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Infant colic is a common condition with unclear biologic underpinnings and limited treatment options. We hypothesized that complex molecular networks within human milk (i.e., microbes, micro-ribonucleic acids (miRNAs), cytokines) would contribute to colic risk, while controlling for medical, social, and nutritional variables. This hypothesis was tested in a cohort of 182 breastfed infants, assessed with a modified Infant Colic Scale at 1 month. RNA sequencing was used to interrogate microbial and miRNA features. Luminex assays were used to measure growth factors and cytokines. Milk from mothers of infants with colic (<i>n</i> = 28) displayed higher levels of <i>Staphylococcus</i> (adj. <i>p</i> = 0.038, <i>d</i> = 0.30), miR-224-3p (adj. <i>p</i> = 0.023, <i>d</i> = 0.33), miR-125b-5p (adj. <i>p</i> = 0.028, <i>d</i> = 0.29), let-7a-5p (adj. <i>p</i> = 0.028, <i>d</i> = 0.27), and miR-205-5p (adj. <i>p</i> = 0.029, <i>d</i> = 0.26) compared to milk from non-colic mother–infant dyads (<i>n</i> = 154). Colic symptom severity was directly associated with milk hepatocyte growth factor levels (<i>R</i> = 0.21, <i>p</i> = 0.025). A regression model involving let-7a-5p, miR-29a-3p, and <i>Lactobacillus</i> accurately modeled colic risk (<i>X</i>² = 16.7, <i>p</i> = 0.001). Molecular factors within human milk may impact colic risk, and provide support for a dysbiotic/inflammatory model of colic pathophysiology.