Introduction

Autism Spectrum Disorder (ASD) is characterized by a wide range of symptoms and severity levels, thus the term “spectrum”. Common features include difficulties with social interaction and communication, as well as repetitive behaviors and restricted interests [1], [2], [3]. In 2025, autism is estimated to affect approximately 1 in 31 children in the United States according to the Centers for Disease Control and Prevention’s [4]. Globally, the World Health Organization estimates that about 1 in 100 children are diagnosed with autism [5].

Animal models are crucial in autism research to understand the complex biological and behavioral aspects of autism in a controlled environment, which is often impossible with human subjects. These models, particularly rodents, offer a platform to investigate the genetic, environmental, and epigenetic factors contributing to autism, as well as to test potential therapeutic interventions [6], 7]. Valproic acid (VPA), or 2-propylpentanoic acid, is a short-chained fatty acid widely used as an antiepileptic drug and has been utilized to model autism in rodents. VPA exposure in pregnant rats causes offspring to exhibit core ASD features such as impaired social interaction, increased repetitive behaviors, and altered sensory processing, making it an excellent model for studying the biological mechanisms of ASD and testing potential treatments [8], [9], [10], [11].

Numerous studies have linked maternal infections, autoimmune conditions, and high Body Mass Index (BMI) during pregnancy to an increased risk of ASD in offspring, an association mediated by Maternal Immune Activation (MIA). [12], [13], [14], [15]. MIA is a condition where the mother’s immune system is activated during pregnancy, either by infection (bacterial or viral) or other inflammatory stimuli. This activation can lead to the release of inflammatory molecules (cytokines), which can cross the placenta and affect the developing fetus [12], 15], 16].

Lipopolysaccharide (LPS), is a molecule found in the outer membrane of Gram-negative bacteria and a potent activator of the innate immune system, triggering the release of cytokines [17]. MIA by LPS refers to a process where exposure of a pregnant mother to LPS triggers an immune response in the mother. This immune response can have lasting effects on the developing offspring, potentially leading to neurodevelopmental issues. LPS binds to Toll-like receptor 4 (TLR4) on maternal immune cells (macrophages, monocytes, dendritic cells), initiating a strong inflammatory cascade and leads to disrupting fetal brain development and potentially increase the risk of ASD in offspring [16], [18], [19], [20].

Moreover, offspring exposed to LPS-induced MIA often exhibit a range of behavioral and neurobiological deficits that resemble symptoms of neurodevelopmental disorders such as social interaction deficits, repetitive behaviors (increased grooming, stereotypies), communication impairments, cognitive deficits, and anxiety-like behaviors [12], [13], [14].

Despite extensive preclinical and clinical research, there are currently no effective preventive or therapeutic strategies to mitigate the impact of maternal inflammation on fetal brain development. With no cure for ASD and it’s continuing rise, there is growing interest in dietary interventions. However, there is no consensus on the optimal nutritional approach. The potential of specific dietary compositions to regulate or alleviate ASD symptoms has been highlighted in recent reviews [21], 22].

Probiotics, which are living bacteria that provide health advantages to the host, and prebiotics, which are nondigestible compounds used exclusively by beneficial gut microbiota to boost host health, are two of the most promising dietary strategies [23], [24], [25].

Artichoke-derived inulin possesses an exceptionally high degree of polymerization, ensuring prolonged colonic persistence and potent prebiotic efficacy. By selectively modulating gut microbiota, inulin increases short-chain fatty acid (SCFA) production, which acidifies the colon to favor beneficial taxa (Bifidobacterium, Lactobacillus) and suppress pathogens [26], 27]. These microbial shifts further fortify host immunity [28], 29]. Additionally, artichoke polyphenols (e.g., dicaffeoylquinic acids, flavonoids) likely synergize with inulin to optimize gastrointestinal metabolic and oxidative health [30], [31], [32]. Artichoke extracts can act as antioxidants and anti-inflammatories, which may be beneficial in protecting against various insults during pregnancy. In 2032, a study done by Alsubaiei and collaborators, has shown that supplementation with yogurt, artichoke (as a prebiotic source), or specific probiotic strains (e.g., Lacticaseibacillus rhamnosus GG) can improve biochemical markers of oxidative stress (increase GSH, GPx) and reduce neuroinflammation (decrease IL-6, TNF-α) in the brains of propionic acid-treated rats, correlating with behavioral improvements [33].

Despite these robust gut-modulating properties, their application in autism is largely uncharacterized. Consequently, this study evaluates the impact of artichoke prebiotics and synbiotic formulations on behavioral deficits in LPS- and VPA-induced autism rat models.

This study builds upon previous research and being a part of our KSU research team into the use of artichoke as a therapeutic intervention to improve behavioral consequences of MIA [33], 34].