Clostridioides difficile uses amino acids associated with gut microbial dysbiosis in a subset of patients with diarrhea

Eric J. Battaglioli, Vanessa L. Hale, Jun Chen, Patricio Jeraldo, Coral Ruiz-Mojica, Bradley A. Schmidt, Vayu M. Rekdal, Lisa M. Till, Lutfi Huq, Samuel A. Smits, William J. Moor, Yava Jones-Hall, Thomas Christopher Smyrk, Sahil Khanna, Darrell Spencer Pardi, Madhusudan Grover, Robin Patel, Nicholas D Chia, Heidi Nelson, Justin L. SonnenburgGianrico Farrugia, Purna C Kashyap

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Abstract

The gut microbiota plays a critical role in pathogen defense. Studies using antibiotic-treated mice reveal mechanisms that increase susceptibility to Clostridioides difficile infection (CDI), but risk factors associated with CDI in humans extend beyond antibiotic use. Here, we studied the dysbiotic gut microbiota of a subset of patients with diarrhea and modeled the gut microbiota of these patients by fecal transplantation into germ-free mice. When challenged with C. difficile, the germ-free mice transplanted with fecal samples from patients with dysbiotic microbial communities showed increased gut amino acid concentrations and greater susceptibility to CDI. A C. difficile mutant that was unable to use proline as an energy source was unable to robustly infect germ-free mice transplanted with a dysbiotic or healthy human gut microbiota. Prophylactic dietary intervention using a low-proline or low-protein diet in germ-free mice colonized by a dysbiotic human gut microbiota resulted in decreased expansion of wild-type C. difficile after challenge, suggesting that amino acid availability might be important for CDI. Furthermore, a prophylactic fecal microbiota transplant in mice with dysbiosis reduced proline availability and protected the mice from CDI. Last, we identified clinical risk factors that could potentially predict gut microbial dysbiosis and thus greater susceptibility to CDI in a retrospective cohort of patients with diarrhea. Identifying at-risk individuals and reducing their susceptibility to CDI through gut microbiota-targeted therapies could be a new approach to preventing C. difficile infection in susceptible patients.

Original languageEnglish (US)
Article numbereaam7019
JournalScience Translational Medicine
Volume10
Issue number464
DOIs
StatePublished - Oct 24 2018

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Dysbiosis
Diarrhea
Amino Acids
Infection
Proline
Anti-Bacterial Agents
Protein-Restricted Diet
Microbiota
Gastrointestinal Microbiome

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Clostridioides difficile uses amino acids associated with gut microbial dysbiosis in a subset of patients with diarrhea. / Battaglioli, Eric J.; Hale, Vanessa L.; Chen, Jun; Jeraldo, Patricio; Ruiz-Mojica, Coral; Schmidt, Bradley A.; Rekdal, Vayu M.; Till, Lisa M.; Huq, Lutfi; Smits, Samuel A.; Moor, William J.; Jones-Hall, Yava; Smyrk, Thomas Christopher; Khanna, Sahil; Pardi, Darrell Spencer; Grover, Madhusudan; Patel, Robin; Chia, Nicholas D; Nelson, Heidi; Sonnenburg, Justin L.; Farrugia, Gianrico; Kashyap, Purna C.

In: Science Translational Medicine, Vol. 10, No. 464, eaam7019, 24.10.2018.

Research output: Contribution to journalArticle

Battaglioli, EJ, Hale, VL, Chen, J, Jeraldo, P, Ruiz-Mojica, C, Schmidt, BA, Rekdal, VM, Till, LM, Huq, L, Smits, SA, Moor, WJ, Jones-Hall, Y, Smyrk, TC, Khanna, S, Pardi, DS, Grover, M, Patel, R, Chia, ND, Nelson, H, Sonnenburg, JL, Farrugia, G & Kashyap, PC 2018, 'Clostridioides difficile uses amino acids associated with gut microbial dysbiosis in a subset of patients with diarrhea', Science Translational Medicine, vol. 10, no. 464, eaam7019. https://doi.org/10.1126/scitranslmed.aam7019
Battaglioli, Eric J. ; Hale, Vanessa L. ; Chen, Jun ; Jeraldo, Patricio ; Ruiz-Mojica, Coral ; Schmidt, Bradley A. ; Rekdal, Vayu M. ; Till, Lisa M. ; Huq, Lutfi ; Smits, Samuel A. ; Moor, William J. ; Jones-Hall, Yava ; Smyrk, Thomas Christopher ; Khanna, Sahil ; Pardi, Darrell Spencer ; Grover, Madhusudan ; Patel, Robin ; Chia, Nicholas D ; Nelson, Heidi ; Sonnenburg, Justin L. ; Farrugia, Gianrico ; Kashyap, Purna C. / Clostridioides difficile uses amino acids associated with gut microbial dysbiosis in a subset of patients with diarrhea. In: Science Translational Medicine. 2018 ; Vol. 10, No. 464.
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abstract = "The gut microbiota plays a critical role in pathogen defense. Studies using antibiotic-treated mice reveal mechanisms that increase susceptibility to Clostridioides difficile infection (CDI), but risk factors associated with CDI in humans extend beyond antibiotic use. Here, we studied the dysbiotic gut microbiota of a subset of patients with diarrhea and modeled the gut microbiota of these patients by fecal transplantation into germ-free mice. When challenged with C. difficile, the germ-free mice transplanted with fecal samples from patients with dysbiotic microbial communities showed increased gut amino acid concentrations and greater susceptibility to CDI. A C. difficile mutant that was unable to use proline as an energy source was unable to robustly infect germ-free mice transplanted with a dysbiotic or healthy human gut microbiota. Prophylactic dietary intervention using a low-proline or low-protein diet in germ-free mice colonized by a dysbiotic human gut microbiota resulted in decreased expansion of wild-type C. difficile after challenge, suggesting that amino acid availability might be important for CDI. Furthermore, a prophylactic fecal microbiota transplant in mice with dysbiosis reduced proline availability and protected the mice from CDI. Last, we identified clinical risk factors that could potentially predict gut microbial dysbiosis and thus greater susceptibility to CDI in a retrospective cohort of patients with diarrhea. Identifying at-risk individuals and reducing their susceptibility to CDI through gut microbiota-targeted therapies could be a new approach to preventing C. difficile infection in susceptible patients.",
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AU - Ruiz-Mojica, Coral

AU - Schmidt, Bradley A.

AU - Rekdal, Vayu M.

AU - Till, Lisa M.

AU - Huq, Lutfi

AU - Smits, Samuel A.

AU - Moor, William J.

AU - Jones-Hall, Yava

AU - Smyrk, Thomas Christopher

AU - Khanna, Sahil

AU - Pardi, Darrell Spencer

AU - Grover, Madhusudan

AU - Patel, Robin

AU - Chia, Nicholas D

AU - Nelson, Heidi

AU - Sonnenburg, Justin L.

AU - Farrugia, Gianrico

AU - Kashyap, Purna C

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N2 - The gut microbiota plays a critical role in pathogen defense. Studies using antibiotic-treated mice reveal mechanisms that increase susceptibility to Clostridioides difficile infection (CDI), but risk factors associated with CDI in humans extend beyond antibiotic use. Here, we studied the dysbiotic gut microbiota of a subset of patients with diarrhea and modeled the gut microbiota of these patients by fecal transplantation into germ-free mice. When challenged with C. difficile, the germ-free mice transplanted with fecal samples from patients with dysbiotic microbial communities showed increased gut amino acid concentrations and greater susceptibility to CDI. A C. difficile mutant that was unable to use proline as an energy source was unable to robustly infect germ-free mice transplanted with a dysbiotic or healthy human gut microbiota. Prophylactic dietary intervention using a low-proline or low-protein diet in germ-free mice colonized by a dysbiotic human gut microbiota resulted in decreased expansion of wild-type C. difficile after challenge, suggesting that amino acid availability might be important for CDI. Furthermore, a prophylactic fecal microbiota transplant in mice with dysbiosis reduced proline availability and protected the mice from CDI. Last, we identified clinical risk factors that could potentially predict gut microbial dysbiosis and thus greater susceptibility to CDI in a retrospective cohort of patients with diarrhea. Identifying at-risk individuals and reducing their susceptibility to CDI through gut microbiota-targeted therapies could be a new approach to preventing C. difficile infection in susceptible patients.

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