Nickel as a Catalytic Driver of Necrotizing Enterocolitis: Dietary Nickel, Microbial Metallomics, and the Activation of Nickel-Dependent Virulence Pathways in the Preterm Gut

Necrotizing enterocolitis (NEC) has long been framed as a disease of prematurity driven by “dysbiosis,” formula feeding, and opportunistic pathogens. Yet despite decades of research, a central mechanistic question has remained unanswered: why do the same microbial taxa repeatedly dominate in NEC, and what enables them to so effectively overwhelm the immature infant gut?

This paper argues that the missing variable has been hiding in plain sight: nickel.

By integrating microbiome data, microbial enzymology, nutritional immunology, and infant feeding practices, this work reframes NEC as a nickel-enabled disease state. The pathogens consistently enriched in NEC, particularly Escherichia coli and related Enterobacteriaceae, rely on nickel-dependent enzymes such as urease, [NiFe]-hydrogenases, and glyoxalase I to alkalinize their environment, detoxify metabolic stress, evade neutrophil killing, and thrive under inflammatory conditions. At the same time, host defenses such as lactoferrin and calprotectin explicitly function to withhold nickel as part of nutritional immunity.

The paradox is dietary.

Human breast milk is naturally nickel-poor. In contrast, infant formulas, especially soy-based formulations, contain orders of magnitude higher nickel concentrations, effectively delivering a bolus of the exact metal cofactor required to activate these microbial virulence pathways. When combined with formula-associated elevations in gut pH and reduced colonization by acidifying commensals, excess dietary nickel functionally licenses pathogenic metabolism while undermining host metal sequestration strategies.

Viewed through this metallomic lens, the classic NEC findings suddenly align: reduced alpha diversity, Proteobacteria blooms, loss of protective taxa, epithelial injury, and inflammation are no longer isolated observations but predictable consequences of a nickel-replete gut ecosystem.

The conclusion is difficult to ignore: the microbiology, the biochemistry, and the feeding data were already there. What was missing was the recognition that nickel is not a passive contaminant, but a catalytic driver.

This work introduces a unifying framework with immediate implications for infant formula composition, NEC risk stratification, biomarker development, and the design of nickel-targeted preventative and therapeutic strategies. It invites neonatology, microbiome science, metallomic science, and nutrition to confront an uncomfortable possibility: that one of the most devastating diseases of prematurity has been unintentionally fueled by an overlooked trace metal all along.