Targeted microbiome and drug therapies show promising results against autism spectrum disorders

Autism spectrum disorders are characterized by persistent difficulties in social interactions, verbal and non-verbal communication, as well as repetitive behaviors. These challenges, often accompanied by digestive symptoms, highlight the complexity of this neurodevelopmental condition. While behavioral interventions remain the primary clinical approach, their effectiveness varies by region and available resources, making the development of targeted pharmacological treatments necessary.

Animal models, particularly rodents, play a key role in understanding the molecular mechanisms and developing therapies. These models replicate behaviors similar to those observed in humans, such as impairments in social interactions, vocalizations, and stereotyped behaviors. The causes of these disorders are multiple: genetic, environmental, or idiopathic. For example, prenatal exposure to certain medications or infections increases the risk of developing autism spectrum disorders.

A recent systematic review analyzed 52 studies published between 2010 and 2025, exploring the effectiveness of pharmacological therapies and those targeting the gut microbiome. The interventions studied include oxytocin agents, drugs acting on the balance between neuronal excitation and inhibition, cannabinoids, purines, as well as microbiome-focused strategies such as probiotics, prebiotics, and fecal transplants. These approaches aim to modulate various biological systems, including neurotransmission, neuroinflammation, metabolism, and the gut-brain axis.

The results show that behavioral deficits related to autism spectrum disorders in preclinical models can be mitigated by interventions targeting these systems. For example, oxytocin, a hormone involved in the regulation of social behaviors, has demonstrated positive effects on sociability and the reduction of repetitive behaviors in several animal models. However, its effectiveness depends on the therapeutic regimen, the developmental stage and sex of the animals, as well as the specific model used. In some cases, oxytocin had no effect on repetitive behaviors, or even worsened them.

Other interventions, such as oxytocin receptor antagonists, have also shown promising results. For example, atosiban, an oxytocin receptor antagonist, improved social deficits, anxiety, and repetitive behaviors in female rats exposed to valproic acid during pregnancy. This surprising result suggests that, in some cases, excessive activation of the oxytocinergic system may contribute to symptoms, and an antagonist could therefore be beneficial.

Therapies targeting the balance between neuronal excitation and inhibition have also shown encouraging results. For example, memantine, an NMDA receptor antagonist, improved sociability and reduced repetitive behaviors in rats exposed to valproic acid. Similarly, positive allosteric modulators of mGlu5 receptors, such as CDPPB, have mitigated behavioral deficits in genetic models of autism spectrum disorders.

Gut microbiome-based interventions represent an innovative approach. Fecal transplants and probiotics, such as Bifidobacterium longum, have shown improvements in social behaviors and a reduction in anxiety. These interventions work by modulating gut metabolism and influencing communication between the gut and the brain. For example, the administration of Bifidobacterium longum increased tryptophan levels and reduced kynurenine levels, metabolites linked to neurotransmission and inflammation.

Metabolic therapies, such as metformin and pioglitazone, have also demonstrated positive effects. These drugs, often used to treat diabetes, have improved sociability and reduced repetitive behaviors in animal models. Their effects appear to be mediated by a reduction in oxidative stress and neuroinflammation, mechanisms often disrupted in autism spectrum disorders.

Cannabinoids, such as cannabidiol and tetrahydrocannabinol, have also been studied. While their effects vary depending on the dose, certain formulations have shown improvements in social behaviors and a reduction in repetitive behaviors. For example, Avidekel oil, rich in cannabidiol, reduced grooming time and improved sociability in mice.

Interventions targeting the purinergic system, such as suramin, have also demonstrated beneficial effects. Suramin, a purinergic antagonist, improved social behaviors and reduced anxiety in models of autism spectrum disorders induced by maternal immune activation or prenatal exposure to valproic acid.

Finally, vitamins, such as vitamin D3 and retinoic acid, have shown promising effects. Retinoic acid, for example, improved social behaviors and reduced repetitive behaviors in rats exposed to valproic acid. These effects appear to be mediated by modulation of microglial activation and neuroinflammation.

These results highlight the multifactorial nature of autism spectrum disorders, where systemic processes interact rather than a single molecular defect. This could explain the limited success of traditionally targeted interventions and suggests a paradigm shift toward a more systemic approach, combining pharmacological, metabolic, and microbiome-targeted therapies.

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Reference Document

DOI: https://doi.org/10.1038/s41380-026-03663-8

Title: Efficacy of pharmacological and microbiota-based therapies in preclinical models of autism spectrum disorder: a systematic review

Journal: Molecular Psychiatry

Publisher: Springer Science and Business Media LLC

Authors: Arnas Kunevičius; Kinga Gawlińska; Aurelijus Burokas; Dawid Gawliński