Cholera toxin promotes pathogen acquisition of host-derived nutrients
Open accessAbstract
Vibrio cholerae is the causative agent of cholera, a potentially lethal enteric bacterial infection 1. Cholera toxin (CTX), a protein complex that is secreted by V. cholerae, is required for V. cholerae to cause severe disease. CTX is also thought to promote transmission of the organism, as infected individuals shed many litres of diarrhoeal fluid that typically contains in excess of 10 11 organisms per litre. How the pathogen is able to reach such high concentrations in the intestine during infection remains poorly understood. Here we show that CTX increases pathogen growth and induces a distinct V. cholerae transcriptomic signature that is indicative of an iron-depleted gut niche. During infection, bacterial pathogens need to acquire iron, which is an essential nutrient for growth 2. Most iron in the mammalian host is found in a chelated form within the porphyrin structure of haem, and the ability to use haem as a source of iron is genetically encoded by V. cholerae 3. We show that the genes that enable V. cholerae to obtain iron via haem and vibriobactin confer a growth advantage to the pathogen only when CTX is produced. Furthermore, we found that CTX-induced congestion of capillaries in the terminal ileum correlated with an increased bioavailability of luminal haem. CTX-induced disease in the ileum also led to increased concentrations of long-chain fatty acids and L-lactate metabolites in the lumen, as well as the upregulation of V. cholerae genes that encode enzymes of the tricarboxylic acid (TCA) cycle that contain iron-sulfur clusters. Genetic analysis of V. cholerae suggested that pathogen growth was dependent on the uptake of haem and long-chain fatty acids during infection, but only in a strain capable of producing CTX in vivo. We conclude that CTX-induced disease creates an iron-depleted metabolic niche in the gut, which selectively promotes the growth of V. cholerae through the acquisition of host-derived haem and fatty acids.
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Haem uptake efficiency is dependent upon bacterial toxin production in Vibrio cholerae.
“Moreover, recent findings demonstrate that haem uptake efficiency is dependent upon bacterial toxin production in Vibrio cholerae 46 , raising the possibility that virulence factors may have a role in enhancing bacterial haem uptake in vivo.”
From Nutritional immunity: the battle for nutrient metals at the host–pathogen interface (2022) · cites this paper as [46]
The paper reports that haem-uptake genes conferred a fitness advantage in the mouse gut when V. cholerae produced cholera toxin, but not when toxin production was absent (Abstract, Fig. 2d discussion; no page given). It also reports more luminal haem in rabbits infected with toxin-producing bacteria. These findings support toxin-dependent benefits of haem utilisation in vivo, but do not directly measure haem uptake efficiency. (LLM, conf=0.84)
Experimental — accuracy not yet measuredVirulence factors may have a role in enhancing bacterial haem uptake in vivo.
“Moreover, recent findings demonstrate that haem uptake efficiency is dependent upon bacterial toxin production in Vibrio cholerae 46 , raising the possibility that virulence factors may have a role in enhancing bacterial haem uptake in vivo.”
From Nutritional immunity: the battle for nutrient metals at the host–pathogen interface (2022) · cites this paper as [46]
Cholera toxin was recently shown to produce a growth-enhancing effect on Vibrio cholerae growth in the gut lumen by facilitating iron acquisition.
“however, cholera toxin was recently shown to produce a growth‐enhancing effect on Vibrio cholerae growth in the gut lumen by facilitating iron acquisition. 147”
From The battle for iron in enteric infections (2020) · cites this paper as [147]
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Self-citation
- Authors
- Rivera-Chávez, F., & Mekalanos, J. J.
- Affiliations
- Harvard University (US)
- Corresponding author
- Mekalanos, John J.
- Venue
- Nature
- Published
- 2019-07-31
- Volume
- 572
- Issue
- 7768
- Pages
- 244-248
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6727848
- OpenAlex
- W2966823177
- Cited by
- 124
- References
- 36
- Citations by year
- 2026: 9 · 2025: 21 · 2024: 16 · 2023: 22 · 2022: 15 · 2021: 24 · 2020: 16 · 2019: 1
- FWCI
- 9.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases (R01AI018045, R37AI018045, T32AI007061)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Vibrio bacteria research studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Escherichia coli research studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Keywords
- cholera toxin, Vibrio cholerae, long-chain fatty acids, L-lactate, iron-sulfur clusters, TCA cycle, terminal ileum, capillary congestion, bacterial transcriptome, host-pathogen interaction
- MeSH terms
- Animals, Cholera, Cholera Toxin, Citric Acid Cycle, Fatty Acids, Heme, Rabbits, Vibrio cholerae, Sequence Analysis, RNA, Lactic Acid, Mice, Host-Pathogen Interactions, Transcriptome
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