期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：9
DOI：10.1073/pnas.2108581119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Maternal obesity is a growing public health concern and is linked to an increased risk of neurodevelopmental and psychiatric disorders in humans. Despite accumulating evidence for the important role maternal microbes play during gestation and nursing, the longitudinal effect of maternal nutrition on offspring metabolism across the gut–brain axis at different ages remains unexplored. We provide evidence for the protective efficacy of perinatal probiotic exposure against increased anxiety-like behaviors induced by maternal obesity. Protection was maintained into adulthood, which may be mediated by the enhancement of brain energy metabolites and an increase in gut butyrate. These findings reveal the importance and long-lasting role of maternally derived microbiota and metabolites in increasing resilience to mood disorders in the offspring.
Maternal obesity disturbs brain–gut–microbiota interactions and induces negative affect in the offspring, but its impact on gut and brain metabolism in the offspring (F1) are unknown. Here, we tested whether perinatal intake of a multispecies probiotic could mitigate the abnormal emotional behavior in the juvenile and adult offspring of obese dams. Untargeted NMR-based metabolomic profiling and gene-expression analysis throughout the gut–brain axis were then used to investigate the biology underpinning behavioral changes in the dams and their offspring. Prolonged high-fat diet feeding reduced maternal gut short-chain fatty acid abundance, increased markers of peripheral inflammation, and decreased the abundance of neuroactive metabolites in maternal milk during nursing. Both juvenile (postnatal day [PND] 21) and adult (PND112) offspring of obese dams exhibited increased anxiety-like behavior, which were prevented by perinatal probiotic exposure. Maternal probiotic treatment increased gut butyrate and brain lactate in the juvenile and adult offspring and increased the expression of prefrontal cortex
PFKFB3, a marker of glycolytic metabolism in astrocytes.
PFKFB3 expression correlated with the increase in gut butyrate in the juvenile and adult offspring. Maternal obesity reduced synaptophysin expression in the adult offspring, while perinatal probiotic exposure increased expression of brain-derived neurotrophic factor. Finally, we showed that the resilience of juvenile and adult offspring to anxiety-like behavior was most prominently associated with increased brain lactate abundance, independent of maternal group. Taken together, we show that maternal probiotic supplementation exerts a long-lasting effect on offspring neuroplasticity and the offspring gut–liver–brain metabolome, increasing resilience to emotional dysfunction induced by maternal obesity.
