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Obesity is a global phenomenon that increasingly affects Western societies and is prevalent among women of reproductive age. Epidemiological studies have shown that maternal obesity before and during pregnancy is associated with increased prevalence of neuropsychiatric conditions in the offspring, including the rapidly increasing prevalence of attention-deficit/hyperactivity disorder, autism spectrum disorder and cognitive impairments.

“…perinatal influences play an important role in brain development…”

As discussed in previous posts, perinatal influences play an important role in brain development, starting with environmental influences on the pregnant mother in the form of diet and psychosocial stress, to the mode of delivery and postnatal events, including breastfeeding. The developing central nervous system is highly sensitive to nutrient changes during the perinatal period, emphasizing the potential impact of alterations of maternal diet on offspring brain development and behavior. A growing body of research implicates the gut microbiota in neurodevelopment and behavior.

“…changes in maternal gut microbiota, due to a high fat diet, … leading to long-term behavioral outcomes in adolescent offspring”.

An article by Anna Ratsika from the research team of John Cryan at the APC Microbiome Ireland, Biosciences Institute, University College Cork recently published in the journal Brain, Behavior and Immunity entitled “Maternal high-fat diet-induced microbiota changes are associated with alterations in embryonic brain metabolites and adolescent behaviour” focuses on how a maternal high-fat diet (mHFD) during pregnancy impacts the microbiota, brain development, and behavior of the offspring. The study results suggest that changes in maternal gut microbiota, due to a mHFD, alter the fetal brain’s metabolic environment and influence neurodevelopment, leading to long-term behavioral outcomes in adolescent offspring. The results emphasize the importance of the maternal microbiome, signaling through the placenta to the developing fetal brain in modulating brain function and behavior in the offspring.

The study performed in laboratory mice showed that a mHFD during pregnancy altered the gut microbiota in the mother, particularly increasing levels of certain microbial taxa including Akkermansia municiphila and Bacteroides vulgatus, while decreasing beneficial short-chain fatty acid (SCFA)-producing bacteria such as Lachnospiraceae. These changes in maternal microbiota were linked to increased levels of neuroactive metabolites like the tryptophan metabolite kynurenine, which can negatively affect brain plasticity and behavior. The observed altered microbiota profile was associated with the potential release of neurotoxic substances that can be transferred to the fetus via the maternal bloodstream.

At embryonic day 18, fetal brains from mothers on a HFD showed altered neuroactive metabolites, particularly those involved in neuronal signaling involving glutamate. Glutamate is the major excitatory neurotransmitter in the brain, and imbalances can lead to impaired neural communication in fetal brains from mHFD mothers. Significant reductions in glutamate and glutathione disulfide, a natural antioxidant produced by the brain were observed, both of which are key in maintaining proper neuronal function. The kynurenine pathway (which plays a role in brain health) was also disrupted, with elevated levels of kynurenine observed in fetal brains, potentially leading to neurotoxicity and neurodevelopmental challenges.

“Microglia showed increased activation and altered gene expression in fetuses exposed to mHFD.”

Microglia are the primary immune cells in the brain and their numbers equal the numbers of nerve cells. Microglia showed increased activation and altered gene expression in fetuses exposed to mHFD. These alterations are significant as microglia play a critical role in neuroinflammation and in shaping synaptic connections during early brain development. Based on their findings, the authors hypothesized that changes in maternal microbiota due to mHFD influence fetal microglia development, leading to potential disruptions in brain development and synaptic formation.

Offspring exposed to mHFD exhibited behavioral changes during adolescence, including increased locomotor activity and anxiety-like behavior. These changes were found to be sex-dependent, with females showing greater hyperactivity and anxiety. The investigators observed alterations in the expression of glutamate-related genes in the amygdala, a region of the brain linked to emotion and anxiety. In particular, key glutamate receptors and enzymes involved in glutamate metabolism were dysregulated in mHFD offspring, suggesting that these neurochemical changes may underlie the observed behavioral outcomes.

“The study emphasizes the role of maternal diet in priming the brain for altered neurodevelopmental outcomes.”

The mHFD not only influenced brain development in the fetal stage but also had enduring effects on the expression of genes related to glutamatergic signaling in the adolescent brain. This was particularly evident in the amygdala, where changes in the expression of glutamate receptors and other related genes persisted into adolescence, contributing to the observed behavioral alterations. The study emphasizes the role of maternal diet in priming the brain for altered neurodevelopmental outcomes, with a particular focus on glutamate signaling pathways. This priming may predispose offspring to behavioral and neurodevelopmental disorders, such as anxiety and hyperactivity.

The findings are consistent with previous preclinical and clinical observations, underscoring the importance of maternal diet during pregnancy in shaping the gut-brain axis and influencing offspring brain development and behavior. Even though it is always challenging to translate mechanistic data from experiments in laboratory mice to human subjects, clinical reports about the correlation of maternal metabolic health and obesity with increased risks for developmental disorders are consistent with these preclinical findings. With the growing prevalence of obesity related largely to the unhealthy Standard American Diet, high in sugar and fat, and the associated increase in mental disorders, in particular autism spectrum disorders in children and adolescents, these findings highlight the importance of maintaining a healthy diet for women planning to become pregnant, as maternal nutrition plays a critical role in the long-term health of the offspring.

“Adhering to a healthy diet during pregnancy, and aiming for a normal BMI should be viewed as a key strategies to prevent the development of chronic mental problems in the offspring.”

The study suggests that changes in maternal gut microbiota due to an mHFD can lead to altered fetal brain metabolites, particularly glutamate-related compounds, which in turn impact neurodevelopment and contribute to behavioral changes in adolescence. These results highlight the potential for early interventions targeting maternal diet and microbiota to mitigate adverse neurodevelopmental outcomes in offspring.

Maintaining a healthy diet during pregnancy, and aiming for a normal BMI should not be considered as part of what is often referred to as “fat shaming”, and get embroiled in political disagreements, but should be viewed as a key strategy to prevent the development of chronic mental problems in the offspring.