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Cooperative Metabolic Adaptations in the Host Can Favor Asymptomatic Infection and Select for Attenuated Virulence in an Enteric Pathogen
Open accessAbstract
Pathogen virulence exists on a continuum. The strategies that drive symptomatic or asymptomatic infections remain largely unknown. We took advantage of the concept of lethal dose 50 (LD50) to ask which component of individual non-genetic variation between hosts defines whether they survive or succumb to infection. Using the enteric pathogen Citrobacter, we found no difference in pathogen burdens between healthy and symptomatic populations. Iron metabolism-related genes were induced in asymptomatic hosts compared to symptomatic or naive mice. Dietary iron conferred complete protection without influencing pathogen burdens, even at 1000× the lethal dose of Citrobacter. Dietary iron induced insulin resistance, increasing glucose levels in the intestine that were necessary and sufficient to suppress pathogen virulence. A short course of dietary iron drove the selection of attenuated Citrobacter strains that can transmit and asymptomatically colonize naive hosts, demonstrating that environmental factors and cooperative metabolic strategies can drive conversion of pathogens toward commensalism.
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“In fact, dietary iron has been shown to regulate insulin resistance to affect susceptibility to infection, highlighting the importance of evolved co-operative mechanisms (Sanchez et al., 2018).”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Sanchez et al., 2018
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“supplementation in experimental mice was recently found to suppress virulence of the rodent enteric pathogen Citrobacter rodentium, essentially converting the pathogen to a commensal microbe (53).”
From The gut microbiota at the intersection of diet and human health (2018) · cites this paper as [53]
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“5359% according to the method in a previous study (Sanchez et al., 2018).”
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“rodentium) by inducing systemic insulin resistance, which increased glucose availability to the pathogen through decreased absorption from the lumen of the intestines [70].”
BackgroundBeyond tug-of-war: Iron metabolism in cooperative host–microbe interactions
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“Many investigations, based in clinical and laboratory settings, have shown that iron supplementation causes more severe infections of Mycobacterium tuberculosis (46) but lower virulence of the enteric pathogen Citrobacter (47).”
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“Animals infected with a 50% lethal dose (LD 50 ) of a pathogen often show distinct health and sickness trajectories due to differences in disease tolerance 1,3 and can be used to define tolerance mechanisms.”
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Dietary L-arabinose-induced gut dysbiosis exacerbates Salmonella infection outcome
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Self-citationInfection-elicited microbiota promotes host adaptation to nutrient restriction
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“In contrast, dysregulated host metabolism can disrupt or alter the microbiota’s resistance to pathogens (19, 20), but to date, whether infection can in turn impact the microbiota’s regulation of host metabolism warrants further exploration.”
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“Other metabolic targets, including iron (Sanchez et al. 2018), immunomodulatory metabolic enzymes like arginase (Elahi et al. 2013, El Kasmi et al. 2008, Pesce et al. 2009), and metabolic hormones (Luan et al. 2019) have high potential to reduce pathology during infection.”
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Metadata
- Authors
- Sanchez, K. K., Chen, G. Y., Schieber, A. M. P., Redford, S. E., Shokhirev, M. N., Leblanc, M., Lee, Y. M., & Ayres, J. S.
- Affiliations
- Salk Institute for Biological Studies (US)
- Corresponding author
- Ayres, Janelle S.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2018-09
- Volume
- 175
- Issue
- 1
- Pages
- 146-158.e15
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC6447043
- OpenAlex
- W2886798301
- Cited by
- 175
- References
- 64
- Citations by year
- 2026: 10 · 2025: 11 · 2024: 23 · 2023: 18 · 2022: 18 · 2021: 29 · 2020: 36 · 2019: 22 · 2018: 7
- FWCI
- 17.02
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (R01AI114929, CA014195)
- Nomis Foundation
- Searle Scholar Award
- Ray Thomas Edward Foundation
- DARPA (YFA15 D15AP00097)
- Leona M. and Harry B. Helmsley Charitable Trust (2017-PG-MED001)
- Topics
- Life Sciences › Immunology and Microbiology › Microbiology › Escherichia coli research studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Keywords
- asymptomatic infection, pathogen virulence, Citrobacter, enteric pathogens, dietary iron, insulin resistance, host-pathogen interaction, virulence attenuation, commensalism, host genetic variation, lethal dose 50
- MeSH terms
- Animals, Colitis, Colon, Enterobacteriaceae Infections, Female, Insulin Resistance, Intestine, Small, Iron, Lethal Dose 50, Male, Mice, Inbred C3H, Mice, Inbred DBA, Virulence, Dietary Supplements, Citrobacter rodentium, Mice, Host-Pathogen Interactions, Asymptomatic Infections
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