Early-life gastrointestinal inflammation and the developing brain: Unravelling the pathways to long-term cognitive dysfunction

Table 4 The longitudinal human cohort studies linking the burden of early childhood enteric infections to long-term cognitive and neurodevelopmental deficits

Ref.	Population/cohort	Exposure	Key findings on learning, memory, and intelligence quotient
Niehaus et al[141], 2002 and Pinkerton et al[142], 2016	Cohort of children from a Brazilian shantytown (followed to 5.6-12.7 years)	ECD in the first 2 years of life	ECD is a significant inverse predictor of later childhood cognitive function (lower test of nonverbal intelligence and Wechsler Intelligence Scale for Children-Third Edition Coding scores). This effect was independent of malnutrition (stunting/wasting) and maternal education
MAL-ED Network Investigators[139], 2014	Multi-site longitudinal birth cohort	Enteropathogen infection causing intestinal inflammation	Established the core study hypothesis: Enteropathogen infection leads to intestinal inflammation, which causes growth faltering and deficits in cognitive development
MAL-ED Network Investigators[140], 2018	Longitudinal birth cohort in 6 low/middle-income countries (birth to 24 months)	Higher rates of enteropathogen detection and days with illness	Negatively associated with lower cognitive scores at 24 months. Higher illness rates were linked to lower hemoglobin concentrations, which in turn predicted lower cognitive scores
Upadhyay et al[143], 2021	low birth weight infants (North India)	Increased number of diarrheal episodes in the first year	Negatively influenced composite scores in all three domains assessed: Cognitive, motor, and language at 12 months. Linear growth and diarrheal prevention are crucial factors
El Wakeel et al[144], 2022	Malnourished, stunted children (Egypt, age 1-10 years)	Intestinal inflammation (high fecal markers) and micronutrient deficiency (zinc, iron, vitamin D)	Showed impaired neurocognitive and psychomotor functions. Cognitive performance was negatively correlated with both fecal and serum inflammatory markers
Streit et al[145], 2021	Children (n = 380, age 45 months)	Fecal microbiome profile (relative abundance of specific taxa)	Microbiome profile was significantly associated with cognitive functioning (Wechsler Preschool and Primary Scale of Intelligence-Third Edition scores). Found a strong inverse correlation between cognitive scores and a genus related to Enterobacter asburiae

It aggregates evidence from large-scale human cohort studies (like MAL-ED) that track the long-term relationship between early childhood gut health (measured by diarrheal frequency, pathogen detection, and intestinal inflammation markers) and neurodevelopmental outcomes in later childhood (measured by intelligence quotient, cognitive, motor, and language scores). Findings highlight that the negative impact of early enteric disease on cognitive function is often independent of malnutrition, suggesting a direct gut-brain axis mechanism. ECD: Early childhood diarrhea.