Scientists are uncovering how what mothers eat during pregnancy could influence gut microbes and shape brain development in their children, potentially influencing autism risk in the next generation.
Study: Effect of maternal diet on gut bacteria and autism spectrum disorder in offspring. Image credit: Prostock-studio/Shutterstock.com
Autism spectrum disorder (ASD) covers a range of early childhood neurodevelopmental disorders with some common features but widely varying manifestations. Over decades, there has been extensive research into the role of gut dysbiosis in children, indicating the importance of the maternal diet. A paper published on Frontiers in Cellular Neuroscience reviewed how unhealthy maternal dietary patterns may influence the microbiota-gut-brain axis (MGBA) and potentially increase the risk of ASD in offspring.
Introduction
ASD is linked to genetic and environmental factors, including immune-inflammatory pathways, and the resulting dysregulation of neural pathways; however, 40% of ASD patients present with gut symptoms. Typically, the severity of ASD correlates with the severity of gut issues.
Dysbiosis-activated immune pathways could impair the regulation of brain neurotransmission networks and trigger hyper-inflammatory responses. These may both initiate and promote the progression of ASD.
A healthy gut microbiome has between 500 and 1,000 bacterial species. These trillions of microbes regulate the energy balance and nutritional cycle. They help preserve the integrity of the intestinal mucosa, promote innate and adaptive immunity, and drive neurodevelopment.
In fetal life, the gut is colonized by metabolically active bacteria, albeit in lower abundance than in later life. The fetal and newborn gut microbiome is influenced by exposure to the maternal gut microbiome and, hence, by the maternal diet.
Unhealthy dietary habits during pregnancy induce maternal gut dysbiosis, adversely affecting the fetal gut microbiome via the gut-placental axis. Such habits occurring during breastfeeding alter breast milk composition, impacting the infant’s gut bacteria.
The current study examined the inter-relationship of maternal diet with ASD risk via the gut microbiome.
The role of food
Preclinical research suggests that a diet high in sugar, salt, and unhealthy fats (saturated and trans fats, for instance) could promote the growth of pathogenic bacteria and inhibit beneficial bacteria (such as Bifidobacterium and Lactobacillus species). Pathogenic bacterial proliferation triggers the immune system, induces intestinal inflammation, and damages the intestinal mucosa. Excessive sugar also thins the protective mucus covering the intestinal lining epithelium, potentially leading to colitis.
Mothers exposed to highly salted diets around the time of childbirth are more likely to have offspring with gut dysbiosis. Glucocorticoid production in the gut is observed with a high-salt diet, driving up local and blood levels of stress hormones. Excess salt also worsens colitis and decreases serum short-chain fatty acids (SCFAs), which have a range of vital homeostatic functions.
When exposed to a high-fat diet, gut microbes produce reactive oxygen species. This oxidative stress disrupts mitochondrial function and leads to the apoptosis of intestinal epithelial cells, injuring the epithelial barrier. Interestingly, female mice had different, though specific, changes in their gut microbiota compared to males, suggesting that there are sex-specific responses to a high-fat diet and that sex differences appear across multiple MGBA signaling pathways.
Ultraprocessed food (UPF) is rich in unhealthy fat, sugar, salt, and additives. It can trigger gut dysbiosis, especially via ingredients like artificial sweeteners, emulsifiers, and colorants. This is observed in children who consume too much UPF. Again, UPF intake in pregnancy correlated inversely with language development in early childhood, indicating its impact on developing cognitive functions.
In contrast, green or oolong tea and probiotics improve the microbiome profile. Dietary supplements could help reduce the impact of such high-fat diets by providing probiotics like Lactobacillus species that correct or prevent the impending imbalance of the gut microbiota and metabolism. Such species may improve lipid metabolism and enhance SCFA production via gut microbiome modulation.
Alcohol
Drinking may negatively affect the gut microbiome, causing increased gut permeability and micronutrient deficiencies. Endotoxins enter the bloodstream from the gut lumen and may predispose offspring to a host of autoimmune conditions, neurological illnesses, and metabolic disorders. The SCFA butyric acid is produced at lower levels.
Inert carbohydrates like inulin do not improve liver function or reduce inflammation in alcoholics. They improve social behavior and increase the blood levels of brain-derived neurotrophic factor (BDNF), a key molecule for synaptic plasticity and brain recovery from injury.
Fiber
Fiber is key to enzymatic activity that produces active molecules, including SCFAs, from residual carbohydrates. It enhances gut microbial diversity and has an anti-inflammatory effect. Preclinical research suggests that too little dietary fiber is associated with functional and immune-linked gut disorders and memory deficits.
A fiber-rich diet during pregnancy is linked to a lower risk of obesity and diabetes, with fewer risk factors in the offspring. Inulin supplementation during pregnancy boosts SCFA production and improves the gut microbiome.
Maternal and fetal microbiome
The maternal gut microbiome alters gene expression in multiple areas, such as neurological function, energy balance, and immunity. It changes considerably over pregnancy, increasing the levels of key nutrients that promote fetal growth.
A healthy maternal diet stimulates proper placental growth and nutrient transfer. The gut microbes produce extracellular vesicles that interact with the fetus and trigger the nascent immune system and newborn gut colonization. Gut dysbiosis deprives the fetus of critical metabolites, disrupting immune regulation and predisposing to later-life inflammation and infection.
Breastfeeding provides nutrients and commensal bacteria to seed the infant's oral cavity and gut. Simple sugars may encourage pathogens like Enterobacteriaceae in breast milk while reducing good bacteria like Bifidobacterium species.
Formula-fed infants have the same altered gut microbiome picture. Failing exclusive breastfeeding, infant formulas should include specific human milk oligosaccharides (HMOs), like HMO-2’-fucose-based lactose, either alone or supplemented with lactulose-n-neotetrasaccharide.
“This adjustment can stimulate the development of gut bacteria, predominantly Bifidobacterium spp., balance the gut microbiota, and enhance the immunity of newborns.”
A formula based on goat milk has been reported to selectively increase beneficial taxa compared to standard cow’s milk formula; whether this is a clinical benefit remains to be tested in trials. Other options are maternal probiotics or ensuring that the maternal diet includes polyunsaturated fatty acids and vitamins.
ASD and gut dysbiosis
The microbiota-gut-brain axis is a two-way communication system that regulates and directs neurodevelopment via a host of pathways. These involve the immune system, neurotransmitters, the hypothalamo-pituitary-adrenal (HPA) axis, and microbial metabolites, including SCFAs and amino acids like tryptophan derivatives. The gut microbiota has a bidirectional relationship with the levels of sex steroids, leading to sex-specific differences.
Multiple hypotheses have been put forward to explain the cause of ASD. Some scientists consider that the leaky gut is the root of systemic inflammation, with a neuroinflammatory component that causes ASD. Immunotherapy to suppress neuroinflammation warrants investigation.
Alternatively, gut dysbiosis can lead to neurotransmitter imbalance, including excitatory and inhibitory networks involving GABA, serotonin, and dopamine. This, in turn, can create a feedback loop that maintains dysbiosis.
A third hypothesis sees ASD as a disorder caused by abnormal gut microbial metabolites, especially the SCFA butyric acid, which shows neuroprotective effects in models; human data on prevention are currently insufficient.
Increased ammonia levels could reduce GABA levels in the brain, resulting in hyperexcitation. Again, dysbiosis-linked lipopolysaccharide release triggers inflammation. Sulfide is another microbial product that can damage the intestinal barrier cells at high concentrations. At low concentrations, however, it could exert antioxidant and anti-inflammatory functions.
The paper also notes that non-bacterial gut components, such as fungi and viruses, are emerging as possible contributors to ASD via MGBA interactions.
Large-scale controlled prospective trials are required to assess potential interventions for their clinical safety and efficacy, whether probiotic formulations, fiber-enriched foods, or personalized nutritional interventions in pregnancy. The question is whether these can prevent ASD or reduce its severity by improving the maternal gut microbiota. Experiments must also look at the mechanisms by which maternal gut bacteria or their metabolites influence neurodevelopmental pathways in fetal and newborn life.
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