How Severe Anemia Might Influence the Risk of Invasive Bacterial Infections in African Children Original paper

What Was Reviewed?

This review investigates the hypothesis that severe anemia contributes to the elevated risk of invasive bacterial infections in African children through dysregulation of iron homeostasis, including the disruption of hepcidin—a hepatic hormone that governs iron availability in the body. The authors synthesize evidence from epidemiological, mechanistic, and experimental studies, proposing that the interplay between anemia, haemolysis, immune dysfunction, and gut permeability collectively facilitates systemic infections. The paper places particular emphasis on how bacterial pathogens exploit iron and haem to thrive under conditions of anemia-induced iron dysregulation, especially in regions with high burdens of infectious disease and malnutrition.

Who Was Reviewed?

The review draws on research concerning sub-Saharan African children who commonly experience severe anemia due to malaria, nutritional deficiencies, sickle cell disease, and HIV. It includes human observational data, animal model findings, and in vitro studies related to bacterial infections, immune response, and iron regulation pathways.

What Were the Most Important Findings?

Severe anemia in African children correlates strongly with an increased risk of invasive bacterial infections, particularly with Gram-negative organisms such as non-typhoidal Salmonella (NTS), E. coli, and Haemophilus influenzae, as well as Gram-positive organisms including Staphylococcus aureus and Streptococcus pneumoniae. This elevated susceptibility is mechanistically linked to increased erythropoietic drive and haemolysis, both of which suppress hepcidin via the erythroid hormone erythroferrone (ERFE). Reduced hepcidin enhances plasma iron levels and promotes the release of iron from macrophage stores, thereby removing the “nutritional immunity” that would otherwise limit iron availability to pathogens. Simultaneously, haemolysis releases non-transferrin-bound iron (NTBI) and free haem, which are more readily exploited by pathogens through siderophore-mediated and haem-binding iron acquisition systems.

Of particular relevance to microbiome researchers, the review notes that severe anemia can disrupt gut barrier integrity and provoke dysbiosis. The increased gut permeability facilitates the translocation of enteric pathogens, notably NTS and E. coli, into systemic circulation. This breach is exacerbated by inflammation, destabilization of tight junction proteins like ZO-1, and macrophage-mediated changes to mucosal immunity. The review references mouse models where anemia-induced epithelial dysfunction was dependent on macrophage-driven cytokine signaling, especially IFN-γ, as well as bacterial studies showing enhanced virulence and iron uptake capacity in haem-rich or iron-rich conditions. Importantly, these microbial strategies overlap with the exact niches disrupted in severe anemia, such as haem overload, NTBI availability, and compromised mucosal defenses.

Major microbial associations (MMAs) include:

What Are the Greatest Implications of This Review?

The review suggests that treating severe anemia in high-infection-burden areas like sub-Saharan Africa should involve caution, particularly regarding iron supplementation. While iron repletion is essential, excessive or unregulated iron can exacerbate infection risk, especially in the presence of low hepcidin levels. This carries profound public health implications, as many iron supplementation programs do not account for concurrent infectious burdens or the child’s hepcidin status. Clinically, these insights demand a reevaluation of iron therapy protocols, particularly in settings where malaria, HIV, or bacterial sepsis are endemic. The review also encourages further exploration of therapies that modulate iron availability (e.g., hepcidin agonists or iron chelators) and highlights the need for comprehensive microbiome assessments in anaemic populations. The tight interconnection between gut microbiota, intestinal permeability, and systemic iron overload represents a mechanistic intersection worth pursuing in microbiome-targeted interventions.