Neurological disorders are common and can involve both children and adults with various prevalence, depending on geographic region, age, and gender. For instance, the prevalence of autism spectrum disorder (ASD), also termed autism, is approximately 2.21% in adults (1) and 1.4–2.8% in children aged 8 years in the United States (2, 3). In children, the prevalence of ASD increases with age, with a higher prevalence in boys (4.4% at the age of 10 years) than in girls (1.2% at the age of 10 years) (4). Similarly, a higher portion of adults with ASD are men (69.3% vs. 30.7%) (5). However, the gender differences in prevalence decline after age of 35 years (5). Moreover, a higher prevalence was observed in North America and high-income countries than in other regions and low-income countries (6). In adults, ASD is associated with intellectual, physical, and mental disabilities (5). Children with ASD display delayed mental development in multiple domains, with a negative correlation of developmental levels with disease severity (7). The annual medical costs for adult outpatients with ASD are five times of that for those without ASD ($4,375 vs. $824) (8). Average annual medical costs for children with ASD are nine times for those without ASD ($9,980 vs. $1102) (9). Thus, ASD is common and can negatively impact patients’ lives and economy.

ASD includes non-syndromic and syndromic autism. The latter is mainly caused by chromosomal abnormalities or monogenic alterations (10). Regarding the etiologies of non-syndromic ASD, it is still unclear yet. Although genetic and environmental factors can contribute to the development of ASD (11), evidence also indicates an association of ASD with immune function. For example, the prevalence of allergies and autoimmune diseases is higher in individuals with ASD than in those without ASD in both children and young adults (12–15). Epidemiological studies reveal a higher prevalence of ASD in individuals with inflammatory skin disorders, such as atopic dermatitis and psoriasis (12, 16). A recent study demonstrates epidermal dysfunction, which can provoke cutaneous and systemic inflammation, in children with ASD (17). In this perspective review, we summarize the evidence of a link between the skin and ASD and discuss the implication.

The pathogenic role of inflammation in ASD has been well demonstrated (18, 19). Individuals with ASD display the upregulation of activator protein-1-mediated neuroinflammation and insulin/insulin-like growth factor-1 signaling pathways in the brain (20) although one study showed no significant differences in expression levels of either proinflammatory or anti-inflammatory genes, including IL-1β, in both the gray and white matter of the brain in normal vs. individuals with ASD (21). Moreover, the activation state of astrocytes is increased in both the gray and white matter of prefrontal areas in individuals with ASD, indicating the presence of chronic inflammation in the brain (22). Furthermore, circulating levels of some proinflammatory cytokines, such as IL-1β, IL-6, TNF-α, and IFN-γ, are also higher in individuals with ASD than in the controls (23–25), while circulating levels of anti-inflammatory cytokines, such as IL-10 and IL-1Ra, are decreased in individuals with ASD (26). Although this line of evidence suggests a pathogenic role of inflammation in ASD, the origins of inflammation are still inconclusive. Some studies demonstrate the contribution of inflammation associated with dysbiosis and/or with the increased gut permeability to the pathogenesis of ASD (26–30). Maternal immune activation is also a risk factor for ASD in offspring (31–33). However, a great bulk of evidence indicates a link between cutaneous inflammation to ASD. Moreover, the association of other cutaneous conditions with ASD has also been reported. The evidence of the link between the skin and ASD is summarized in Table 1 (12, 16, 34–67).

As aforementioned, ASD is associated with a number of skin disorders. Recent studies also demonstrated alterations in epidermal function in ASD. In the murine model of ASD, mice with ASD exhibit dry skin and a remarkable increase in transepidermal water loss rates, an indicator of epidermal permeability barrier function, compared to normal mice (76). Similarly, adult humans with ASD also display elevated transepidermal water loss rates (76). Recently, Wang et al. compared epidermal biophysical properties in 48 control children and 56 children with ASD (17). All participants were without a current or previous history of inflammatory skin disorders. Children with ASD exhibited higher transepidermal water loss rates, lower stratum corneum hydration levels, and elevated skin surface pH (all p < 0.0001 vs. controls), indicating epidermal dysfunction in ASD. Most importantly, the ASD symptom such as the Social Responsiveness Scale was significantly improved following the correction of epidermal functional abnormalities with topical emollient (CURECODE^®) twice daily for 2 months (146.40 ± 4.83 vs. 136.8 ± 5.70, t = 2.988, p < 0.01). The autism treatment evaluation checklist and repetitive behaviors scale-revised were also markedly reduced (p = 0.0777 and p = 0.0621, respectively) (101). These results suggest that ASD is also linked to epidermal dysfunction.

ASD is a common neurological disorder with a worldwide prevalence of as high as 4.36% (102). The etiologies of ASD have been widely speculated. Evidence suggests that ASD can be attributed to genetic, epigenetic, and environmental factors in addition to microbiome (10, 103–105). Indeed, a family history of ASD increases the odds of ASD in their children by 7.4–16.2 times (106). Somatic variants account for 3–5% of ASD (107, 108). If one has ASD, the other one is more likely to have it in monozygotic twins (109). Epigenetic modifications, such as DNA methylation and histone modification, also contribute to the development of ASD (105). Moreover, several studies demonstrate the role of gut microbiota in the pathogenesis of ASD (110, 111). Children with ASD have a high incidence of gastrointestinal disorders, such as constipation and diarrhea (112). Children with constipation have a higher risk of ASD (adjusted hazard ratio = 1.431, 95% CI = 1.083–1.891) (54). Both gut microbiota and their metabolic products are altered in humans and animals with ASD (113–115). In comparison to the non-ASD controls, children with ASD have higher fecal levels of Caloramator, Sarcina, and Clostridium genera and lower levels of Eubacteriaceae (116). The pathogenic role of gut microbiota in ASD is further supported by the evidence that oral probiotics during pregnancy prevent both the development of ASD symptoms and the increases in IL-6 and IL-17a levels in the brain of offspring induced by maternal immune activation (117). Similarly, orally given human commensal bacteroides fragilis alleviates ASD symptoms, improves gut permeability, and alters microbial composition in a mouse model of ASD induced by maternal immune activation (118). Apparently, the pathogenic role of microbiota in ASD is mediated by inflammation. The structural components of the bacteria can induce the production of proinflammatory cytokines, including IL-1β, IL-6, and TNF-α (110, 119). Individuals with ASD exhibit high intestinal permeability, resulting in an increased antigenic load from the gastrointestinal tract (113). Similarly, the brain–blood barrier is also compromised in individuals with ASD (120). Cytokines, such as IL-1β, IL-6, IFN-γ, and TNF-α, released from the intestine can easily penetrate into the circulation and cross the blood–brain barrier into the brain, consequently leading to the development of ASD (110). In support of the inflammation theory, individuals with ASD display higher levels of proinflammatory cytokines in both circulation and the brain (74, 76, 117, 121), while circulating levels of anti-inflammatory cytokines, such as IL-10 and IL-1Ra, are lower in individuals with ASD vs. normal controls (122). Accordingly, an anti-inflammation regimen improves symptoms of ASD (123). Thus, inflammation plays a central role in the development of ASD.

Consistent with the notion of the central role of inflammation in ASD, inflammatory dermatoses, such as psoriasis and eczematous dermatitis, predispose to the development of ASD. First, the development of ASD occurs approximately 6 months following the first appearance of allergic disorders in children (55). Second, in the murine model of ASD, increased cytokine levels in the brain are later than those in the skin (76). Third, the treatment of psoriasis with Secukinumab improves the symptoms of ASD (78). Coupling with the evidence of a positive correlation of the severity of ASD symptoms with the severity of atopic dermatitis, cytokines of cutaneous origin can also contribute to the development of ASD. However, a maximum of 28% of individuals with ASD have atopic dermatitis (45). Not all individuals with ASD have gastrointestinal disorders. Then, the question is where the inflammation is in individuals without either gastrointestinal disorders or inflammatory skin diseases. A bulk of evidence suggests a possible contribution of epidermal dysfunction to inflammation in both circulation and the brain. First, children with ASD, but without allergic disorders nor inflammatory dermatoses, display alterations in epidermal biophysical properties, including elevations in transepidermal water loss rates and skin surface pH and reduction in stratum corneum hydration levels (17). Second, elevation in transepidermal water loss rates increases levels of proinflammatory cytokines in both circulation and the skin (124). Third, reduction in stratum corneum hydration levels increases cutaneous inflammation (125–127), while circulating levels of proinflammatory cytokines are negatively correlated with stratum corneum hydration levels in humans without apparent inflammatory cutaneous inflammation (128). Because of the huge surface area of the skin (2 m² for adult males and 1.7 m² for adult females) (129), even mild cutaneous inflammation induced by epidermal dysfunction can increase proinflammatory cytokines in circulation. Elevated circulating levels of proinflammatory cytokines downregulate expression levels of a tight junction protein (occludin 1), as well as vascular cell adhesion molecule 1 in the endothelial cells of the brain, leading to an increase in blood–brain permeability, subsequently resulting in inflammation in the brain (130). Finally, improvement in epidermal function lowers circulating levels of proinflammatory cytokines in both humans and mice (124, 131) and alleviates some symptoms of ASD in children without any inflammatory dermatoses in addition to mitigation of other psychological symptoms such as cognitive impairment in adults (101, 132). Hence, this pile of evidence indicates that the development of ASD can be attributable, at least in part, to epidermal dysfunction. Because of the regulatory role of epidermal function in cutaneous inflammation, improvement in epidermal function can benefit ASD.

ASD is common in both adults and children. Although therapeutic regimens, such as medication and behavior management, are available, there are still challenges in clinical practice. Medicines, such as risperidone and aripiprazole, can cause some side effects, including somnolence, extra-pyramidal symptoms, hyperprolactinemia, body weight gain, headache, and urinary incontinence. (133, 134). Moreover, either medication or behavior management can only improve symptoms without solving the fundamental problem, inflammation, a key contributor to the pathogenesis of ASD. However, recent studies showed that an improvement in epidermal function with topical emollients can lower cytokine levels in both the skin and circulation of mice and humans (124, 131). Similarly, topical emollients can both improve and prevent the development of inflammatory skin disorders, including atopic dermatitis and psoriasis (135–139), which both are associated with ASD, as mentioned above. Taken together with the evidence that topical emollients improve symptoms of ASD and mitigate the progression of cognitive impairment, which both are linked to inflammation, either improvement in epidermal function with emollients, especially in individuals with epidermal dysfunction or effective treatments of inflammatory dermatoses can be an alternative approach in the management of ASD. However, this speculation needs to be validated in appropriate clinical trials.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.

M-QM: Conceptualization, Writing – original draft, Writing – review & editing. SY: Data curation, Formal analysis, Investigation, Writing – original draft. TM: Writing – review & editing. GZ: Conceptualization, Data curation, Formal analysis, Writing – review & editing. TZ: Writing – review & editing, Conceptualization, Data curation.