Role of Milk-Derived Opioid Peptides and Proline Dipeptidyl Peptidase-4 in Autism Spectrum Disorders


It has been widely discussed that individuals with ASD may have undiagnosed gastrointestinal conditions and hypersensitivities, which are the effects of the ingestion of casein and gluten. This disorders may result in an exacerbation of ASD behaviors (e.g., tantrums, screaming, and aggression) and inattention to tasks due to the distraction, and because of the pain [7]. According to the previous hypothesis postulated by Panksepp, disruptions in opioid system are possible because of the so-called autistic behavior [8] and this opioid theory of autism was also proved by pharmacological studies [9]. Exogenous opioid peptides released during the digestion of dietary proteins, such as casein and gluten were suggested to contribute to autism development, leading to the announcement of the opioid excess hypothesis of autism [10].

Discussion:
Autism is a developmental disorder, which usually manifests itself in the first years of life. Children with autism exhibit abnormal behavior in social interaction and communication problems. As indicated by the global statistics from year-to-year, the incidence of autism increases and is currently epidemic of this disease should be considered [1,33]. ASD prevalence is strongly associated with the male gender [3], which is also represented by our sex distribution in the ASD group. The causes of autism are not fully explained, but it is clear that the development of the disease is affected by genetic and autoimmune factors, metabolic disorders, and epigenetic changes depending on the environmental and nutritional factors. In recent years, researchers have focused on the role of the opioid system in various pathological processes [33].

Numerous studies confirmed, that milk-derived opioid peptides may penetrate the intestinal barrier and induce biological effects through the opioid receptors of the immune and nervous system [12,34,35]. We found that the content of BCM7 in serum was significantly higher (p < 0.0001) in ASD than in the control group (Figure 1A). Elevated level of BCM7 in serum of autistic children was reported by several authors [9,17], which is consistent with our results. We also noticed a difference between gender—in ASD girls there was the highest level of BCM7 in serum (p < 0.05) among all patients (Figure 1A). Statistical difference between ASD girls and boys can be explained as small number of girls. However, obtaining a similar number of girls and boys in ASD group was difficult because it is associated with a higher incidence of autism in boys than in girls. Hyperpeptidemia and increased blood–brain barrier permeability may cause accumulation of BCM7 in the blood and the brain, leading to the development of ASD [24,26]. We did not observe differences in BCM7 concentration in urine (Figure 1B), whereas Sokolov et al. [17] demonstrated that autistic children have significantly higher levels of urine BCM7 than healthy children, and the severity of autistic symptoms were correlated with concentrations of the peptide in the urine.

These authors suggested that peptiduria in autistic children is the potential defect in their proteolytic and/or peptide excretion systems, consistent with previous studies that infants with delayed psychomotor development had elevated levels of the postprandial bovine BCM7 compared with a healthy control group. Chronic exposure to elevated levels of bovine casomorphins may contribute to disorders during early child development, also including autistic disorders, because these peptides interact with opioid and serotonin receptors, the known modulators of synaptogenesis [17,24]. Opioid peptides alter not only the mechanism of neuromodulation in the central nervous system (CNS), but also trigger inflammation and food allergy [12,36]. It is known that subcutaneous injection of BCM7 causes local pseudo-allergic reactions, masts cell degranulation, and histamine secretion even in healthy children [37].

β-casomorphin-5 may cause mast cells degranulation in mice, confirming the nature of the allergenic potential of this peptide [38]. Consequently, consumption of bovine milk containing BCM7 may induce inflammatory response in intestine by activating Th2 pathway [36], which was described in our previous research [12]. According to this approach, BCM7 consumption by autistic children induces gastrointestinal problems, such as abnormalities of the bowel mucosa, dysfunctions associated with intestine permeability, and changes in the gut microbiota [39]. High-protein diet may result in increased BCM7 concentration in the serum and urine of autistic children (Figure 1A,B).

Consequently, milk-derived opioid peptides may reduce the uptake of cysteine, resulting in a decrease in glutathione synthesis and availability of the methyl donor S-adenosylmethionine (SAM). The decrease in SAM translates into effects on global DNA methylation, with epigenetic consequences, which alter neurological disorders such as autism [40]. Therefore avoiding milk-derived opioid peptides may lead to reduced peptiduria in children with autism and improves health, including silenced autoimmunity, improved emotional state and the opportunity to establish social relationships [24,29,41,42].

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