Rethinking Attention Deficit and Hyperactivity Disorder (ADHD): The Emerging Role of Neuroinflammation and Gut Microbiota

Attention Deficit Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder with higher prevalence in males, affecting both childhood and adulthood, and significantly impairing the individual’s ability to integrate and adapt to the network of rules and conventions that structure our society. This impairment translates into substantial difficulties in relational, academic, occupational, and civic functioning, attributable to deficits in executive functions such as reward regulation, working memory, inhibitory control, vigilance, and planning. The reduction in quality of life and the risks associated with ADHD are linked not only to the direct expression of the disorder’s neurobiology but also to adaptive, psychophysical, and secondary reactions stemming from the challenges patients face in managing daily demands. The clinical picture is further complicated by the frequent comorbidities-both psychiatric and somatic-that suggest the role of a common genetic background, thereby supporting heredity as an etiological factor. Current evidence highlights a strong genetic involvement in ADHD, although its multifaceted, polygenic nature has thus far prevented the identification of reliable markers. Moreover, gene expression is modulated by environmental factors, positioning ADHD as a complex, multifactorial condition. The etiological and clinical complexity of ADHD is mirrored in its pathophysiology. Alongside macro- and microstructural alterations in cortical, cortico-striatal, cortico-cerebellar, cortico-limbic regions and the corpus callosum, as well as functional communication anomalies such as those involving the default mode network (DMN), strong evidence points to dysfunction in neurotransmission systems (particularly, but not exclusively) dopaminergic pathways. Nonetheless, even this composite framework does not fully capture the disorder’s architectural complexity. Oxidative stress, neuroinflammation, and dysbiosis have been investigated as causal, implicated, and exacerbating factors in ADHD pathophysiology. These processes interact dynamically, where disruption in one system can trigger or intensify alterations in another, ultimately contributing to the central structural and functional anomalies observed in ADHD. From this perspective, expanding the etiological and pathophysiological framework of the disorder may also broaden therapeutic opportunities: interventions targeting neuroinflammation and the microbiota may lead, as some studies suggest, to improvement, resolution, or even prevention of a condition that can be severely disabling. Finally, recognizing these factors in the context of ADHD could open the way to redefining diagnostic criteria, including the hypothesis of an “ADHD type 2”: a condition clinically indistinguishable from the primary form in terms of symptoms, but with late onset and an etiology more closely tied to immune, inflammatory, and environmental factors. This variant would therefore not constitute a neurodevelopmental disorder in the strict sense, yet would share with it both clinical manifestations and therapeutic approaches.