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Thursday, March 9, 2017

Zinc in Gut-Brain Interaction in Autism and Neurological Disorders

Research from the last decades clearly shows that zinc has a vital role in neonatal development. Zinc is an essential trace element in humans and animals and is involved in countless metabolic and signaling pathways within the body. However, a particular role of zinc in the immune system and brain has been reported [1]. Zinc is one of the most prevalent metal ions in the brain and participates in the regulation of neurogenesis, neuronal migration, and differentiation, thereby shaping cognitive development and maintaining healthy brain function. Zinc deficiency during pregnancy results in specific impairments in the offspring, which have been observed in animal models but might also be present in humans [2]. Intriguingly, among individuals with Autism Spectrum Disorders (ASD), the incidence rate of zinc deficiency has been reported to be significantly increased compared to age matched healthy control subjects [3]. The occurrence of zinc deficiencies in ASD is particularly pronounced in very young age [4, 5], where a rate of almost 50% was reported in the age group of 0–3 years [5]. These low levels of zinc often occur along with copper overload and the Cu/Zn ratio was reported to correlate with the severity of symptoms associated with autism [6–8]. This early occurrence of zinc deficiency with decline later in life and the manifestation of some of the core features of ASD, such as impaired social behavior and language and communication problems in prenatal zinc deficient mice [9], have recently put maternal zinc status in the focus as a possible environmental factor in the etiology of ASD. Thus, maintaining adequate zinc status during pregnancy might be a promising approach to prevent cognitive and neurobehavioral deficits later in life. However, meeting the zinc requirement of the mother can be challenging.

Two major pools of zinc can be found within the body: a slowly zinc exchanging pool that contains about 90% of the body's zinc and a pool that rapidly exchanges zinc with the plasma. The latter, which contains the other 10% of zinc, is the one that is especially reactive to the amount of absorbed zinc and is the first to be depleted under conditions of zinc deficiency. Plasma zinc is also the source of the embryo's zinc supply. In order to maintain proper zinc levels during pregnancy, both endogenous losses and the increased demand resulting, for example, from synthesis of novel tissue must be covered by absorption of zinc from dietary sources. Thus, while the metabolic zinc requirement of 2.5 mg/d for an adult woman is generally met when consuming daily 10 to 15 mg zinc, due to the additional need for zinc during pregnancy, an additional 5–10 mg zinc per day must be consumed to meet the increasing demand of 0.08, 0.24, 0.53, and 0.73 mg of metabolic zinc per day for the four quarters of pregnancy [10]. Similarly, during lactation, the metabolic daily requirement increases by another 2.5 mg per day. Meeting these requirements is challenged by several factors. First, it is not uncommon for women of childbearing age to consume low zinc diets. Second, zinc status of women may be compromised due to increased intake of dietary constituents that reduce the availability of zinc.

Impact of low zinc status of the mother can be magnified depending on time and severity of the deficiency, ranging from teratogenic effects with severe deficiency to functional impairments acting, for example, on brain development with mild deficiency. In particular, teratogenic effects have been reported in rodent models [11, 12] as well as in humans, where women with Acrodermatitis enteropathica, a genetic disorder resulting in impaired zinc absorption, show a high incidence of birth defects [13]. In general, although the brain seems most vulnerable, all organ systems are affected by systemic zinc deficiency in times of active proliferation and differentiation. Thus, although mild zinc deficiency does not lead to gross morphological malformations in the offspring, the reported behavioral impairments might result from a combination of alterations in brain development and other organ systems. This novel vista on the role of zinc deficiency in ASD broadens the focus from the action of zinc within the brain to other organs such as the GI system.

Proper zinc status is necessary for healthy gut development and both pre- and perinatal zinc deficiency might affect the neonate and potentially trigger downstream events that contribute to pathological processes [14]. These processes may, among others, include inflammation due to increased intestinal epithelium permeability and immune system abnormalities including the generation of autoantibodies. Another consequence of impaired or delayed gut development will be lowered trace metal absorbance, which might contribute to the slow normalization of biometals in children with ASD after birth [5]. GI discomfort, changes in gut microbiome, food aversion, and an increased intestinal permeability have been shown to correlate with the severity of behavioral symptoms in individuals with ASD [15–21].

Given that inflammatory cytokines and other immune signaling molecules originating from the GI tract interact with the hypothalamic-pituitary-adrenal gland (HPA) stress axis, prenatal stress itself can be integrated in this pathomechanism, targeting the same structures [22]. Thus, some of the major environmental risk factors for the development of ASD are linked in this model.

Taken together, maternal zinc deficiency might impair the gut development of the offspring and thereby increase the risk for GI problems, inflammatory events, abnormal immune signaling, trace metal imbalances, and ultimately altered brain function. Data supporting this hypothesis will be discussed further in more detail.


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