Zinc in gut-brain interaction in autism and neurological disorders

Abstract

A growing amount of research indicates that abnormalities in the gastrointestinal (GI) system during development might be a common factor in multiple neurological disorders and might be responsible for some of the shared comorbidities seen among these diseases. For example, many patients with Autism Spectrum Disorder (ASD) have symptoms associated with GI disorders. Maternal zinc status may be an important factor given the multifaceted effect of zinc on gut development and morphology in the offspring. Zinc status influences and is influenced by multiple factors and an interdependence of prenatal and early life stress, immune system abnormalities, impaired GI functions, and zinc deficiency can be hypothesized. In line with this, systemic inflammatory events and prenatal stress have been reported to increase the risk for ASD. Thus, here, we will review the current literature on the role of zinc in gut formation, a possible link between gut and brain development in ASD and other neurological disorders with shared comorbidities, and tie in possible effects on the immune system. Based on these data, we present a novel model outlining how alterations in the maternal zinc status might pathologically impact the offspring leading to impairments in brain functions later in life.

Figure 1

Influence of zinc levels on gut formation. Zinc levels mediate villus height and villus/crypt ratio in the jejunum. Zinc deficiency results in a shortening and narrowing of the villi and thus a reduction in absorptive surface. This may be mediated by a reduction in mucosal cell proliferation and slower cell migration, as well as an increase in the number of apoptotic cells in villi and crypts. The zinc finger transcription factors Gata4 and Gata6 are involved in intestinal epithelial cell differentiation and promote enteroendocrine cell differentiation. Moreover, the number of goblet cells increases after zinc supplementation and is dependent on the activity of the zinc binding matrix metalloproteinase-9 (MMP-9). Goblet cells secrete mucins and an altered composition of intestinal mucin was reported in zinc deficient animals. Additionally, several alterations in the activities of brush border enzymes result from zinc deficiency. The development of paneth cells is accelerated by the zinc dependent transcription repressor BLIMP1. Furthermore, zinc deficiency is accompanied with mucosal necrosis and ulceration, inflammation, and oedema.

Figure 2

GI abnormalities, immune system dysfunction, stress, and zinc deficiency may be highly linked processes contributing to the development of ASD. Zinc deficiency mediates GI system abnormalities, severely affects many components of the immune system, and is linked to physiological and psychological stress. Although there is good reason to believe that maternal zinc deficiency might be the initial trigger, once this vicious cycle is activated in the offspring, GI abnormalities, impaired immune system, stress, and zinc deficiency can be both cause and consequence of each other and influence the development of ASD. This is in line with the often reported symptoms and comorbidities in ASD associated with problems linked to these four key features.

Figure 3

A model for Zinc in gut-brain interaction in ASD and other neurological disorders. Zinc is taken up from our dietary sources and/or supplements in the proximal small intestine. However, absorption of zinc can be decreased in response to various agents such as iron and/or calcium supplements, high copper levels, folic acid, phytate, high fructose corn syrup (HFCS), and/or several drugs. Alternatively, zinc levels may be low due to genetic variants in zinc homeostasis genes or general low availability of zinc in the diet. As a result of this, zinc deficiency of the embryo may occur. Zinc deficiency might influence embryonic and fetal development affecting the GI system through impaired function of several key proteins contributing to many of the reported GI problems associated with ASD such as metallothionein dysfunction, plasma Cu/Zn inversion, heavy metal overload, Candida and Clostridium overgrowth, constipation and/or diarrhea, leaky gut, food sensitivities and allergies, inefficient processing of gluten and casein, enzyme deficiency, vitamin and mineral malabsorption, inefficient fat digestion and metabolism, and esophagitis and GI ulcers. These GI symptoms can give rise to behavioral difficulties.

Figure 4

Prevention and treatment strategies. Zinc amino acid complexes might be an effective source to overcome the negative effects of dietary constituents and nutrients in prenatal supplements and help women to maintain adequate zinc status (prenatal prevention, left panel). Zinc supplementation might also be useful in young children with ASD helping to overcome some impairments associated with acute zinc deficiency (diarrhea, impaired immune function, and neurosensory deficits) (postnatal treatment, right panel). Furthermore, young children with ASD might benefit from probiotic therapy that may correct gut permeability, alter microbial composition, reduce burden of bacterial waste products and metabolites, and thereby ameliorate ASD symptoms. Additionally, a gluten and milk protein-free diet was proposed to potentially be beneficial for individuals with ASD. 5-HT signaling may mediate both innate and adaptive responses in the immune system and 5-HT signaling important in the brain and in the GI tract; 5-HT receptors are expressed. Thus, 5-HT3 antagonists or 5-HT4 agonists may have a modulatory effect. Moreover, therapeutics used to treat inflammatory events caused by abnormal GI function (anti-inflammatory and immune-modulating therapies) might be beneficial. Stress is linked to abnormalities in the GI tract and mediated by, among others, the corticotropin-releasing factor (CRF) system on molecular level. The use of CRF receptor antagonists might therefore provide new treatment approaches.