Ketogenic diet ameliorates autism spectrum disorders-like behaviors via reduced inflammatory factors and microbiota remodeling in BTBR T+ Itpr3tf/J mice

Autism Spectrum Disorder (ASD) is one of the most complex neurodevelopmental syndromes having an enormous impact during the childhood stage in terms of prevalence, morbidity, family, and society burdens (Lyall et al., 2017). The main features characterizing such a disorder include impaired social interaction and communication ability, coupled with restricted and repetitive patterns of behaviors, which constitute the behavioral basis of its diagnosis (Kodak and Bergmann, 2020). In addition, psychiatric and medical comorbidities include gastrointestinal symptoms, anxiety, plus cognitive impairments that seem to occur at different frequencies thus overlapping and masking the main features of ASD (Alò et al., 2021; Shu et al., 2022). At date, both pathological processes and molecular etiology of this disorder have not yet been fully established due to genetic events interacting negatively with environmental factors (Cheroni et al., 2020). Consequently, therapeutic approaches used for their treatment are often limited and do not act on main symptoms of this neurodevelopmental disorder. From several studies, it appears that the different inflammatory events exert a key role on the pathogenesis of ASD and above all on the majority of its behavioral symptoms (Lee et al., 2016; Abruzzo et al., 2019; Tzanoulinou et al., 2022). Indeed, ASD patients largely display altered inflammatory states and immune abnormalities, showing very high levels of pro-inflammatory cytokines, such as interleukins (IL) and the tumor necrosis factor alpha (TNF-α), together with microglia activation (Ahmad et al., 2019). It is also known that under physiological conditions, microglia regulate the formation, pruning and elimination of synapses, together with their plasticity through an appropriate release of cytokines and chemokines. At the same time, an abnormal activation of microglia has been shown to induce an altered release of these factors and reactive oxygen species (ROS) leading to loss of neuronal functions and altered synaptic density (Simpson and Oliver, 2020). In particular, notable oxidative stressful conditions have been observed throughout the pathogenesis of ASD (Pangrazzi et al., 2020), which leads to an excessive ROS production with neuro-inflammatory dysfunctions accounting for the abnormal behavioral performances (Teleanu et al., 2022).

Increasing evidence points to the intestinal microbiota and the central nervous system (CNS) (i.e. gut microbiome–brain axis) as a principal target for the altered behavioral events in ASD (Avolio et al., 2022). It seems that microbiota can trigger inflammatory process throughout the release of metabolites and pro-inflammatory mediators, which reach CNS through the bloodstream thus inducing neuro-inflammatory events. The gut microbiota has emerged as an important factor in the brain development, capable of controlling the various neurodevelopmental brain activities, as suggested by its ability to induce the synthesis and secretion of neuroactive factors like serotonin, dopamine, GABA and glutamate, which are able to interfere with neuronal pathways in the different brain regions as well as with neuronal survival and trafficking events (Di Vito et al., 2014; Chen et al., 2021).

It is already known that the individual's metabolic state can strongly influence neuronal activities that in turn modify neurophysiological conditions of the brain and consequently behavioral performances. In this context, a ketogenic diet (KD) by drastically reducing carbohydrates, while increasing proteins and especially fats, forces body to use them as a source of energy so leading to diminished inflammatory events of numerous neurodegenerative syndromes (Jiang et al., 2022). Accumulating evidence have also shown that KD is able to exert a valuable role for the treatment of multiple diseases including epilepsy, depression, migraine, Alzheimer's and Parkinson's diseases (Pietrzak et al., 2022). Furthermore, KD has been correlated to improved behaviors in ASD (Ruskin et al., 2017) very likely via a modulation of gut microbiota conditions thus contributing to maintain homeostasis within CNS (Kaviyarasan et al., 2022).

On the basis of the above indications, it was the aim of this study to investigate KD effects on typical ASD behaviors (social and cognitive deficits, repetitive behaviors and anxiety) in BTBR T+ Itpr3tf/J (BTBR) mice, a valuable mouse model of idiopathic ASD (Arakawa, 2021). Specifically, behavioral results were correlated to plasma and brain expression of TNF-α, IL-1β and IL-6, which are main mediators of inflammation and are implicated in the bidirectional pathway between gut and brain (Zhao et al., 2021; Avolio et al., 2022). In addition, oxidative stress levels (Thiobarbituric Acid Reactive Substances, TBARS; superoxide dismutase, SOD) in the prefrontal cortex (PFC) plus hippocampus (HIP) as well as gut microbiota changes were also detected. The results of these evaluations are aimed to establish possible pathways plus specific molecular factors by which KD ameliorates neurological-related disturbances in BTBR mice thus further supporting its possible role as an appropriate therapeutic approach not only for the treatment of the above neurodegenerative diseases but also for ASD.

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