Reconsidering early-life bile acid amidation defect in environmental enteric dysfunction

Abstract

Hasan et al presented compelling cross-sectional evidence that Bangladeshi infants aged 6-9 months with environmental enteric dysfunction (EED) exhibit an age-dependent defect in primary bile acid conjugation, concurrent elevations in unconjugated and sulfated primary bile acids, reduced primary conjugated bile acids, and associations between bile acid profiles, small intestinal bacterial overgrowth, enteric inflammation, and impaired linear growth. Their findings have raised important mechanistic and translational questions: Was delayed maturation of bile acid amidation a driver of malabsorption and growth faltering in EED, or a downstream marker of intestinal injury and microbiome immaturity? Did altered bile acid pools contribute to intestinal inflammation and barrier dysfunction via signaling pathways (farnesoid X receptor/Takeda G protein-coupled receptor 5) or via nutrient malabsorption, like lipid and fat-soluble vitamins? Could targeted bile acid replacement, like glycocholic acid or microbiome-directed interventions, offer therapeutic benefit in selected infants? This Letter highlights these key considerations, outlines testable hypotheses and practical next steps for the field, and calls for coordinated longitudinal, mechanistic, and interventional studies to clarify causality and translate these observations into interventions that might mitigate EED-associated stunting.

Keywords: Bile acid metabolism; Malnutrition; Environmental enteric dysfunction; Small intestinal bacterial overgrowth; Bangladesh

Core Tip: This study identifies a previously unrecognized defect in bile acid conjugation among Bangladeshi infants with environmental enteric dysfunction, linking altered bile acid metabolism to poor growth and intestinal inflammation. Elevated unconjugated primary bile acids were strongly associated with anthropometry. Further, the findings highlight a possible age-related delay in the maturation of bile acid conjugation pathways in impoverished children. This study may provide the initial insights for exploring novel therapeutic targets through bile acid pathways for treating malnourished children worldwide.