Plasma lipopolysaccharide levels predict mortality in acutely ill children in Low- and Middle-Income Countries

Chris A. D. Allen, Arya Ghate, James M. Njunge, Lisa Gartner, Abdoulaye Hama Diallo, Christina Lancioni, Ezekiel Mupere, Agnes Gwela, Caroline Tigoi, Benson O. Singa, Wilson Gumbi, Robert H. J. Bandsma, Wieger P. Voskuijl, Mohammod Jobayer Chisti, Tahmeed Ahmed, Abu Sadat Mohammad Sayeem Bin Shahid, Dilruba Ahmed, Ali Saleem, Zaubina Kazi, Kelsey Jones, Kirkby D. Tickell, Judd L. Walson, James A. Berkley and Holm H. Uhlig ()
Additional contact information
Chris A. D. Allen: University of Oxford, Translational Gastroenterology Unit
Arya Ghate: University of Oxford, Translational Gastroenterology Unit
James M. Njunge: The Childhood Acute Illness and Nutrition Network
Lisa Gartner: University of Oxford, Translational Gastroenterology Unit
Abdoulaye Hama Diallo: The Childhood Acute Illness and Nutrition Network
Christina Lancioni: The Childhood Acute Illness and Nutrition Network
Ezekiel Mupere: The Childhood Acute Illness and Nutrition Network
Agnes Gwela: The Childhood Acute Illness and Nutrition Network
Caroline Tigoi: The Childhood Acute Illness and Nutrition Network
Benson O. Singa: The Childhood Acute Illness and Nutrition Network
Wilson Gumbi: The Childhood Acute Illness and Nutrition Network
Robert H. J. Bandsma: The Childhood Acute Illness and Nutrition Network
Wieger P. Voskuijl: The Childhood Acute Illness and Nutrition Network
Mohammod Jobayer Chisti: The Childhood Acute Illness and Nutrition Network
Tahmeed Ahmed: The Childhood Acute Illness and Nutrition Network
Abu Sadat Mohammad Sayeem Bin Shahid: The Childhood Acute Illness and Nutrition Network
Dilruba Ahmed: The Childhood Acute Illness and Nutrition Network
Ali Saleem: The Childhood Acute Illness and Nutrition Network
Zaubina Kazi: Aga Khan University, Department of Pediatrics and Child Health
Kelsey Jones: Great Ormond Street Hospital, UKPaediatric Gastroenterology
Kirkby D. Tickell: The Childhood Acute Illness and Nutrition Network
Judd L. Walson: The Childhood Acute Illness and Nutrition Network
James A. Berkley: The Childhood Acute Illness and Nutrition Network
Holm H. Uhlig: University of Oxford, Translational Gastroenterology Unit

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Childhood mortality remains high in low-resource settings, where environmental enteric dysfunction (EED) is prevalent. Peripheral blood bacterial lipopolysaccharides (LPS) are potential biomarkers of intestinal microbial translocation and inflammation; however, the effects of LPS translocation on mortality in this context remains unexplored. We investigate the association between plasma LPS and mortality among 638 acutely ill hospitalised children and compare them to 251 well community peers in a nested case-cohort (NCC) conducted between November 2016 and January 2019 across 9 sites in 6 countries in sub-Saharan Africa and South Asia. Higher levels of plasma LPS and inflammatory biomarkers (fecal calprotectin, plasma myeloperoxidase, and CD14) are associated with elevated 90-day mortality, and those associations are independent of wasting status. Non-survivors with high plasma LPS exhibit elevated gram-negative enteric microbiota, increased fecal biomarkers of EED, systemic inflammatory proteins, and differentially expressed proteins linked to the Insulin-like growth factor (IGF) nutritional axis, Interleukin-1 and collagen regeneration. Cellular interaction network models deconvoluted from a single-cell transcriptomic dataset enable an exploratory investigation of systemic immune responses and epithelial-immune cells crosstalk active in pathways leading to mortality. This knowledge can guide the identification of potential therapeutic signaling pathways in settings with high EED and malnutrition.

Date: 2025
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DOI: 10.1038/s41467-025-65429-0

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