Gut microbiome-derived short-chain fatty acids are associated with cognitive development among undernourished infants in Northern Ghana: a case-control study

ABSTRACT Infant undernutrition is linked to cognitive deficits and reduced future economic productivity. This makes mitigating its effects on neurodevelopment an important health priority. The gut microbiome is hypothesised to influence host physiology, including brain function, through the production of microbial metabolites such as the short-chain fatty acids (SCFAs). However, direct epidemiological evidence linking SCFAs to infants’ cognitive development remains scarce in low-resourced settings. This study aimed to assess the association between SCFA concentrations and infants’ (6 to 23 months) cognitive development at a tertiary hospital in Northern Ghana. This age- and sex-matched case-control study included 132 infants admitted with severe acute malnutrition and 132 healthy counterparts. Cognitive development was assessed using the Ages and Stages Questionnaire-3. Infant faecal SCFAs (acetate, propionate, butyrate) were quantified via Gas Chromatography-Mass Spectrometry. Associations between SCFAs and atypical cognitive development were analysed using conditional logistic regression, adjusting for covariates. The prevalence of atypical cognitive development was 18.2%. The mean age of infants was 14.92 ± 5.13 months. In the adjusted models, each unit increase in acetate (AOR = 0.88, 95% CI: 0.82-0.95), propionate (AOR = 0.75, 95% CI: 0.63-0.87), and butyrate (AOR = 0.72, 95% CI: 0.60-0.87) was associated with 12%, 25% and 28% significantly reduced likelihood of atypical cognitive development, respectively (p < 0.001 for all). This study provides evidence that SCFAs may influence cognitive development among infants. Effective strategies are urgently needed to specifically enhance SCFA production among undernourished infants. Such strategies may include continued breastfeeding, diversified dietary intake, or targeted prebiotic supplementation.