Impact of Asymptomatic Enteroaggregative <i>Escherichia coli</i> Infection and Co-Pathogen Burden on Intestinal Barrier Function, Linear Growth, and Cognitive Development in Early Childhood: Insights from a Birth Cohort Study

ABSTRACT Introduction Enteroaggregative Escherichia coli (EAEC) is a major enteric pathogen in low-resource settings and can infect children with or without causing diarrhea. However, limited data exists on the impact of subclinical EAEC infections, particularly when co-detected with other pathogens. This study aimed to evaluate socioeconomic risk factors and the effects of subclinical EAEC infection—alone or in combination with other pathogens—on intestinal barrier function, enteric inflammation, linear growth, and cognitive development in children aged 0–24 months, using quantitative molecular diagnostics. Methods We analyzed 1,618 non-diarrheal samples from children enrolled in eight sites of the MAL-ED birth cohort. A quantitative PCR-based TaqMan Array Card was used to detect 29 enteropathogens. Children were categorized by infection status: EAEC alone, or EAEC with one, two, or three or more co-pathogens. Associations with socioeconomic indicators (e.g., maternal education, household income, sanitation), clinical symptoms, use medication, anthropometry, biomarkers (myeloperoxidase [MPO], neopterin [NEO], α1-antitrypsin, lactulose:mannitol ratio), nutritional z-scores, and Bayley developmental scores were assessed. Results Lower socioeconomic and sanitation scores, as well as lower WAMI index values, were significantly associated with EAEC infection and increased pathogen burden ( p < 0 . 001 ). Children with subclinical EAEC infection and high pathogen loads also had a higher frequency of antibiotic use. Subclinical EAEC infection—either alone or with ≥3 co-pathogens—was associated with elevated fecal neopterin (β = 687.5; 95% CI: 129.7 to 1245.3), increased intestinal permeability (% lactulose Z-score, β = 0.41; 95% CI: 0.058 to 0.77), lower linear growth (LAZ, β = –0.44; 95% CI: –0.76 to –0.12), and reduced cognitive scores at 15 and 24 months (β = –2.82; 95% CI: –5.15 to –0.48; β = –5.02; 95% CI: –9.81 to –0.22, respectively). Conclusion Quantitative molecular diagnostics revealed that subclinical EAEC infections with high pathogen burden are associated with adverse socioeconomic conditions, frequent antibiotic use, intestinal inflammation, increased permeability, impaired linear growth, and poorer cognitive development. Even isolated EAEC infection was linked to cognitive deficits, underscoring its potential role in the pathogenesis of environmental enteropathy and early childhood developmental delays. What Is Known Enteroaggregative Escherichia coli (EAEC) is a prevalent enteropathogen in children under two years in low-resource settings and has been associated with intestinal inflammation and linear growth faltering. Prior studies, largely based on conventional microbiological techniques, reported associations between EAEC and undernutrition, particularly in children with persistent diarrhea or multiple infections. The contribution of subclinical EAEC infections—especially in the context of co-infections—to intestinal barrier dysfunction, growth impairment, and cognitive development remained poorly understood. What Is New This study demonstrates that isolated subclinical EAEC infection during the first six months of life is not associated with impaired growth. In contrast, EAEC infections co-occurring with three or more pathogens are significantly associated with increased intestinal permeability, elevated fecal neopterin (inflammation), and reduced linear growth (LAZ) in infants. Notably, even isolated subclinical EAEC infection is independently associated with lower cognitive and language scores at 15 and 24 months of age. These findings, enabled by quantitative molecular diagnostics, underscore the role of EAEC—both alone and in combination with other pathogens—in the pathogenesis of environmental enteric dysfunction and early childhood developmental delays.

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