From Microbes to Behavior in Autism: A Key Role of the Immune System: Preclinical Insights into Mechanisms

Abstract

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by deficits in social communication and repetitive behaviors. While genetic factors are significant contributors, increasing attention is being paid to environmental influences, especially the gut microbiota and immune system, in shaping neurodevelopmental outcomes. This thesis explores the interplay between the gut microbiota, immune function, and ASD-related behaviors using various preclinical mouse models. The gut-brain axis, a bidirectional communication pathway between the gastrointestinal tract and the brain, is central to this investigation. Individuals with ASD often present with gastrointestinal symptoms and distinct gut microbiota profiles, suggesting a link between microbial composition and behavioral traits. Chapters 2 and 3 review clinical and preclinical evidence supporting this connection, emphasizing how microbial metabolites, immune modulation, and gut-brain signaling influence neurodevelopment. In Chapter 4, the thesis uses a valproic acid (VPA)-induced mouse model of ASD to examine the effects of prebiotic dietary interventions. VPA exposure leads to ASD-like behaviors in mice. Administering a prebiotic diet improved microbial balance, strengthened the intestinal barrier, reduced neuroinflammation, and improved social behavior, highlighting the therapeutic potential of targeting the microbiota via immune modulation. Chapter 5 investigates the effects of human fecal microbiota transplantation (hFMT) from children with ASD into microbiota-depleted mice. The behavioral outcomes varied depending on the genetic background of the recipient mice, indicating that host genetics modulate gut-brain interactions. hFMT induced changes in behavior, immune profiles, inflammation, and metabolism, reinforcing the importance of microbial and host factors in ASD. In Chapter 6, the combined effect of hFMT and cow’s milk allergy (CMA), an immunological trigger, was explored. This dual challenge significantly worsened ASD-like behaviors and was associated with altered mucosal and humoral immune responses, as well as increased activation of astrocytes in the brain. These results support the hypothesis that immune dysregulation plays a central role in ASD. Chapter 7 focuses on splenocyte transfer from dual-trigger mice (hFMT + CMA) to naïve mice. Remarkably, even in the absence of direct exposure to hFMT or CMA, recipient mice developed ASD-like behaviors. This demonstrated that immune cells alone could drive behavioral changes, further establishing a mechanistic link between immune status and neurodevelopment. The transfer also altered the gut microbiota and immune profiles of recipient mice. Chapter 8 synthesizes the findings and emphasizes the critical role of the gut-immune-brain axis in ASD. The thesis proposes that targeting this axis may offer new therapeutic avenues for ASD intervention. Titled “From Microbes to Behavior in Autism: A Key Role of the Immune System – Preclinical Insights into Mechanisms,” this thesis provides compelling evidence that gut microbiota and immune interactions are integral to ASD pathophysiology. These findings open avenues for microbiota-targeted therapies and underscore the importance of integrative approaches to understanding neurodevelopmental disorders.