Maternal factors contributing to variability in gut microbiota and gastrointestinal function in autism spectrum disorders

Abstract

Autism spectrum disorder is a mental neurodevelopmental condition characterized by social deficits and repetitive behavior, and its development is influenced by genetic and environmental factors. Furthermore, an important factor in etiology is the health status of the mother during pregnancy. Maternal health can critically affect the development of the offspring’s nervous system, including the central nervous system and enteric nervous system. Unfavorable maternal health can disrupt the normal development of the offspring’s nervous system in various ways, such as changes in microbiota composition. As one of the common comorbidities of autism spectrum disorder, no consistent conclusion has been drawn on how poor maternal health affects enteric nervous system and central nervous system development in offspring. From the perspective of maternal health, this review discusses how maternal status affects the gastrointestinal health of offspring and the development of mental systems to raise public awareness of maternal health and provide a new idea for eugenics and childbearing.

Key Words: Autism spectrum disorders; Gastrointestinal problem; Maternal factors; Gut microbiota; Immune activation; Neuron development

Core Tip: The pathogenic factors of autism are closely related to maternal health during pregnancy. Adverse factors during pregnancy, such as infections and psychological stress, can affect the development of the offspring’s central and enteric nervous systems, leading to core symptoms of autism and gastrointestinal problems. Therefore, maternal health during pregnancy must be monitored to reduce the incidence of autism.

INTRODUCTION

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by core symptoms of impaired social communication, repetitive behaviors, and sensory abnormalities[1]. The estimated global prevalence of ASD is approximately 1%; however, it can be higher in some regions[2]. Concurrently, ASD is frequently accompanied by various comorbidities, such as gastrointestinal (GI) symptoms and sleep disturbances[3]. Among these, GI symptoms are the most prevalent comorbidities, affecting up to 4.2%-96.8% of individuals with ASD, and are considered a significant contributor to the overall disease burden[4]. In general, GI symptoms include constipation, abdominal pain, and diarrhea[5]. Emerging evidence suggests a strong link between GI dysfunction and severity of core ASD symptoms; children with more pronounced GI issues often exhibit severe behavioral impairments[6]. Intriguingly, interventions alleviating GI symptoms were found to mitigate core autistic traits, further supporting a potential gut-brain interaction in ASD pathogenesis[7].

The etiology of ASD involves both genetic predisposition and environmental influences. Among environmental factors, maternal health during pregnancy is crucial in fetal neurodevelopment. Maternal immune activation (MIA), metabolic status, and stress during pregnancy can affect the maternal gut microbiota[8], which is associated with abnormal fetal neurodevelopment and increased ASD risk[9].

Maternal abnormalities during pregnancy can affect the development of the offspring’s nervous system, including the central nervous system (CNS) and enteric nervous system (ENS)[4]. In a previous review[10], maternal exposure was reported as a harmful factor affecting microbiota during pregnancy, which can influence the development of the offspring’s CNS and lead to ASD. In addition, the ENS is mainly involved in the mediation of GI motility and GI sensation. If the mother is exposed to harmful environmental factors during pregnancy, the ENS is affected, leading to abnormal conditions[11]. Thus, we can infer that maternal health during pregnancy can affect the gut microbiota. The disruption of the gut microbiota can lead to the abnormal development of the offspring’s ENS and CNS, resulting in ASD-related GI problems.

Given the increasing prevalence of ASD and the substantial effect of GI comorbidities, further investigation into the interplay among maternal influences, gut dysregulation, and neurobehavioral outcomes is essential for the development of targeted therapeutic strategies. This review aimed to discuss the effects of pregnancy on the GI tract and gut microbiota and the role of these effects in the neurodevelopment of offspring and ASD-related GI symptoms, providing more insights into the treatment of ASD-related GI problems.

EFFECT OF PREGNANCY ON A WOMAN’S GI TRACT

As early as 1982, researchers found that pregnancy can affect the GI motility in women through hormones. High progesterone and estradiol levels can prolong the GI transport time[12]. A recent study showed that pregnancy can remodel the intestinal tract and alter intestinal functions[13]. This evidence indicates that pregnancy is among the factors that alters intestinal function and structure, leading to intestinal dysfunction.

Influence of pregnancy on the gut microbiota

Pregnancy is a very complex physiological process that involves changes in multiple aspects of immunity, hormones, circulation, microbial system, etc. During pregnancy, a woman’s gut microbiota is affected by various factors, such as nutrition, mental state, and toxins[14]. Moreover, pregnancy can affect the function of the GI tract and lead to changes in gut microbiota[15].

During pregnancy, the levels of progesterone and estrogen increase dramatically. Meanwhile, the immune system of pregnant women undergoes considerable changes. Progesterone exhibits an immunosuppressive function, inhibiting T cell activation and natural killer cell toxicity, which promotes a Th2 immune response[16,17]. During pregnancy, regulatory T cells expand and secrete anti-inflammatory factors, such as interleukin (IL)-10, to inhibit the antigenic immune response of the mother to the fetus[18]. IL-10 can suppress inflammation during pregnancy in autoimmune model mice and improve the intestinal flora[19]. Estrogen can increase the proportion of regulatory B cells, regulate macrophage function, and indirectly affect the metabolism of the intestinal flora[20-22]. These findings suggest that under normal pregnancy conditions, hormones and immunity influence women’s health, leading to changes in the gut microbiota.

Gut microbiome changes during pregnancy have been studied extensively. In normal pregnancies, beta diversity increases markedly from the first trimester (T1) to the third trimester (T3). Conversely, alpha phylogenetic diversity decreases substantially from T1 to T3. In T1, Clostridium genera such as Faecalibacterium and Eubacterium are significantly increased. In T3, members of the Enterobacteriaceae family and Streptococcus genus are enriched[23]. Bifidobacterium, a probiotic, plays a role in maintaining intestinal health and defending against pathogens. In mice, researchers found significantly increased abundance of Bifidobactem in T3, and progesterone also affected the abundance of several bacterial species[24]. This evidence indicates that pregnancy can affect the microbial community through related hormones such as progesterone. In summary, various factors, such as immunity and hormones, influence the intestinal flora during pregnancy, which is vital to the health of pregnant women.

GUT MICROBIOTA CHANGES UNDER DISEASE CONDITIONS DURING PREGNACY

The gut microbiota is sensitive to various environmental factors. Adverse factors such as infections and pregnancy-related stress can cause changes in women’s gut microbiota, leading to abnormalities in their offspring[15,25]. Thus, this review explored changes in the gut microbiota of women who experienced adverse events during pregnancy, such as pregnancy-related diseases, infections, and mental factors.

Obesity during pregnancy

Due to the physiological changes that occur during pregnancy, many pregnant women may experience different pregnancy-related conditions, such as gestational diabetes and GI symptoms[26]. Buffington et al[27] found that the offsprings of mice that were fed a high-fat diet during pregnancy exhibited impaired social skills and social novelty deficits. Concurrently, oxytocin neurons located in the hypothalamus were damaged, accompanied by changes in the ecology of the gut microbiota. Moreover, supplementation of Lactobacillus reuteri may improve social dysfunction and repair oxytocin neuron function in offspring. Aljumaiah et al[28] found that Clostridium species in type 1 diabetic rats showed overgrowth and could induce autism-like behaviors in the offspring. Treating type 1 diabetic pregnant rats with insulin can reduce inflammation in the brains of their offspring. These findings indicate the importance of fat metabolism for the health of both mother and offspring during pregnancy. It can affect the neurodevelopment of the offspring by influencing the extent of inflammation.

GI symptoms during pregnancy

GI symptoms are common and reduce the quality of life during pregnancy. Owing to the influence of hormones, particularly progesterone, pregnant women often experience symptoms of reduced GI motility, such as constipation[29]. Despite the lack of clinical studies on constipation-related changes in the gut flora in pregnant women, a clinical trial revealed that administering a combination of probiotics to pregnant women can relieve constipation symptoms, such as anorectal sensation and incomplete evacuation[30]. The effect of constipation during pregnancy on the intestinal flora of pregnant women and their offspring’s mental development must be further examined. However, probiotics may be promising agents to treat GI disorders during pregnancy. These findings imply that physiological changes during pregnancy can cause GI symptoms.

Inflammatory bowel disease and infection during pregnancy

Inflammatory bowel disease (IBD) is a chronic disease related to immune system disorders, changes in the intestinal microbiota, and malabsorption of micronutrients. Evidence suggests an association between the genetic susceptibility of mothers to IBD and the characteristics of autism in children[31]. Perinatal IBD may be related to ASD occurrence[32-35]. In a clinical research, women with IBD during pregnancy had reduced gut microbiota diversity and altered bacterial composition. Moreover, the mothers with IBD during pregnancy and their offspring showed decreased levels of Gammaproteobacteria and Bacteroidetes. This phenomenon may be related to the conversion of memory B cells and regulatory T in the colon[36].

MIA during pregnancy

MIA during pregnancy is an important pathogenic factor of ASD. In multiple animal models of MIA, the offspring of animals with perinatal MIA showed high levels of inflammatory factors, social deficits, and stereotyped behaviors[37-39]. Meanwhile, IL-6 and IL-17a are considered to be significantly related to ASD development, and they are significantly increased in the MIA model[40,41].

Maternal prenatal stress

Pregnancy is a long-term process of physiological and psychological changes. During this process, mothers are exposed to various stressors, including social, personal, and psychological factors and disasters[42,43]. The relative abundance of Proteus and Escherichia coli increased in the intestines of mice exposed to maternal prenatal tress, whereas the relative abundance of Lactobacillus decreased[44]. Clinical studies have suggested that during pregnancy, women with high anxiety levels exhibit relatively higher abundance levels of oxalate, acetic acid bacteria, Acidinococcus, and Staphylococcus[45,46]. Maternal prenatal stress induces changes in the composition of the maternal GI and vaginal microbiota, which are vertically transmitted to the offspring, leading to an imbalance in the offspring’s gut microbiota[44,47,48]. Furthermore, stress during pregnancy can lead to the excessive release of cortisol, which can pass through the placenta and breast milk to the fetus, affecting the composition of the fetal gut microbiota[45,49,50]. Maternal prenatal stress can lead to changes in the diversity and abundance of the offspring’s gut microbiota, cause immune and GI dysfunction, and reduce neural innervation of the colon (Figure 1). These effects may increase the risk of digestive symptoms in the offspring[51,52]. Therefore, maternal stress during pregnancy may alter the composition of the maternal gut microbiota and affect the neurodevelopment and behavioral performance of the offspring.

Figure 1 Influence of different conditions on the maternal gut microbiota during pregnancy. A: Effect on the mother’s gut microbiota during normal pregnancy; B: Effect on the mother’s intestinal flora under adverse conditions.

ABNORMAL MATERNAL GUT MICROBIOTA CONTRIBUTES TO ASD, PARTICULARLY GI SYMPTOMS

Many factors can cause disturbances in the gut microbiota during pregnancy, such as obesity and infection. Abnormal maternal microbiome during pregnancy contributes to ASD development[53]. A clinical meta-analysis found that the offspring of women who were obese during pregnancy had a higher risk of developing ASD than those born to women with a normal weight[54]. Importantly, the gut microbiota is formed in the first few years of life. It regulates important processes such as digestion and immune response. A widespread consensus is that patients with ASD have abnormal intestinal microbiota[4,55]. The etiology of and abnormal gut microbiota in ASD are closely linked to changes in the maternal microbiota[55,56]. Meanwhile, the GI problem is one of the complications of ASD, which commonly occur in individuals with ASD. Moreover, the correlation between GI dysfunction and behavioral symptom severity is evident. The GI system is not only regulated by the CNS but also by the ENS. Therefore, the effect of abnormalities in the maternal intestinal microbiota on individuals with ASD is discussed from the perspectives of both CNS and ENS.

CNS

In a review by Sarkar et al[57], the gut microbiota was reported to be crucial to the development of social brain. The gut microbiota can affect the expression of oxytocin in the hypothalamus as well as the development of the hypothalamic-pituitary-adrenal axis and hypothalamic-pituitary-gonadal axis[57]. Moreover, the excitability of oxytocin neurons projected from the paraventricular nuclei to the ventral tegmental area has been reported to decrease. Furthermore, the administration of Lactobacillus reuteri to the offspring can repair the function of oxytocin neurons and improve ASD-like symptoms[27]. Maternal stress can lead to an increase in cortisol levels in the brain of the offspring and a decrease in the abundance of Parasutterella excrementihominis in the gut[8]. Besides, the placenta secretes corticotropin-releasing factor to regulate the fetal hypothalamic-pituitary-adrenal axis, which is an important factor for the fetal adrenal gland to produce glucocorticoids and androgens[58,59]. When the mother is under stress, fetal hypothalamic-pituitary-adrenal axis development is negatively regulated through the increase in placental corticotropin-releasing factor production and signaling[60]. In the MIA model, increased levels of inflammatory factors were observed in several regions of the brain of the offspring, such as the hippocampus and hypothalamus. Meanwhile, the abundance of Bacteroidaceae, Cytophagaceae, and Lactobacillaceae in the gut microbiota is higher in MIA offspring. Interestingly, the Bacteroidetes/Firmicutes ratio was higher in the gut microbiota of female MIA offspring[9]. In some ASD gene-related animal models, such as the shank3-mutant mouse, the gut microbiota is disrupted[61]. Meanwhile, abnormal synaptic function has also been observed in the brain of shank3-mutant mice[62]. The diversity of the gut microbiota in the offspring and the number of oxytocin neurons in the hypothalamus decrease. In maternal high-fat diet mice model, the offspring exhibited ASD-like symptoms.

Mothers following a high-fat diet may experience metabolic problems that affect metabolic derivatives, potentially resulting in abnormal neural development in their offspring through the bloodstream[63]. The above results suggest that the risk factors that the mother is exposed to during pregnancy can cause abnormalities in the offspring’s CNS and affect the composition of the offspring’s intestinal microbiota, disrupting the brain-gut axis in the offspring and resulting in ASD-like changes in the behavior of the offspring.

ENS

ASD is a CNS-mediated neurobehavioral disorder; thus, most studies on ASD have focused on the CNS. However, GI function is not only affected by the abnormal function of the neural mechanistic nature of ASD but also by ENS. Therefore, it is not surprising that GI diseases, particularly diarrhea and abdominal pain, have high comorbidity rates in patients with ASD[4]. As for the CNS, substantial data about ENS deficiency in ASD have been obtained using germ-free mice. In these mice, abnormalities in ENS development included a reduction in the total number of neurons in the intestine and changes in subtype distribution, which were associated with abnormal gut motility[64-67]. Coincidentally, in the valproic acid-induced (VPA) rat model, rats exposed to VPA during pregnancy exhibited abnormal gut microbiota and intestinal pathological alteration. The offspring of VPA rats also showed intestinal dysfunction, including impaired intestinal motility, high levels of intestinal inflammation, and changes in the microbiota composition[68,69]. For instance, some ASD-related genes, such as shank3, are also expressed in the ENS. Thus, reduced intestinal motility can be observed in shank3-mutant mice and zebrafish. The expression of serotonin, which is associated with intestinal motility, decreased in the ENS, whereas the expression of inflammatory factors and permeability increased in the ENS[62,70]. Therefore, both the CNS and ENS are deemed crucial in the pathogenesis of ASD. Abnormalities in either the CNS or ENS can lead to the occurrence of ASD-related GI problems.

MECHANISM OF ABNORMAL MATERNAL GUT MICROBIOTA AFFECTING OFFSPRING DEVELOPMENT

In humans and other mammals, the intestinal microbiota in early life is seeded by microorganisms found in the environment. Gut microbiota colonization can be influenced by maternal symbiotic bacteria, which are present in several parts of the maternal body such as the birth canal, skin, and gut[71,72]. The maternal intestinal microbiota can disrupt the balance of the offspring’s intestinal microbiota by influencing the colonization, hormone levels, and gene expression of the offspring and then mediating the development of the offspring’s nervous system, leading to ASD occurrence.

Vertical transmission

An offspring inherits commensal microbiota from their mother[72]. Immediately after birth, the same intestinal and vaginal microbiota as the mother can be found in the infant’s feces[73]. Moreover, the gut microbiota of vaginally delivered infants is similar to that of their mothers, with Lactobacillus and Prevotella being the main organisms. In addition, the types of bacteria acquired by infants born through cesarean section are similar to those on the skin surface of their mothers, with Staphylococcus, Corynebacterium, and Propionibacterium being the main organisms[73]. Ferretti et al[74] reported that the maternal gut microbiota is the largest donor of acquired strains in infants. Maternal gut microbial strains are more persistent and stable in the infant’s intestinal tract[74]. Notably, the 6-8 weeks period after birth is crucial. This time is not only critical for neural development but is also associated with changes in the gut microbiota composition[75-77]. This result indicates that abnormalities in the maternal gut microbiota can affect the offspring through vertical transmission. The normal gut microbiota of the mother is crucial for offspring development.

Placenta transmission

During normal pregnancy, inflammatory and immune changes required for pregnancy affect maternal intestinal function and microbiota composition, which are caused by hormonal changes, in particular the pregnancy-specific hormone secreted by the placenta, i.e., human chronic gonadotropin. Human chronic gonadotropin regulates estrogen and progesterone secretion, thereby influencing the composition of the maternal gut microbiota. High progesterone levels increase the GI transit time, which is a key factor in shaping the composition of the intestinal microbiota[78,79]. More importantly, the placenta influences fetal development and is an important barrier between the mother and the fetus for hormone production and nutrient secretion and absorption. In a healthy pregnancy, the placenta also has a microbiota that helps in the development of the immune system of the fetus. Metabolites of the maternal intestinal microbiota, such as short-chain fatty acids (SCFAs), can enter the bloodstream through the liver, pass through the placental barrier, and promote the formation of the fetal blood–brain barrier and innate immunity. SCFAs can cross the blood-brain barrier, influencing CNS activity, including microglia and cytokine modulation[80]. Women who follow a vegetarian diet during pregnancy can produce SCFAs with immune-protective effects, which is associated with the high relative abundance of Roseburia and Lachnospiraceae[81]. In the maternal stress model, the abnormal composition of the maternal intestinal microbiota caused abnormalities in the transfer of placental nutrients, resulting in the abnormal development of the hypothalamus and limbic system in male offspring[82]. These findings indicate that the maternal gut microbiota during pregnancy can affect the development of the nervous system of the offspring, and the mechanism is influenced by the immune system and hormones produced by the placenta. The transmission of maternal intestinal microbiota to offspring is illustrated in Figure 2.

Figure 2 Mechanism by which the maternal microbiome influences offspring development. The maternal microbiome can affect the development of the offspring’s immune and nervous systems through vertical and placental transmission.

Inflammatory activation

Perinatal immune activation, including infections and psychological stress, can lead to abnormalities in the gut flora and severe inflammation in the mother. Pregnancy-related stress can affect the microbial composition and gut function of the offspring[72,83-85]. In the stress mouse model, the high levels of IL-6 and IL-1β in the placenta downregulate the level of dopamine receptors in the nucleus accumbens of male offspring, resulting in motor dysfunction[86]. Garcia-Flores et al[87] demonstrated a systemic reduction in B and T cells in the F1 and F2 offsprings of mice after prenatal stress. In women with anxiety and depression during pregnancy, the methylation coding of 11β-HSD2 and Nr3c1 in the placenta increased, which was positively correlated with neurobehavioral defects in infants[88,89]. Another study indicated that stress during pregnancy cannot only cause methylation of the placental 11β-HSD2 promoter but can also increase in DNA methyltransferase 3A[90].

Lombardo et al[91] evaluated the transcriptome in the cerebral cortex of MIA rat offspring. The offspring showed downregulation of many gene enrichment pathways associated with permeability, and these genes were associated with ASD development. In human fetal brain tissue and human neural stem cells, although MIA did not cause abnormal expression levels in FMRP and CHD8, the expression of downstream targets was disrupted. These downregulated genes are involved in axonal routing, synaptogenesis, and network formation[91]. Overall, at the molecular level, prenatal stress alters placental function and signaling by altering epigenetic mechanisms.

GI SYMPTOMS IN ASD: THE INTERACTION OF THE NERVOUS AND IMMUNE SYSTEMS

During pregnancy, after exposure to adverse factors (such as stress and infections), the maternal intestinal flora becomes disordered, which eventually affects the development of the offspring’s nervous and immune systems. Abnormal neurodevelopment in the offspring affects not only the CNS but also the ENS. In some animal models of ASD with microbiota problems, the regions of the brain that regulate cognition and emotion were disturbed[92]. Some neurotransmitters that regulate GI function are impaired[68,93]. In the MIA model, IL-17a levels in the cerebral cortex increased[41]. IL-17a is secreted by Th17 cells. Under normal pregnancy conditions, Th17 cells can inhibit mucosal inflammation and exert a protective effect on the mucosal barrier[25,94]. The GI symptoms of ASD have also been confirmed to be related to barrier disruption[95]. Therefore, inferring that the GI symptoms of ASD are the result of the interaction between the nervous system and the immune system (Figure 3) is not difficult. It is precisely for this reason that GI symptoms have become one of the most common ASD complications.

Figure 3 The intestinal microbiota is affected by adverse factors experienced by the mother during pregnancy. Abnormal gut microbiota can affect the neurodevelopment of the offspring in different ways, leading to autism spectrum disorder.

TREATMENT OF GI PROBLEMS IN ASD: DUAL REGULATION OF THE NERVOUS AND IMMUNE SYSTEMS

Maternal health is crucial for the normal development of the offspring. Therefore, paying attention to maternal health during pregnancy and adjusting the intestinal flora during this period are important measures to reduce ASD prevalence. First, women should take care of their health during pregnancy to avoid infections, maintain a positive mood, and reduce negative emotions caused by stress and anxiety. Pregnant women with underlying medical conditions should increase their communication with doctors. This will help control the effect of pregnancy on the primary disease. In clinical research, certain studies have attempted to use probiotics for intervention during pregnancy. For example, Lactobacillus species play an important role in supporting intestinal health and regulating immunity. Bifidobacterium species maintain intestinal barrier function and aid in the treatment of irritable bowel syndrome. Saccharomyces species can reduce diarrheal symptoms caused by antibiotics and support the immune function[96]. However, the results of studies analyzing the effects of probiotics remain inconsistent[97,98]. Given the importance of the gut microbiota during pregnancy in offspring development, future therapeutic directions should focus more on identifying the types and causes of the abnormal microbiota by conducting research and developing targeted therapeutic methods. In the future, interventions aiming at improving abnormal gut flora during pregnancy can lead to improvement in maternal health during pregnancy and reduction in the risk of ASD in their offspring.

In addition, the feasibility of using probiotics for intervention during pregnancy needs to consider ethical issues. Bacteria used as probiotics must undergo a thorough safety assessment. Probiotics to be used as drugs must be approved by the Food and Drug Administration[99]. Previous studies have not clearly concluded on the optimal duration of probiotic use. For instance, in a study conducted by Ouyang et al[100], pregnant women suffering from subclinical hypothyroidism were administered probiotics during the second trimester of pregnancy. This treatment was found to alleviate symptoms related to small intestinal bacterial overgrowth[100]. Halkjær et al[101] started using probiotics in pregnant women at 14-20 weeks of gestation until delivery to observe the effect of probiotics on the microbiota of the offspring. The variations in the duration of probiotic use stem from the differing therapeutic purposes. However, the timing of using probiotics and its safety during pregnancy remain to be clarified. We hope that more strategies will be developed in the future to achieve the goal of eugenics.

Improving the intestinal flora is a common treatment approach in patients with ASD. Many studies have performed microbiota transplantation and oral supplementation of probiotics to treat ASD[102,103]. Microbiota regulation can improve the core symptoms of ASD model mice, and mechanisms may be related to the intestinal microbiota and vagus nerve[104,105]. The vagus nerve, which is composed of 80% afferent fibers and 20% efferent fibers, is crucial for internal sensing. It can detect metabolites produced by the microbiota through its afferents and transmit intestinal information to the CNS for processing[106]. In addition, the vagus nerve is influenced by the intestinal microbiota and helps regulate the cholinergic anti-inflammatory pathway, thereby reducing inflammation and lowering intestinal permeability[107]. Therefore, certain methods are available for treating autism through neuroregulation that positively affect the social interaction of ASD[68,108]. Our unpublished data indicate that transcutaneous electrical acupoint stimulation can significantly improve intestinal motility disorders in autistic rats. Our next study will improve the therapeutic effect of neuroregulation on GI symptoms in patients with autism and explore the possibility of treating the core and somatic symptoms of autism considering neuroregulation.

LIMITATIONS

At present, no direct evidence supports the analysis of the interaction between the quality of a person’s diet and changes in the gut microbiota during pregnancy. Moreover, currently, the effects of maternal microbiota on offspring are primarily investigated through animal experiments, with few reports on clinical applications. Thus, clinical treatment is challenging. Furthermore, conducting clinical trials during pregnancy raises ethical issues and remains challenging. Nevertheless, we hope that future research will build on animal experiments to guide clinical applications.

CONCLUSION

In addition to the core symptoms of social deficits, stereotyped behaviors, and abnormal sensations, GI problems are common comorbidities in patients with ASD. The main symptoms include abdominal pain, diarrhea, and constipation, which seriously affect the quality of life of people with ASD. The abnormality of the maternal intestinal flora is a significant cause of ASD onset. MIA and psychological stress during pregnancy are the main factors that affect the maternal gut microbiota and can lead to a number of neuroimmune reactions. Abnormal gut flora in the mother can affect the neurodevelopment and immune development of the offspring, including the CNS and ENS, through vertical transmission, placenta, and other means. It leads to behavioral and GI problems in the offspring. To reduce the risk of ASD, future intervention studies should focus on providing interventions during women’s pregnancy. Meanwhile, more attention should be given to the physical symptoms of patients with ASD to improve their standard of living.