Natural history and impact of Giardia lamblia on child growth attainment and associated pathway-specific biomarkers in a Nicaraguan birth cohort

BackgroundGiardia lamblia (Giardia) is one of the most common intestinal parasitic infections globally, with an estimated 280 million symptomatic infections annually. In children from low-and middle-income countries (LMICs), Giardia is highly prevalent and has been associated with loss of intestinal barrier function, nutrient-metabolic dysregulation, and linear growth impairment, but specific mechanisms linking Giardia to these outcomes remain poorly understood. Methods and resultsWe used data and samples from a subset of 76 children in a longitudinal birth cohort in Nicaragua to evaluate the natural history and geospatial distribution of Giardia infections, child growth outcomes (weight-for-age [WAZ] and length-for-age [LAZ] z scores), and relationships with established biomarkers of inflammation, intestinal damage, and growth-signaling. During the first 36 months of life, we tested 2,305 stools (1,903 surveillance stools and 402 diarrheal stools) for Giardia by qPCR. The incidence of Giardia-positive stools was 59.6 per 100 child-years. Any detection of Giardia was associated with a reduction in LAZ at 36 months of life ({beta}:-0.16, P=0.042). This effect increased when considering persistent or recurrent Giardia detections ({beta}:-0.26, P=<0.001) as well as living in a high-density Giardia detection area ({beta}:-0.44, P=<0.001). Among intestinal markers, Giardia was only associated with lower median fecal neopterin (a marker of chronic intestinal T cell activation) at 24 and 36 months of age. Among serum systemic biomarkers measured at 24 months, Giardia detections were associated with indicators of intestinal epithelial cell damage (higher median Intestinal Fatty Acid Binding Protein (P=0.002) and Anti-FliC IgA (P=0.033), and reduced growth-signaling hormone (lower median Insulin-like Growth Factor (IGF-1) (P=0.005). ConclusionGiardia detection was negatively associated with linear growth in an exposure-dependent manner. Simultaneously, Giardia associates with diminished serum growth-signaling hormones. Patterns of serum and fecal intestinal biomarkers suggest that Giardia-mediated epithelial disruption is dissociated from markers of intestinal inflammation. Author SummaryAlthough Giardia was recognized as a pathogen by the World Health Organization in 1981, its long-term effects on child health, particularly in endemic areas, remain poorly understood. One major challenge is that most Giardia infections are asymptomatic and go unreported, leading to an underestimation of not only its true burden but also its association with child health outcomes. While a link between Giardia and impaired linear growth is becoming clearer in large prospective child cohorts, considerable variability persists in the strength and consistency of this association across studies. Moreover, the mechanistic pathways underlying long-term sequelae in children remain elusive. To contribute to this field, we leveraged a birth cohort with longitudinal biosampling to study Giardia infections and their impact on child growth. We found that Giardia infection was negatively associated with length-for-age and Insulin-like Growth Factor 1 (IGF-1) levels, positively associated with biomarkers of intestinal epithelial disruption, yet uncoupled from markers of systemic inflammation and intestinal inflammation. The association with poor linear growth, epithelial disruption, and reduced growth signaling from intestinal inflammation which is a unique characteristic of Giardia, requires further investigation of its pathophysiology.