Impact of Shigella infections and inflammation early in life on child growth and school-aged cognitive outcomes: Findings from three birth cohorts over eight years

Abstract

Background Shigella infections cause inflammation, which has been hypothesized to mediate the associations between Shigella and child development outcomes among children in low-resource settings. We aimed to assess whether early life inflammation and Shigella infections affect school-aged growth and cognitive outcomes from 6–8 years of age. Methodology/principal findings We conducted follow-up assessments of anthropometry, reasoning skills, and verbal fluency in 451 children at 6–8 years of age in the Brazil, Tanzania, and South Africa sites of MAL-ED, a longitudinal birth cohort study. We estimated the associations between Shigella burden and inflammation with linear growth at 2, 5, and 6–8 years of age, and with the cognitive test scores using linear regression and adjusting for potential confounding variables. We also assessed whether inflammation mediated the associations between Shigella and school-aged outcomes using a regression-based approach to mediation analysis. A high prevalence of Shigella was associated with a 0.32 (95% CI: 0.08, 0.56) z-score lower height-for-age z-score (HAZ) at 6–8 years compared to a low prevalence of Shigella. Intestinal inflammation had a smaller association with HAZ at 6–8 years. Shigella burden had small and consistently negative associations with cognitive outcomes in Brazil and Tanzania, but not South Africa, and the estimates were not statistically significant. Systemic inflammation was strongly associated with lower verbal fluency scores in Brazil (semantic fluency z-score difference: -0.57, 95% CI: -1.05, -0.10; phonemic fluency z-score difference: -0.48, 95% CI: -0.93, -0.03). There was no evidence that intestinal inflammation mediated the association between Shigella and HAZ or cognitive outcomes. Conclusions/significance While Shigella infections were consistently associated with long-term deficits in linear growth, the estimates of the negative associations between Shigella and cognitive outcomes were imprecise and only observed in the Brazil and Tanzania sites. Systemic inflammation was strongly associated with lower semantic and phonemic fluency scores in Brazil only, highlighting the site-specificity of effects.

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“…A broad range of enteric bacterial, viral, or parasitic pathogens can cause diarrhea and associated short-and long-term complications. Host vulnerabilities associated with poor nutritional status, anemia, inadequate sanitation and hygiene, overcrowded living conditions, and gaps in health literacy could facilitate repeated infections with certain pathogens, leading to severe consequences, including enteric and systemic inflammation, increased risk of stunting, impaired cognitive development, and/or death [2,[8][9][10][11][12]. Recent data from the Global Enteric Multicenter Study (GEMS) on the burden and etiology of diarrhea among children residing in developing countries showed that rotavirus, Cryptosporidium spp., enterotoxigenic Escherichia coli (ETEC), and Shigella spp.…”

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“…Our studies and those of others have highlighted the importance of a healthy gut-brain axis to protect brain development in impoverished areas of the developing world where poor sanitation and hygiene result in environmental-related enteric dysfunction [1][2][3][4][5]. If enteric dysfunction is chronic and persistent, even at a low-grade insult, it could facilitate the mounting of a vicious cycle of malnutrition and enteric infections that can disturb normal developmental trajectories and even cause irreversible physical and cognitive faltering [6][7][8][9].…”

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