Autism spectrum disorder (ASD) is a neurodevelopmental disorder displaying altered human behaviors, such as social interaction impairments, stereotypical/repetitive activities and emotional dysregulation. Children with ASD are often affected by gastrointestinal problems and gut microbiota dysbiosis. Inflammation and immune dysfunction are key contributors to ASD, as shown by high proinflammatory cytokines and oxidative stress. Indeed, notable implication of the nuclear factor kappa B in the severity of ASD derives from its ability to amplify neuroinflammation. This narrative review focused attention on neuronutrition and gut microbiota manipulation for mitigation of ASD symptoms, including neuroinflammation and oxidative stress. Studies in both rodents and humans with ASD have revealed that both pure and mixed Lactobacillus and Bifidobacterium were effective in ameliorating behavioral symptoms and GABA/glutamate imbalance. Often, the combined use of probiotics and prebiotics can have greater health benefits in ASD. Additionally, dietary interventions and microbiota transfer therapies along with low-to-moderate-intensity exercise have been proposed to improve gastrointestinal and behavioral symptoms. However, despite some encouraging results, biases in the neuronutrition/microbiota literature still exist. Indeed, many studies rely on small sample sizes, cross-sectional designs, and heterogeneous populations that differ in diet, medications, and comorbidities. In this context, the development of a precision diet tailored to individual gut microbiome profiles will allow for a broader understanding of the microbial ecosystem and relative therapeutical applications. Hence, by integrating metagenomics, metabolomics, epigenomics, with evaluation of environmental and nutritional factors, it will be possible to significantly improve the quality of life for people with ASD and their families.

Lead (Pb) has progressively become ubiquitous due to widespread use. The liver represents a target of Pb toxicity due to its central role in metabolism and detoxification. The mechanisms of Pb hepatotoxicity have not yet been fully elucidated, although oxidative stress and iron dysregulation suggest the involvement of the ferroptosis pathway. It has been hypothesized that exposure to environmental Pb concentrations induces the activation of ferroptosis as a mechanism involved in Pb hepatotoxicity, an iron-mediated regulated cell death. To test this hypothesis, we exposed adult zebrafish to environmentally relevant Pb concentrations (2.5 and 5 μg/L), combining ultrastructural analysis (TEM) with the study of key markers of ferroptosis (GPX4, SLC7A11, NRF2, KEAP1 and ACSL4). The results demonstrated that Pb exposure induced dose-dependent and progressive mitochondrial damage in hepatocytes, characterized by loss of cristae and membrane rupture. At the same time, consistent with a ferroptotic molecular profile, increased expression of ACSL4, reduced levels of the protective factors NRF2, KEAP1 and SLC7A11, and altered expression of GPX4 were observed. Overall, our data collectively identify ferroptosis as a pathogenic pathway in Pb-induced hepatotoxicity.

Strobilurin fungicides are among the most widely used agrochemicals worldwide. Dimoxystrobin has been shown to induce hepatic injury in adult zebrafish; however, whether this damage also involves early extracellular matrix remodelling and hepatobiliary remodelling remains unknown. Here, we investigated early remodelling of the extracellular matrix, focusing on initial collagen deposition and glycosaminoglycan redistribution after a short-term exposure (96 h) to two environmentally relevant concentrations of dimoxystrobin (6.56 and 13.13 µg/L) on the liver of Danio rerio using an integrated histological, histochemical, and semi-quantitative approach. The results showed a progressive dose-dependent alteration of hepatic architecture, accompanied by a significant increase in bile pigment-like deposits and collagen deposition. Exposure also induced a significant increase in the deposition of acidic glycosaminoglycans and a severe depletion of glycogen-dependent Periodic Acid–Schiff positivity components, accompanied by an increase in amylase-resistant Periodic Acid–Schiff reactive components. Overall, these findings indicate that dimoxystrobin-induced hepatotoxicity extends beyond parenchymal degeneration to encompass coordinated stromal and hepatobiliary remodelling. The present study also indicates that the periductal microenvironment may represent a sensitive target of dimoxystrobin toxicity and supports the use of histochemical and semi-quantitative analyses as sensitive tools for detecting sublethal pesticide-induced early extracellular matrix remodelling in fish liver.