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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Dietary iron regulates insulin resistance to affect susceptibility to infection.
“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
Iron supplementation in experimental mice suppressed virulence of Citrobacter rodentium, converting the pathogen to a commensal microbe.
“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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MethodEfficacy of Resistance to Francisella Imparted by ITY/NRAMP/SLC11A1 Depends on Route of Infection
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MethodLercher, A., Bhattacharya, A., Popa, A., Caldera, M., Schlapansky, M. F., Baazim, H., Agerer, B., Gürtl, B., Kosack, L., Májek, P., et al. (2019) · Immunity · doi:10.1016/j.immuni.2019.10.014 · Cited by 120 · see citing works
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BackgroundGut Microbiota in Acute Ischemic Stroke: From Pathophysiology to Therapeutic Implications
Battaglini, D., Pimentel‐Coelho, P. M., Robba, C., dos Santos, C. C., Cruz, F. F., Pelosi, P. P., & Rocco, P. R. M. (2020) · Frontiers in Neurology · doi:10.3389/fneur.2020.00598 · Cited by 99 · see citing works
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“and anti-virulence tactics promote host health without affecting the ability of a microbe to occupy the host niche or replicate within it (5, 23, 25, 26).”
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“It should be noted that not all host-microbe interactions result in a Red Queen effect; some scenarios invoke a cooperative defense strategy that can result in commensalism (317, 318).”
BackgroundOat β-glucan alleviates DSS-induced colitis via regulating gut microbiota metabolism in mice
Bai, J., Zhao, J., AL‐Ansi, W., Wang, J., Xue, L., Liu, J., Wang, Y., Fan, M., Qian, H., Li, Y., et al. (2021) · Food & Function · doi:10.1039/d1fo01446c · Cited by 86 · see citing works
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BackgroundThe intersection of undernutrition, microbiome, and child development in the first years of life
Fontaine, F., Turjeman, S. C., Callens, K., & Koren, O. (2023) · Nature Communications · doi:10.1038/s41467-023-39285-9 · Cited by 79 · see citing works
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A Th17 cell-intrinsic glutathione/mitochondrial-IL-22 axis protects against intestinal inflammation
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BackgroundSpatial IMA1 regulation restricts root iron acquisition on MAMP perception
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“For example, iron supplementation increases intestinal glucose availability leading to a significant decline in microbial virulence in mice infected with a lethal dose of Citrobacter rodentium (36).”
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“In contrast, dietary iron promoted the attenuation of C. rodentium by interfering with intestinal glucose uptake (149).”
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“5359% according to the method in a previous study (Sanchez et al., 2018).”
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Blood glucose regulation in context of infection
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Cellular and Exosomal Regulations of Sepsis-Induced Metabolic Alterations
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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
Chen, G. Y., & Ayres, J. S. (2020) · PLoS Pathogens · doi:10.1371/journal.ppat.1008698 · Cited by 16 · see citing works
“An example is changes in intestinal carbohydrate availability to down-regulate pathogen virulence genes and sustain host health without inhibiting pathogen replication [6, 7].”
BackgroundInfluentialSelf-citationWhat’s for dinner? How Citrobacter rodentium’s metabolism helps it thrive in the competitive gut
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EMC is required for biogenesis of Xport‐A, an essential chaperone of Rhodopsin‐1 and the TRP channel
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Overview of the Effect of Citrobacter rodentium Infection on Host Metabolism and the Microbiota
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Host A-to-I RNA editing signatures in intracellular bacterial and single-strand RNA viral infections
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Dual Regulatory Role Exerted by Cyclic Dimeric GMP To Control FsnR-Mediated Bacterial Swimming
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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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BackgroundThe energetics and ion coupling of cholesterol transport through Patched1
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Disease tolerance and infection pathogenesis age-related tradeoffs in mice
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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.”
Self-citationTranscriptional and metabolic regulation of EHEC and Citrobacter rodentium pathogenesis
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Dietary L-arabinose-induced gut dysbiosis exacerbates Salmonella infection outcome
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“Simple sugar metabolism plays a crucial role in the ecophysiology of the human gut microbiota, which overrides host genetic effects (11, 12).”
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Infection Heterogeneity and Microbiota Differences in Chicks Infected by Salmonella enteritidis
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“Host susceptibility to pathogen infection is frequently heterogeneous [7], as demonstrated by the phenomenon of the median lethal dose (lethal dose 50 [LD50]), which describes the microbe dose that will kill only 50% of a test population [8].”
BackgroundCooperative defenses during enteropathogenic infection
Troha, K., & Ayres, J. S. (2021) · Current Opinion in Microbiology · doi:10.1016/j.mib.2021.11.003 · Cited by 9 · see citing works
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.”
BackgroundInsulin Resistance and Glucose Metabolism during Infection
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- 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 · 2012: 1
- 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 › Biochemistry, Genetics and Molecular Biology › Endocrinology › 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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