumoniae fecal CFU for mice on a FF (open circles) or HF (closed circles) diet measured 4 weeks after K. pneumoniae gavage. (D) Stool ammonia was quantified before and after antibiotic treatment (gray shading) and K. pneumoniae gavage for mice subjected to a FF (open circles) or HF (closed circles) diet. (E) Stool urea levels were quantified for mice provided a FF diet. (F) Heatmap of amino acid concentrations in mice on a FF or HF diet after colonization with K. pneumoniae. Data are presented as the mean ± SD (A–E). n = 5 mice per group. Data are representative of 2–3 independent experiments (C–F). *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by multiple 2-tailed t tests with Bonferroni’s correction for multiple comparisons (A, C, and D), 1-way ANOVA with Bonferroni’s correction for multiple comparisons (E), or multiple Mann-Whitney U tests with the FDR method of Benjamini, Krueger, and Yokutieli (F).