Periplasmic detoxification of urate hydroperoxide underpins E. coli survival in the inflamed gut
Abstract
Uric acid, the final product of purine metabolism in humans, accumulates in blood and tissues at relatively high concentrations 1 as humans lack the enzyme uricase 2,3 . Under inflammatory conditions, uric acid can be oxidised to yield reactive intermediates 4 . In activated neutrophils, myeloperoxidase (MPO) catalyses the oxidation of uric acid by hydrogen peroxide, leading to the formation of urate hydroperoxide (UH) 5,6 . While recent studies have shown that UH is toxic to bacteria lacking peroxiredoxins 7 , its precise mechanism of toxicity and the existence of dedicated bacterial defence systems remain unknown. Here, we identify HiuH as a periplasmic enzyme, conserved across E. coli strains, that specifically degrades UH. Our findings reveal that UH selectively induces the expression of hiuH and that HiuH efficiently detoxifies UH both in vitro and in bacterial cells. HiuH cooperates with MsrP, a periplasmic methionine sulfoxide reductase that repairs UH-induced protein-bound methionine oxidation. This combined defence offering both direct detoxification and damage repair, is essential for bacterial survival under UH stress, and confers a competitive fitness advantage in a DSS-induced mouse model of colitis. Although UH is chemically transient, our work shows that it imposes durable biological consequences and a sufficient fitness cost in the in vivo niches occupied by E. coli to favour the evolution of a dedicated detoxification pathway beyond general oxidative-stress responses, defining a key adaptation to periods of gut inflammation.
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BibTeX
@misc{vincent2026periplasmic,
title = {{Periplasmic detoxification of urate hydroperoxide underpins E. coli survival in the inflamed gut}},
author = {Maxence Vincent and Laurent Loiseau and Matthew Jones and Pierre Stocker and Khalid El Karkouri and Marion Chery and Divya Choudhary and Nicolas Vidal and Maria Winter and Natasha Tanner and Sylvia Pietri and Sebastian Winter and Benjamin Ezraty},
howpublished = {HAL},
year = {2026},
month = jun,
doi = {10.64898/2026.06.01.729251},
url = {https://hal.science/hal-05769030v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Periplasmic detoxification of urate hydroperoxide underpins E. coli survival in the inflamed gut
AU - Maxence Vincent
AU - Laurent Loiseau
AU - Matthew Jones
AU - Pierre Stocker
AU - Khalid El Karkouri
AU - Marion Chery
AU - Divya Choudhary
AU - Nicolas Vidal
AU - Maria Winter
AU - Natasha Tanner
AU - Sylvia Pietri
AU - Sebastian Winter
AU - Benjamin Ezraty
PY - 2026
DA - 2026/06/02
PB - HAL
DO - 10.64898/2026.06.01.729251
UR - https://hal.science/hal-05769030v1
AB - Uric acid, the final product of purine metabolism in humans, accumulates in blood and tissues at relatively high concentrations 1 as humans lack the enzyme uricase 2,3 . Under inflammatory conditions, uric acid can be oxidised to yield reactive intermediates 4 . In activated neutrophils, myeloperoxidase (MPO) catalyses the oxidation of uric acid by hydrogen peroxide, leading to the formation of urate hydroperoxide (UH) 5,6 . While recent studies have shown that UH is toxic to bacteria lacking peroxiredoxins 7 , its precise mechanism of toxicity and the existence of dedicated bacterial defence systems remain unknown. Here, we identify HiuH as a periplasmic enzyme, conserved across E. coli strains, that specifically degrades UH. Our findings reveal that UH selectively induces the expression of hiuH and that HiuH efficiently detoxifies UH both in vitro and in bacterial cells. HiuH cooperates with MsrP, a periplasmic methionine sulfoxide reductase that repairs UH-induced protein-bound methionine oxidation. This combined defence offering both direct detoxification and damage repair, is essential for bacterial survival under UH stress, and confers a competitive fitness advantage in a DSS-induced mouse model of colitis. Although UH is chemically transient, our work shows that it imposes durable biological consequences and a sufficient fitness cost in the in vivo niches occupied by E. coli to favour the evolution of a dedicated detoxification pathway beyond general oxidative-stress responses, defining a key adaptation to periods of gut inflammation.
ER -