Oxidized Milk Induces Spatial Learning and Memory Impairment by Altering Gut Microbiota in Offspring Mice during Pregnancy and Lactation

Early adverse diet exposures are known to be associated with increased risk of learning and memory injury in offspring, yet whether oxidized milk is involved in such an effect has been largely unknown. Here, we focused on oxidized milk intake in mice during pregnancy and lactation to measure the changes in the learning and memory ability in offspring and also probed into the relevant association with gut microbiota. Milk was oxidized with H₂O₂-Cu or HClO, resulting in different degrees of oxidative damage. KM female mice were fed H₂O₂-Cu, HClO, or normal control diets immediately after caging until their offspring were 3-weeks old. Behavioral tests were then performed to test the learning and memory ability, and 16S rRNA sequencing was completed with harvested fecal contents. As analyzed, fecal microflora in mice with oxidized milk was affected, mainly reflected in decreased mucin-degrading bacteria, Akkermansia and Lactobacillus, and in reversely increased pro-inflammatory bacteria Shigella, pathobiont Mucispirillum, nervous associated bacteria Ruminococcus, Escherichia, and Desulfovibrio. In the meantime, the inflammation developed in mice was aggravated accompanied by increased expression of relevant genes, while the genes and proteins associated with the learning and memory ability were down-regulated. Further behavioral tests proved impairment of the learning and memory ability in offspring. In general, milk of oxidative damage is a risk factor of the impaired transgenerational ability in learning and memory, which is associated with gut microbiota and intestinal mucosa conditions. This finding may help support the potential of early adverse diet as a harmful factor in learning and memory.