I deficit nutrizionali di Omega-3 possono influenzare il microbiota intestinale e contribuire allo sviluppo dell'autismo?

Intestinal homeostasis, which involves both the gut microbiota and the gut-microbiota-brain axis, both prenatal and postnatal, appears to be one of the important factors involved in the clinical manifestation ofAutism (ASD). Due to the wide heterogeneity among studies, it is not possible to draw any definitive conclusions about the effect of omega-3 PUFAs. The effects of Omega-3 PUFAs have shown limited improvement in autism symptoms, particularly on stereotyped behavior and social behavior, which includes social awareness, social motivation, and communication function, as well as language development, hyperactivity, repetitive behavior, motor skills, and concentration in various studies. 

Maternal inflammation during pregnancy and autism

Epidemiological studies indicate a strong association between maternal inflammation and the pathogenesis of ASD. During pregnancy, pathogens are thought to increase the risk of neurodevelopmental disorders in offspring depending on the timing of infection and the extent of the maternal immune response. Pathogenic microbiota, bacterial metabolites, and their components can stimulate the secretion of proinflammatory cytokines. These maternal cytokines can cross the placental barrier and stimulate de novo synthesis of cytokines in the fetal brain, making the fetal brain sensitive to changes in neurological development. In addition, placental inflammation can induce a systemic fetal inflammatory response that contributes to white matter damage in the fetal brain. This type of inflammation also leads to neonatal brain damage. The presence of various levels of inflammatory cytokines has been found in the blood, especially in monocytes, in serum and plasma, as well as in brain tissue and cerebrospinal fluid of patients with ASD, which leads to impaired immune capacity of the CNS and increased microglial activation in the brain. Chronic microglial activation contributes to the development and progression of neurodegenerative disorders. Active microglia can induce the production of proinflammatory cytokines such as interleukin 1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor α (TNF-α), which are typically intended to prevent further damage to brain tissue. Abnormal activation of microglia is sometimes toxic to neurons and other glial cells.

Many studies have confirmed the presence of activated microglia, accompanied by proinflammatory factors such as cytokines and chemokines in the brain and cerebrospinal fluid in the dorsolateral prefrontal cortex of patients with ASD. Deficits in microglial activity during brain development lead to an increase in the number of immature synapses, and thus to the cognitive and behavioral disorders typical of patients with ASD. Inflammation that occurs in the form of elevated levels of cytokines is transmitted through the blood-brain barrier and initiates a neuroinflammatory response that has been offered as an explanation for subsequent neurological development complications, including cerebral palsy, autism, schizophrenia, and cognitive disorders. Although supplementation with PUFAs may reduce inflammation and improve the balance between pro- and anti-inflammatory cytokines, the effects of PUFAs on subsequent neurological development complications are unclear.

The immunophenotypes that can be observed in patients with ASD are characterized by a high proinflammatory state, i.e., high levels of cytokines and chemokines, including IL-1β, IL-6, interferon µ (IFN-µ), tumor necrosis factor α (TNF-α), interleukin 12 beta subunit (also known as IL-12 p40 subunit), MCP-1 (monocyte chemoattractant protein 1, cytokine also known as CCL-2), TGF-β (transforming growth factor-β), and hyperactive cellular immune responses. However, immune abnormalities, including differentiation of the immune/cytokine profile, are the result of the diet, lifestyle, and genetic profile of each patient with ASD, and this makes it difficult to identify the links between maternal inflammation, diet/supplementation, and changes in ASD in children.

Maternal PUFA status during pregnancy and autism

It has been shown that maternal omega-3 PUFA status not only regulates microglial activity and neuroinflammatory pathways during brain development, but also affects brain plasticity. Omega-3 PUFA intake during pregnancy or the early postnatal period and changes in the structure of the gut microbiota can influence the onset of neuropsychiatric disorders. The authors of the study highlighted that in utero and in the early years of life, the intake of omega-3 PUFAs, particularly EPA and DHA, regulates the development of the gut microbiota, influencing the abundance and types of bacteria in adolescence and adulthood and influences social and communicative behavior throughout life. Reduced omega-3 intake in the early years of life can induce discrete psychiatric abnormalities in adolescence that manifest as communication, behavioral, and memory disorders. Omega-3 PUFAs are essential for preventing behavioral and neurodegenerative disorders later in life. It has been shown that a DHA deficit during the perinatal period is associated with reduced neurogenesis and delays in neuronal migration. These findings suggest that the availability of adequate amounts of various PUFAs (both omega-6 and omega-3 fatty acids), particularly AA and DHA, is recommended for the fetus and newborn. In fact, women with higher PUFA intake before and during pregnancy have a reduced risk of having a child with ASD compared to those with lower PUFA intake. Omega-3 PUFA is recommended for consumption during the last week of gestation and the first month after birth for brain development; supplementation with omega-3 PUFA, especially during pregnancy and breastfeeding, may help prevent ASD in at-risk children.

In the study by Steenweg-de Graaff et al. on pregnancies among younger siblings at high risk, an association was evaluated between higher maternal intake of total omega-3 PUFAs in the second half of pregnancy and a reduced risk of ASD in offspring. A total of 258 mother-child pairs were included. Mothers who consumed more total omega-3 in the second half of pregnancy were 40% less likely to have children with ASD. This study provides suggestive evidence of associations between the risk of ASD in children and maternal omega-3 intake in late pregnancy, but not with third trimester plasma PUFAs.

The role of Omega-3 PUFA supplementation in ASD symptoms

Even though, to date, no treatment has been fully successful in preventing ASD, a combination of complementary interventions, including interventions with PUFAs, which are considered very low risk, could provide added value to standard medical and psychological interventions to reduce behavioral problems in children. The adjuvant effects of interventions with essential fatty acids are reflected in the attenuation of behavioral symptoms and could be studied in addition to behavioral therapy in ASD. Supplementation with PUFAs can be considered only as one aspect in regulating the biological state of the organism, and the balanced biological state of the organism represents the basis for other complementary treatments aimed at improving psychophysiological characteristics in children with ASD. 

However, in order to reach a final conclusion on the effect of omega-3 PUFAs on ASD, high-quality studies on a larger group of children with ASD and on the use of omega-3 PUFAs as the only supplementation are justified.