Short-Chain Fatty Acids May Mediate the Effects of Maternal Malnutrition on Fetal Neurodevelopmental Outcomes via Regulation of HDAC4 Expression
Introduction. In 2019, one-third of women of childbearing age were considered obese.1 Maternal malnutrition, including obesity, high-fat diet, and low-fiber diet, is associated with many neurodevelopmental disorders.2 Gut microbiota dysbiosis may play a mechanistic role in pathogenic pregnancy outcomes because of its role in the production of short-chain fatty acids (SCFAs), which are known to influence central nervous system function in adulthood.2 Methods. A literature review was performed to assess the relationship between maternal obesity, the maternal gut microbiome, and fetal neurocognitive outcomes. This analysis also identified studies in animal models, which were reviewed to assess differences in maternal gut microbiota in pregnant mice and their effects on offspring. Additionally, our literature review identified potential therapeutics that may hold promise in reversing maternal diet-induced neurocognitive deficits. Results. A review of the literature showed that pregnant mice fed a low-fiber (MLFD) or normal (MND) diet exhibited significant differences in beta diversity in their gut microbiome, indicating differences in overall composition.3 Specifically, MLFD mothers had lower Bacteroidetes and higher Firmicutes levels.3 MLFD offspring had decreased levels of butyrate and propionate and exhibited decreased general locomotor activity, increased anxiety levels, and worsened spatial learning and memory compared to MND mice.3 Similarly, transplant of the gut microbiota of a high-fat diet (HFD) mouse into a mouse previously fed the control low-fat diet (CD) resulted in neurocognitive deficits.4 Male offspring of HFD recipients demonstrated more anxiety, compulsive behavior, and worsened memory compared to control mice.4 Interestingly, supplementation of the SCFA butyrate reversed the deficits in MLFD offspring and changed gene expression.3 Butyrate-supplemented MLFD offspring mice showed improved anxiety and spatial memory and increased locomotor activity.3 Butyrate exposure to hippocampal cells from MLFD offspring reduced the expression of the histone deacetylase 4 (Hdac4) gene and increased the expression of the synaptic plasticity-related genes NR2B and GLUR2 in a concentration-dependent manner.3 Hdac4 knockout increased the expression of the proteins NR2B and GLUR2.3 Additionally, probiotics can increase levels of SCFAs in the setting of maternal malnutrition. Perinatal probiotic administration increased levels of gut butyrate, brain lactate, and BDNF and other plasticity-related genes compared to control mice.5 Furthermore, the breast milk of probiotic-fed dams contained significantly higher levels of SCFAs than the control HFD dams.5 Conclusions. Maternal malnutrition disrupts the microbiome, limiting SCFA availability to the fetus in utero. This decrease in SCFA levels may perturb normal neurocognitive development by decreasing inhibition of HDAC4. However, probiotics and SCFA supplementation present promise in preventing these deficits.
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- Sanchez CE, Barry C, Sabhlok A, et al. Maternal pre-pregnancy obesity and child neurodevelopmental outcomes: A Meta-analysis. Obesity Review. 2018;19(4):464-484. doi:10.1111/obr.12643
- Yu L, Zhong X, He Y, Shi Y. Butyrate, but not propionate, reverses maternal diet-induced neurocognitive deficits in offspring. Pharmacological Research. 2020;160:105082. doi:10.1016/j.phrs.2020.105082
- Bruce-Keller AJ, Fernandez-Kim SO, Townsend RL, et al. Maternal obese-type gut microbiota differentially impact cognition, anxiety and compulsive behavior in male and female offspring in mice. PLOS ONE. 2017;12(4):e0175577. doi:10.1371/journal.pone.0175577
- Radford-Smith DE, Probert F, Burnet PWJ, Anthony DC. Modifying the maternal microbiota alters the gut-brain metabolome and prevents emotional dysfunction in the adult offspring of obese dams. Proc Natl Acad Sci U S A. 2022;119(9):e2108581119. doi:10.1073/pnas.2108581119