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Plasma lipopolysaccharide levels predict mortality in acutely ill children in Low- and Middle-Income Countries
Chris A D Allen1, Arya Ghate1, James M Njunge2,3
1Translational Gastroenterology Unit, University of Oxford, Oxford, UK.
Insights
High levels of bacterial lipopolysaccharides (LPS) in the blood are linked to increased mortality in hospitalized children in low-resource areas. This association persists regardless of malnutrition, highlighting LPS as a critical indicator of disease severity.
Area of Science:
- Global Health
- Pediatrics
- Immunology
Background:
- Childhood mortality remains a critical issue in low-resource settings, often exacerbated by environmental enteric dysfunction (EED).
- Bacterial lipopolysaccharides (LPS) in peripheral blood are recognized biomarkers for intestinal barrier dysfunction and inflammation.
- The direct impact of LPS translocation on mortality in vulnerable pediatric populations has not been thoroughly investigated.
Purpose of the Study:
- To investigate the association between plasma LPS levels and 90-day mortality in acutely ill hospitalized children.
- To explore the relationship between LPS, EED biomarkers, and systemic inflammation in relation to mortality outcomes.
- To identify potential molecular pathways and cellular interactions involved in LPS-mediated mortality.
Main Methods:
- A nested case-cohort study involving 638 hospitalized children and 251 healthy controls across sub-Saharan Africa and South Asia.
- Measurement of plasma LPS, inflammatory biomarkers (fecal calprotectin, myeloperoxidase, CD14), and nutritional markers.
- Analysis of enteric microbiota, systemic inflammatory proteins, and gene expression profiles (single-cell transcriptomics) in non-survivors.
Main Results:
- Elevated plasma LPS levels were significantly associated with increased 90-day mortality, independent of wasting status.
- Non-survivors exhibited higher levels of gram-negative enteric microbiota, EED biomarkers, and systemic inflammatory proteins.
- Differential gene expression in non-survivors implicated the Insulin-like growth factor (IGF) axis, Interleukin-1, and collagen regeneration pathways.
Conclusions:
- Plasma LPS is a significant predictor of mortality in acutely ill children in low-resource settings, even in the absence of wasting.
- The findings suggest a complex interplay between gut barrier dysfunction, systemic inflammation, and host response pathways contributing to mortality.
- Identifying these pathways offers potential targets for therapeutic interventions to reduce childhood mortality in EED-endemic regions.
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.
