The role of Zn in human systems with a focus on individuals with ASD

Zn plays an important role in the development and functioning of the immune, gastrointestinal and nervous systems, all of which are frequently dysregulated in individuals with ASD^{(Reference Chasapis, Ntoupa and Spiliopoulou2,Reference Skalny, Aschner and Tinkov3,Reference Sauer, Malijauskaite and Meleady15)} .

Starting from the immune system, Zn performs immunomodulatory functions by regulating the proliferation and maturation of T and B lymphocytes, natural killer cells and dendritic cells, as well as antibody production, phagocytosis and antigen presentation^{(Reference Skalny, Aschner and Tinkov3)}. Therefore, ZD predisposes individuals to immune disruptions and recurrent infections, including intestinal infectious diseases, which are well described in individuals with ASD^{(Reference Chasapis, Ntoupa and Spiliopoulou2,Reference Valenzuela-Zamora, Ramírez-Valenzuela and Ramos-Jiménez6,Reference Siniscalco, Schultz and Brigida20,Reference Ohashi and Fukada21)} .

Focusing on the gut, Zn is involved in its morphological development, microbial composition and function, and barrier maintenance^{(Reference Sauer, Malijauskaite and Meleady15)} due to its essential role in cell turnover and repair systems.

Thus, the negative effects of ZD include dynamic variation in gut microbial composition, increased intestinal permeability (leaky gut), activation of pro-inflammatory pathways, and diarrhoea^{(Reference Chasapis, Ntoupa and Spiliopoulou2,Reference Sauer, Malijauskaite and Meleady15,Reference Ohashi and Fukada21)} , which are common manifestations in individuals with ASD^{(Reference Valenzuela-Zamora, Ramírez-Valenzuela and Ramos-Jiménez6,Reference Sauer, Malijauskaite and Meleady15)} . Mounting evidence strongly supports a positive relationship between the extent of GI symptoms and the severity of ASD symptomatology^{(Reference Fowlie, Cohen and Ming22)}, as well as a close association between Zn status and autism severity^{(Reference Skalny, Aschner and Tinkov3)}. Considering the central role of the intestine in Zn absorption, as well as the common GI symptoms reported in individuals with ASD, the authors delved into each of those aspects. Several landmark studies from the past few decades have concentrated on the gut microbiota in individuals with ASD, revealing a decreased microbial diversity in this population^{(Reference Dhaliwal, Orsso and Richard23)}, along with a significant increase in Clostridioides difficile and Candida albicans, a decrease in Bifidobacterium and Lactobacillus, and low levels of short-chain fatty acids (SCFAs)^{(Reference Dhaliwal, Orsso and Richard23–Reference Srikantha and Mohajeri25)}. Nevertheless, the description of a comprehensive and distinctive gut microbial pattern in individuals with ASD is still under research. Different studies have shown conflicting results, probably due to heterogeneity of the analysed samples in terms of age, diet, pharmacological treatment, geographic area, comorbidities and the severity of neurobehavioral and gastrointestinal symptoms^{(Reference Al-Ayadhi, Zayed and Bhat24,Reference Fattorusso, Di Genova and Dell’Isola26)} . The alterations of gut microbiota in individuals with ASD are known to have a significant impact on the brain through the microbiota–gut–brain axis^{(Reference Sauer, Malijauskaite and Meleady15,Reference Fowlie, Cohen and Ming22,Reference Srikantha and Mohajeri25)} , exacerbating the typical symptoms of ASD (i.e. limitations in social interactions and communications, and repetitive behaviours)^{(13,Reference Al-Ayadhi, Zayed and Bhat24)} . Furthermore, the increased permeability of the intestinal barrier, frequently co-present with dysbiosis, results in the entry of bacterial metabolites, such as lipopolysaccharide (LPS), into the bloodstream. This triggers a significant increase in neurological and systemic inflammation by altering cytokine levels^{(Reference Sauer, Malijauskaite and Meleady15,Reference Srikantha and Mohajeri25,Reference Matta, Hill-Yardin and Crack27)} . Individuals with ASD have been found to have increased levels of these leaky gut syndrome biomarkers^{(Reference Al-Ayadhi, Zayed and Bhat24)}. As it is known, the gut–brain axis operates bidirectionally; therefore, neuroinflammation and alterations in neuronal activities significantly impact the composition of the gut microbiota in individuals with ASD from early childhood^{(Reference Srikantha and Mohajeri25,Reference Saurman, Margolis and Luna28)} .

Dysbiosis and GI symptoms, such as constipation, diarrhoea, bloating, abdominal pain, reflux and vomiting are four times more prevalent in children with ASD compared with neurotypical individuals^{(Reference Srikantha and Mohajeri25)}. Furthermore, there is substantial scientific evidence describing the persistence of GI symptom prevalence into adulthood in individuals with ASD^{(Reference Leader, Barrett and Ferrari29)}. So, considering that Zn plays a key role in gut health and intestinal microbiota, it may be important to prevent ZD from an early age, so as not to exacerbate dysbiosis and GI symptoms frequently found in individuals with ASD.

Regarding brain activity, Zn plays a key role in neuronal learning and memory processes^{(Reference Chasapis, Ntoupa and Spiliopoulou2)}, synaptic plasticity through ProSAP/Shank scaffold, and neurotransmitter metabolism^{(Reference Skalny, Aschner and Tinkov3)}, particularly in glutamate. Specifically, Zn²⁺ is necessary for proper assembly, structuring and functioning of the ProSAP/Shank scaffold^{(Reference Skalny, Aschner and Tinkov3)} protein and is involved in glutamatergic neurotransmission, as Zn²⁺ forms complexes with glutamate in presynaptic vesicles^{(Reference Bhandari, Paliwal and Kuhad30,Reference Zheng, Zhu and Qu31)} . Numerous studies have demonstrated that impairment of the synaptic ProSAP/Shank scaffold promotes the development of behaviours typically observed in ASD^{(Reference Skalny, Aschner and Tinkov3,Reference Alsufiani, Alkhanbashi and Laswad9)} . Alterations in the balance between excitatory and inhibitory pathways in the nervous system are frequently observed in individuals with ASD^{(Reference Skalny, Aschner and Tinkov3,Reference Zheng, Zhu and Qu31)} .

Therefore, it may be relevant to prevent ZD conditions as early as possible to avoid exacerbating these neurological alterations.

Ultimately, it is necessary to emphasise the role of ZD in inflammation (systemic and neurological) and oxidative stress, both of which are often present in individuals with ASD^{(Reference Skalny, Aschner and Tinkov3,Reference Sauer, Malijauskaite and Meleady15,Reference Bjørklund, Meguid and El-Bana16)} . The literature reports significantly higher plasma and serum levels of proinflammatory cytokines (IL-1β, IL-6, IL-8 and IFN-&x0263;) in individuals with ASD, compared with neurotypical controls^{(Reference Sauer, Malijauskaite and Meleady15)}. Moreover, an increase in the levels of IL-1β, IL-6 and IFN-&x0263; in the brain are reported in postmortem ASD studies^{(Reference Sauer, Malijauskaite and Meleady15)}.

Individuals with ASD also present elevated levels of reactive oxygen species (ROS) and are considered more vulnerable to oxidative stress due to their reduced glutathione (GSH) reserve capacity and (GSH) antioxidant defence in specific brain regions^{(Reference Bjørklund, Meguid and El-Bana16)}. Considering that Zn enhances (GSH) biosynthesis^{(Reference Chasapis, Ntoupa and Spiliopoulou2)}, an adequate intake of this mineral could reduce oxidative stress in individuals with ASD.

In conclusion, ASD is frequently characterised by alteration of immune, gastrointestinal and neurological systems, which share inflammation as a common factor. Considering at the same time the potential role of Zn in modulating the previously mentioned systems, it is reasonable that alterations in Zn levels could potentially impact on ASD symptomatology^{(Reference Valenzuela-Zamora, Ramírez-Valenzuela and Ramos-Jiménez6,Reference Siniscalco, Schultz and Brigida20,Reference Fattorusso, Di Genova and Dell’Isola26,Reference Matta, Hill-Yardin and Crack27)} .

The relationships between the role of zinc in metabolism and ASD comorbidities

Considering the underlying pathogenetic mechanisms of ASD metabolic comorbidities and the role of Zn in the same metabolic systems, it is reasonable to assume that ZD status can contribute to the metabolic comorbidities that are present in individuals with ASD leading to bidirectional relationship (graphical abstract), as further explained below.

Scientific research is currently exploring the role of Zn in diabetes mellitus (DM) in terms of glycaemic control, and its role in obesity and metabolic syndrome^{(Reference Skalny, Aschner and Tinkov3)}. Low Zn levels in individuals with type 2 DM and obesity were observed^{(Reference Skalny, Aschner and Tinkov3)}. A recent systematic review with meta-analysis found that the association between ASD and DM is not currently supported by robust evidence^{(Reference Cortese, Gabellone and Marzulli32)}.

Starting from the analysis of carbohydrates metabolism, individuals with ASD often exhibit sugar malabsorption, which may be attributed to a decreased expression of disaccharidases, specifically sodium–glucose transporter 1 (SGLT1) and glucose transporter 5 (GLUT5), in the brush border in the intestinal epithelium^{(Reference Srikantha and Mohajeri25,Reference Vela, Stark and Socha33)} . The remaining sugars in the intestinal lumen can lead to osmotic diarrhoea and can be fermented by the gut microbiota, causing alterations in microbiota composition, small intestinal bacterial overgrowth (SIBO), bloating and flatulence^{(Reference Srikantha and Mohajeri25)}. As 30–50% reduction of disaccharidase activity has been observed in cases of chronic ZD^{(Reference Vela, Stark and Socha33)} and given the higher prevalence of ZD in individuals with ASD, there is a possible role for Zn in alleviating frequent intestinal symptoms observed in ASD.

Zn has a central role in glycaemic control: it is involved in synthesis, storage and release of insulin, and it is present in insulin granules^{(Reference Kambe, Tsuji and Hashimoto1,Reference Olechnowicz, Tinkov and Skalny34,Reference Tamura35)} . It influences the maintenance of the GLUT4 transporter and modulates the insulin receptor (INSR) signalling pathway^{(Reference Wessels, Fischer and Rink4)}. This aspect is particularly significant considering that youths with ASD have, on average, higher homeostatic model assessment of insulin resistance (HOMA-IR) than neurotypical individuals, regardless of their BMI and pharmacological treatment^{(Reference Manco, Guerrera and Ravà36)}.

Moving on to protein metabolism, aside from its role in protein synthesis, protein structure and enzyme catalysis, adequate daily intake of Zn is necessary for proper protein digestion in the gut, due to its role in several digestive enzymes, including carboxypeptidases^{(Reference Kambe, Tsuji and Hashimoto1)}, dipeptidase^{(Reference Berezin, Berezin and Lichtenauer37)} and aminopeptidase^{(Reference Vela, Stark and Socha33)}. Therefore, the possible presence of a ZD condition might favour bacterial proteolytic pathway (putrefaction), which may be associated with dysbiosis and gastrointestinal symptoms observed in individuals with ASD^{(Reference Sanctuary, Kain and Angkustsiri38)}.

Regarding lipid metabolism, individuals with ASD can experience alterations in their blood lipid profile^{(Reference Gillberg, Fernell and Kočovská39,Reference Luçardo, Monk and Dias40)} , on which Zn appears to have an influence^{(Reference Tamura35,Reference Shi, Zou and Shen41,Reference Santos, Teixeira and Schoenfeld42)} . The mechanism behind this is currently not understood, but the effects of Zn levels in terms of both prevention and treatment of cardiovascular diseases (CVDs) have been well described in literature^{(Reference Tamura35)}. In fact, a systematic review of prospective cohort studies showed that higher serum Zn levels are associated with a lower risk of CVDs. Furthermore, a recent meta-analysis indicated that low-dose (<25 mg/d) and long-term (>12 weeks) Zn supplementation is associated with improved blood lipid parameters^{(Reference Santos, Teixeira and Schoenfeld42)}. This aspect seems to be more important when considering that, according to a recent study by Bishop et al. 2022, about 75% of adults with ASD have at least one CVD risk factor, compared with 40% in neurotypical individuals^{(Reference Bishop, Charlton and McLean43,Reference Chu, Foster and Samman44)} .

Regarding adipose tissue, Zn is involved in several related physiological processes, including leptin synthesis and adipocyte lipid metabolism regulation^{(Reference Skalny, Aschner and Tinkov3,Reference Olechnowicz, Tinkov and Skalny34)} . Given this background, many authors have suggested that Zn status could be associated with the state of adipose tissue in obesity^{(Reference Skalny, Aschner and Tinkov3)}. These results are in line with the known higher inflammatory and oxidative state of this tissue in individuals with overweight and obesity^{(Reference Manna and Jain45)}. Considering the role of zinc in the anti-inflammatory and antioxidant systems^{(Reference Skalny, Aschner and Tinkov3,Reference Olechnowicz, Tinkov and Skalny34)} , the authors hypothesise that lower Zn levels in adipose tissue might also be present in individuals with ASD. This suggests that screening Zn levels in such individuals may be beneficial for those showing signs of lipid metabolism dysregulation.

In conclusion, considering the possible links discussed thus far, Zn could play a key role in the frequently observed metabolic comorbidities in individuals with ASD. Consequently, the importance of screening Zn levels in individuals with ASD who present with metabolic comorbidities, emerges as a crucial aspect to better manage their clinical condition^{(Reference Indika, Frye and Rossignol46)}.

Sensory perception, food selectivity and Zn in individuals with ASD

The role of Zn in sensory perception, specifically taste perception, can be discussed by distinguishing between the mechanisms at the oral and neurological levels.

In the mouth, Zn participates in the maintenance and regeneration of the lingual epithelium and taste buds^{(Reference Kumbargere Nagraj, George and Shetty47,Reference Nishiguchi, Ohmoto and Koki48)} . Moreover, it is necessary for the activity of alkaline phosphatase and gustatin, which are associated with taste and smell alterations when their activity is low^{(Reference Kumbargere Nagraj, George and Shetty47)}. Animal studies suggest that Zn influences the expression of some taste receptors and membrane channels, such as bitter taste-sensing type 2 receptors (TAS2Rs) and epithelial Na channel (ENaC)^{(Reference Ikeda, Sekine and Takao49,Reference Onoda, Hirai and Takao50)} , indicating the role of Zn especially in bitter^{(Reference Fábián, Beck and Fejérdy51,Reference Wang, Zajac and Lei52)} and salty taste perception^{(Reference Braud and Boucher53)}. The role of Zn bitter taste perception is supported by the involvement of gustatin itself in bitter taste^{(Reference Fábián, Beck and Fejérdy51)} and the finding of a lower frequency of expression of six TAS receptor genes in individuals with hypogeusia compared with healthy controls^{(Reference Onoda, Hirai and Takao50)}.

Analysing the neural mechanisms, Zn seems to promote the transmission of information to gustatory nerve fibres and to modulate neuropeptides, such as neuropeptide Y (NPY), and neurotransmitter concentrations in the hypothalamus^{(Reference Santos54,Reference Baltaci, Mogulkoc and Baltaci55)} . Moreover, current literature is exploring the influence of Zn on the levels of leptin, insulin and NPY^{(Reference Kambe, Tsuji and Hashimoto1,Reference Olechnowicz, Tinkov and Skalny34,Reference Tamura35,Reference Baltaci, Mogulkoc and Baltaci55–Reference Komai, Goto and Ohinata57)} , in relation to taste perception and taste bud physiology. These peptide hormones are present in saliva, and their respective receptors are expressed in taste cells^{(Reference Fábián, Beck and Fejérdy51)}. The multiple roles played by Zn in taste perception are summarised in Table 1.

Table 1. The multiple roles played by Zn in taste perception

Legend. Explanation of the role of Zn in taste perception, distinguishing between the mechanisms put in place at the oral and neurological level.

In light of the evidence described, it is important to consider that alterations in taste sensory perception (e.g. smell, taste and sight) are among the main symptoms of ASD and may persist throughout life^{(Reference Valenzuela-Zamora, Ramírez-Valenzuela and Ramos-Jiménez6)} and can be modulated by several factors, potentially including ZD. The possible co-presence of ZD in individuals with ASD may also be connected to FS, which can lead to micronutrient malnutrition^{(Reference Valenzuela-Zamora, Ramírez-Valenzuela and Ramos-Jiménez6)}.

FS itself, often present as a life-long clinical feature in individuals with ASD, can be accompanied by a sensory aversion to food, characterised by a rejection of specific textures, temperatures, flavours, colors and smells^{(Reference Valenzuela-Zamora, Ramírez-Valenzuela and Ramos-Jiménez6)}. This attitude leads to the adoption of a diet mainly composed of processed foods with high energy density, rich in sugar and saturated fatty acids, and, consequently, a reduction of dietary diversity^{(Reference Valenzuela-Zamora, Ramírez-Valenzuela and Ramos-Jiménez6)}. The typical treatment strategy for FS in individuals with ASD is a personalised, careful and gradual food reintroduction programme using applied behaviour analysis (ABA) techniques^{(Reference Sarcia58)}. Although useful, these strategies are often time consuming and difficult to carry out over time for individuals and their families, potentially leading to relapses^{(Reference Kodak and Piazza59)}. Due to the potential mechanisms via which ZD could impact in individuals with ASD, described above, it could be relevant to screen ZD in individuals with ASD to design an appropriate and personalised treatment plan. However, there are no current evidence for the role of ZD in FS; therefore, future studies are needed to fill this knowledge gap.

Moreover, taste perception features in individuals with ASD may manifest hyper- or hyposensitivity to food stimuli. In the latter case, individuals may tend towards a greater preference for sweet, salty or spicy foods to achieve an adequate stimulus^{(Reference Valenzuela-Zamora, Ramírez-Valenzuela and Ramos-Jiménez6)}.

Concerning Zn supplementation, which has been used since the 1980s^{(Reference Santos54)}, a recent systematic review has highlighted that it is the most frequently employed intervention for the prevention and treatment of taste disorders (i.e. ageusia/dysgeusia)^{(Reference Braud and Boucher53)}. However, the effectiveness of Zn supplementation and the optimal dosage are still debated and controversial. Moreover, the analysed studies often lacked a control group, and exhibited inconsistencies in terms of intervention duration, sample size, age, sex and comorbidities (often carried out in subjects with cancer or Chronic Kidney Disease). As a result, these studies were generally considered as ‘low quality’ overall^{(Reference Kumbargere Nagraj, George and Shetty47)}. Regarding ASD, there are currently no clinical trials exploring the role of Zn in improving taste perception, indicating the need for further research in this area.

The authors therefore emphasise the need for further investigation in this regard, specifically focusing on evaluating the potential role of Zn supplementation in individuals with ASD in relation to alterations in sensory perception.

Factors influencing dietary Zn intake, absorption and excretion in ASD

Inadequate dietary intake of absorbable Zn represents the primary cause of ZD^{(Reference Roohani, Hurrell and Kelishadi11)}. This deficiency may result from low dietary intake and/or low bioavailability of dietary Zn.

Causes of ZD under the category of reduced Zn absorption primarily include Inflammatory Bowel Diseases, inherited diseases (i.e. acrodermatitis enteropathica and cystic fibrosis), diarrhoea, unbalanced vegetarian or vegan diet, undernutrition or hidden hunger conditions, eating disorders, alcoholism and exocrine pancreatic insufficiency^{(Reference Chasapis, Ntoupa and Spiliopoulou2)}. Causes of ZD under the category of reduced Zn intake are related to food preferences and eating patterns, including conditions such as FS, which is highly prevalent in the ASD population and could lead to suboptimal Zn intake.

Analysing Zn absorption, it is important to point out that the bioavailability of Zn content in food is low, about 20–50%^{(Reference Baj, Flieger and Flieger60,Reference Maares and Haase61)} and it depends on both quantitative and qualitative factors^{(Reference Maares and Haase61,Reference Shkembi and Huppertz62)} . Among the food products, red meat, certain seafood, dairy products, nuts, seeds, legumes and whole-grain cereals are considered good dietary sources of Zn^{(Reference Shkembi and Huppertz62)}. Animal products, in particular, are known to provide a more bioavailable source of Zn than plant foods^{(Reference Maares and Haase61)}.

Factors with a positive, negative or ‘neutral’ effect on dietary Zn bioavailability are presented in Table 2.

Table 2. Factors with a positive, negative or ‘neutral’ effect on dietary Zn bioavailability

Legend. Factors with a positive, negative or ‘neutral’ effect on dietary Zn bioavailability. The authors developed a +/++/+++ classification based on two aspects: (i) the number of papers in the literature supporting or not supporting the ability of dietary factors to positively/negatively affect Zn absorption; (ii) the magnitude of the resulting effect indicated in the papers on dietary Zn absorption.

Although a low intake of phytate-rich food by individuals with ASD might promote better absorption of dietary Zn since phytates are the most potent inhibitors of Zn absorption^{(Reference Maares and Haase61,Reference Bel-Serrat, Stammers and Warthon-Medina63,Reference Agnoli, Baroni and Bertini64)} , this is not advisable since a reduced consumption of vegetables and legumes increases the risk of micronutrient inadequacy and dysbiosis due to low fibre content⁽⁶⁷⁾. Moreover, organic acids, such as malic acid found in fruits, citric acid found in fruits and milk, and lactic acid found in yogurt and fermented foods can improve Zn absorption^{(Reference Maares and Haase61,Reference Agnoli, Baroni and Bertini64,Reference Melse-Boonstra65)} .

Another well-known mechanism that promotes Zn absorption is mediated by the protein content of the diet: free amino acids can bind Zn²⁺ and be transported with it into the enterocyte^{(Reference Maares and Haase61)}. Therefore, eating complete meals with all macronutrients is even more recommendable. This recommendation is also supported by the fact that such individuals with ASD generally accept protein sources, with the exception of legumes^{(Reference Valenzuela-Zamora, Ramírez-Valenzuela and Ramos-Jiménez6)} and fish^{(Reference Park, Choi and Kim68,Reference Ahumada, Guzmán and Rebolledo69)} , which in some cases have a strong smell and taste.

Increased Zn losses represent another category of ZD causes and may result from GI disorders such as diarrhoea, as well as urinary tract disorders including kidney disease and DM^{(Reference Chasapis, Ntoupa and Spiliopoulou2)}.

In this regard, the ratio between the amount of absorbed Zn and the fraction of the mineral excreted is crucial, as it affects the cellular content of Zn and its distribution. Over time, due to the initial protective action of homeostatic mechanisms, it also impacts the plasma Zn concentration itself^{(Reference Chasapis, Ntoupa and Spiliopoulou2,Reference Livingstone5)} . In fact, the amount of retained Zn in the human body is highly dependent on its dietary content^{(Reference Bel-Serrat, Stammers and Warthon-Medina63)}. Therefore, it is not surprising that Zn is primarily excreted with faeces and secondarily with urine^{(Reference Maares and Haase61)}. Severe undernutrition and starvation conditions result in both an increase of urinary Zn losses and a sedentary lifestyle^{(Reference Bel-Serrat, Stammers and Warthon-Medina63)}. In fact, a chronic reduction in physical activity level (i.e. sedentary lifestyle) is associated with loss of muscle mass. Increased urinary zinc excretion has been observed in individuals with chronic reduction in physical activity levels^{(Reference Bel-Serrat, Stammers and Warthon-Medina63)}, as zinc is well represented within muscle tissue^{(Reference Chasapis, Ntoupa and Spiliopoulou2)}. Leading a sedentary lifestyle is common among individuals with ASD^{(Reference Jones, Downing and Rinehart70)}, due also to motor comorbidities, so the presence of increased urinary Zn losses is a concrete potential issue in this population, exposing them (along with the other factors previously described) to an increased risk of ZD.

To summarise, Zn absorption is influenced by the composition of food matrix, vegetable food preparation techniques and full meal consumption. On the other hand, Zn elimination is influenced by the possible presence of existing Zn deficiencies or excesses, as well as ongoing catabolic processes, which can be associated with a sedentary lifestyle.

Zn requirements in individuals with ASD. Conclusions and future prospects

Increased Zn requirement constitutes another recognised cause of ZD^{(Reference Chasapis, Ntoupa and Spiliopoulou2,Reference Roohani, Hurrell and Kelishadi11)} . Considering the potential alterations in Zn absorption, excretion or Zn intake previously discussed, the possibility of increased Zn requirements in this population should be considered. It is important to note that the dietary recommendations provided by national and international organisations are intended for the healthy population^(71–75), and currently, there are no specific dietary guidelines available for individuals with ASD.

This gap in the existing guidelines contradicts the need for personalised and adapted management of this disorder, as emphasised by guidelines and action plans developed at the global⁽⁷⁶⁾, European^(77–80) and Italian^(81,82) levels. These guidelines are endorsed by the most authoritative organisations in the field, that is, Autism Speaks⁽⁸³⁾.

In fact, ASD is a sensitive and lifelong condition that impacts every aspect of life. Hence, there is a crucial need for specific nutritional guidelines to improve the quality of life of those individuals, focusing on their health and inclusion in the community^{(Reference Conti, Breda and Basilico84)}. Considering the role of Zn, the frequent co-presence of ZD risk factors and FS problems in individuals with ASD highlights the potential need for formulating specific dietary recommendations for this population. Furthermore, considering the frequent occurrence of multiple comorbidities in individuals with ASD (e.g. recurrent infection, systemic and neurological inflammation, diarrhoea, microbiota alterations, leaky gut and metabolic disorders), which can either cause or contribute to ZD, relevant attention should be paid on Zn requirement.

Therefore, it is advisable to early detect Zn blood levels and assess dietary intake in individuals with ASD, ideally during infancy at the time of ASD diagnosis, to evaluate the presence of ZD. A potential workflow for proper management would involve following the principles and the structure of the Nutrition Care Process (NCP) developed by the American Dietetic Association, which includes nutrition assessment, nutrition diagnosis, nutrition intervention, nutrition monitoring and evaluation (followed by periodic re-assessment)^(85,86) .

In reference to the results provided by the assessment phase (interview and clinical data collection), the next step would involve analysing plasma Zn levels^{(Reference Berger, Shenkin and Schweinlin87)}. If a ZD condition is identified, that is, <60 μg/dl in healthy adults^{(Reference Maxfield, Shukla and Crane88)}, the most appropriate strategy to address the deficiency would be planned. In this regard, the primary approach to be implemented is to improve dietary intake of Zn. If, on the other hand, the ZD condition is severe and/or persistent, potential supplementation strategies should be considered. In this scenario, recent European Society for Clinical Nutrition and Metabolism (ESPEN) recommendations suggest 0·5–1 mg/kg/d of elemental zinc (Zn²⁺) given orally for 3–4 months^{(Reference Berger, Shenkin and Schweinlin87)}. Moreover, the ESPEN panel emphasises that organic compounds (such as zinc histidinate, zinc gluconate and zinc orotate) are comparatively better tolerated than inorganic zinc sulphate and zinc chloride^{(Reference Berger, Shenkin and Schweinlin87)}. A reasonable approach in this case would be to gradually increase the zinc dosage from supplementation in parallel with an adequate dietary zinc intake, with periodic monitoring of blood levels^{(Reference Berger, Shenkin and Schweinlin87)} to tailor treatment to the subject’s response while avoiding potential side effects. In fact, at doses >50 mg/d, GI symptoms, such as nausea, abdominal discomfort and diarrhoea, commonly occur^{(Reference Maxfield, Shukla and Crane88)}.

In conclusion, future perspectives could concern the development of a comprehensive screening tool that considers all the factors to which individuals with ASD are generally exposed, which can increase the risk of developing ZD, along with the individual’s current symptomatology. This screening tool would take the form of a questionnaire that provides a score indicating the risk of developing ZD, tailored specifically for individuals with ASD.