Microbiota From Human Infants Consuming Secretors Mothers' Milk Affects Murine Intestinal Motility and Enteric Nervous System Development in a Sex‐Dependent Manner

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Abstract
Background: Early life is a critical period in which the gut microbiome and the enteric nervous system (ENS) develop together, shaping long‐term gastrointestinal (GI) function. Human milk feeding and particularly maternal secretor phenotype strongly influence early microbiome composition. However, how human milk promoted microbiomes impact ENS development is still largely unknown. Methods: Male and female juvenile (three weeks old) C57BL/6 germ‐free mice were colonized with fecal microbiota from infants whose mothers were secretors (SMM, 2‐fucosyl lactose in milk) or non‐secretors (NSM) or from infants consuming cow's milk formula (MFM). Non‐transplanted male and female germ‐free mice served as controls. GI transit was assessed at post‐natal day 35‐37. ENS neuronal and glial organization was evaluated in full‐thickness colon preparations using immunohistochemistry and confocal microscopy. Key Results: Female germ‐free mice receiving SMM exhibited higher distal GI transit efficiency and a higher proportion of nitrergic neurons in the myenteric plexus compared to sex‐matched controls and to males. Choline acetyltransferase (ChAT; marker for excitatory cholinergic neurons) immunoreactivity was higher in the myenteric ganglia of germ‐free female compared to male mice. ChAT immunoreactivity increased in SMM and MFM males, while it was significantly reduced in NSM and MFM females compared to controls. Infant microbiomes did not affect myenteric glial cells, which were more abundant in males than females across all groups. Conclusions and Inferences: Our findings demonstrate that early‐life maternal secretor‐associated infant microbiomes exert sex‐specific effects on ENS neuronal phenotypes and GI motility, underlying a previously unrecognized link between infant‐derived microbiomes and ENS development that warrants investigation in larger cohorts.
Funding Information
  • U.S. Department of Agriculture (6026‐10700‐001‐000D)
  • U.S. Department of Agriculture (6026‐51000‐012‐000D)

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