Preface to the Special Issue: “Microbiota and Gut–Brain Axis”

1. Introduction

The microbiota–gut–brain axis has emerged as one of the most dynamic areas of modern neuroscience, transforming our understanding of how microbial communities influence nervous system development, function, and disease in the context of body–brain interactions (O'Riordan et al. ²⁰²⁵). Once largely a neglected bidirectional communication network linking the gastrointestinal tract and the brain, the field has evolved into a mechanistically driven discipline that integrates neurochemistry with neuroimmunology, microbial ecology, metabolism, and systems neuroscience (Greenwood‐Van Meerveld et al. ²⁰²⁶).

Despite remarkable advances, significant challenges remain. Key questions concern how microbial signals are translated into neurochemical and behavioral outcomes, how gut–brain interactions are shaped across critical developmental windows, and how emerging mechanistic insights can be harnessed to improve the prevention and treatment of gastrointestinal, neurological, and psychiatric disorders. The articles assembled in this Special Issue address these challenges through three interconnected themes: microbial metabolites and neurochemistry, developmental and neuroimmune mechanisms, and translation to neurological and psychiatric disease.

Collectively, the articles highlight the importance of studying not only the brain, but also gut health as a fundamental determinant of nervous system function. Across diverse experimental and clinical contexts, the contributions emphasize the roles of microbial metabolites, intestinal barrier integrity, immune signaling, enteric and central neural circuits, and host‐microbial interactions in shaping communication between the gut and the brain (Marco et al. 2026). By spanning molecular mechanisms, critical developmental periods such as adolescence, and disease‐focused translational research, this Special Issue provides an integrated perspective on how neurochemical signaling in the microbiota–gut–brain axis contributes to health and disease across the lifespan.

2. Microbial Metabolites and Neurochemistry

One of the most significant advances in the microbiota–gut–brain field has been the recognition that microbial metabolites serve as active neurochemical mediators capable of influencing neuronal and glial function. Moving beyond descriptive analyses of microbial composition, studies in this Special Issue identify molecular pathways through which microbially derived compounds affect neurobiological processes.

Liao et al. (2026) provide important mechanistic insight into the role of the microbial metabolite para‐cresol, demonstrating its capacity to modulate neuroinflammatory pathways and synaptic function in the context of autism spectrum disorder. Their findings support the concept that gut‐derived metabolites act as direct effectors of neural dysfunction rather than merely biomarkers of altered microbial ecosystems.

Complementing this work, Ganggang et al. (2025) investigate butyrate, a short‐chain fatty acid produced through microbial fermentation of dietary fiber. Using molecular docking approaches alongside experimental models of spinal cord injury, they demonstrate that butyrate modulates HDAC1 and NLRP3 inflammasome signaling, reducing oxidative stress and inflammation. Meanwhile, the work of Collins et al. (2026) reveals that the effects of butyrate on long‐term potentiation (LTP) in the hippocampus were mediated by the free fatty acid receptor 3 (FFAR3) in female but not male animals. Extending the therapeutic potential of microbiota‐derived neuroactive compounds, Matta et al. (2025) demonstrate that a GABA‐producing strain of Levilactobacillus brevis mitigates pentylenetetrazol‐induced gut–brain dysregulation in rats. By linking microbial production of a major inhibitory neurotransmitter to improvements in gut–brain function, this study further illustrates the neurochemical capacity of microbial‐derived signals to influence host physiology. Together, these studies exemplify the growing focus on metabolite‐mediated mechanisms that translate microbial activity into neurochemical and neuroimmune effects, highlighting new opportunities for therapeutic intervention through dietary and microbiome‐based strategies.

3. Developmental and Neuroimmune Mechanisms

A second theme emerging from this Special Issue is the need to understand how gut–brain communication is shaped during critical developmental windows and through interactions between neural and immune systems. While much of the literature has focused on adult disease states, the developmental origins of microbiota–gut–brain axis function remain incompletely understood, particularly during periods of rapid neurobiological and microbial maturation such as adolescence.

Woods et al. (2026) address this gap by examining the effects of prenatal and postnatal stress on the adolescent gut microbiome. Their findings draw attention to adolescence as an important but relatively understudied period in which earlier life experiences continue to shape host‐microbial interactions. By identifying long‐lasting consequences of developmental stress exposure, this work reinforces the concept of vulnerability during temporal windows as a critical determinant of gut–brain axis function. The importance of stress‐related mechanisms is further highlighted by Etienne et al. (2026), who demonstrate distinct adrenal medulla responses in germ‐free and conventionally colonized rats subjected to acute and chronic stress. Their study provides compelling evidence that the microbiota contributes to neuroendocrine regulation and physiological adaptation to environmental challenges.

Additional insight into developmental programming of the gut–brain axis is provided by Kuehnel et al. (2025), who demonstrate that early‐life antibiotic exposure produces long‐term sex‐dependent effects on social behavior and sex hormone deconjugating activity. Likewise, Siegler Lathrop et al. (2025) show that perinatal administration of Limosilactobacillus reuteri leads to enduring sex‐specific changes in social cognition, gene expression, and gut microbial composition. Together, these studies reinforce the importance of critical developmental windows and highlight sex as an important biological variable influencing microbiota–gut–brain interactions.

Several articles further reinforce a central message emerging from this Special Issue: that gut health is not merely a consequence of neurological dysfunction but a fundamental determinant of brain function and behavior. Longo et al. (2025) demonstrate that valproic acid‐induced autistic‐like behavior is associated with intestinal damage and altered gut permeability in a sex‐dependent manner, highlighting barrier integrity as a key component of gut–brain communication. Similarly, Paine et al. (2025) show that IL‐17 directly stimulates sensory neurons and sensitizes colonic afferents through PI3K‐dependent signaling, providing mechanistic evidence linking immune mediators to neural activity within the gastrointestinal tract.

Fundamental neural pathways underlying gut–brain communication are explored by Wang et al. (2025), who characterize distinct splanchnic and pelvic spinal afferent circuits relaying sensory information from the colorectum to the brainstem. The complexity of host‐microbe influences on neural circuitry is further illustrated by Loeven et al. (2026), who report a lack of structural changes in olfactory circuitry following fecal microbiota transplantation from donors subjected to diet‐induced obesity. These findings highlight the importance of identifying the specific neural pathways through which microbiota‐related signals influence brain function and demonstrate that not all microbiome‐associated effects are accompanied by overt neuroanatomical alterations. Together, these studies illustrate how developmental factors, intestinal barrier function, immune signaling, and sensory neurocircuitry converge to shape the flow of information between the gut and the central nervous system.

4. Translation to Neurological and Psychiatric Disease

The translational implications of microbiota–gut–brain research are increasingly apparent, and a major strength of this Special Issue is the breadth of disease contexts represented.

Within neurodevelopmental disorders, Longo et al. (2025) and Liao et al. (2026) collectively demonstrate how alterations in gut permeability, microbial metabolites, neuroinflammation, and synaptic signaling may converge in autism‐related pathophysiology. In neurodegeneration, Valdetaro et al. (2026) highlight the enteric nervous system as a critical mediator of microbiota–gut–brain interactions in Parkinson's disease, emphasizing how neural communication within the gastrointestinal tract may contribute to disease progression. Further evidence for the relevance of gut–brain interactions in neurodegenerative disorders is provided by Das et al. (2025), who review emerging evidence linking the gut microbiome to repeat expansion disorders. Complementing this perspective, Sarkar et al. (2026) demonstrate that inhibition of the NLRP3 inflammasome improves gut health in a mouse model of Huntington's disease, highlighting neuroimmune pathways as potential therapeutic targets in disorders characterized by progressive neurodegeneration.

The potential relevance of the microbiota to psychiatric disorders is addressed by Cussotto et al. (2025), who report alterations in the gut microbiota of antidepressant‐free patients with depression and identify associations with symptom severity. These findings strengthen the link between gut microbiome composition and human psychiatric illness while underscoring the importance of clinically informed microbiome research.

Opportunities for therapeutic translation are explored by Fabius et al. (2026), who demonstrate that a bacterial multi‐strain formulation alters gut microbial composition and influences behavioral responses to repeated cocaine exposure. The relationship between microbial communities and substance use disorders is further explored by Barkus et al. (2025), whose scoping review synthesizes clinical evidence examining alterations in the gut and oral microbiomes associated with psychoactive substance use. Together with the experimental findings of Fabius et al., these studies underscore the growing relevance of microbiome research to addiction neuroscience and behavioral health. More broadly, these findings, alongside the metabolite‐focused work of Ganggang et al. (2025), suggest that microbiota‐targeted interventions may ultimately provide novel approaches for modifying disease‐associated neurochemical and behavioral outcomes.

5. Concluding Remarks

The articles in this Special Issue illustrate the remarkable maturation of microbiota–gut–brain axis research from largely associative observations to mechanistic investigations spanning molecules, cells, circuits, organisms, and human populations. A recurring message across the collection is that understanding brain function requires equal attention to gut health, including intestinal barrier integrity, microbial metabolism, enteric nervous system function, immune signaling, and visceral sensory pathways. The studies assembled here also highlight important future directions, including the need for further exploration of critical developmental windows such as adolescence, greater consideration of sex‐dependent mechanisms, improved understanding of gut health as a determinant of brain function, and continued efforts to establish causal links between microbial activity and neurochemical function. We hope this Special Issue will provide a valuable resource for neuroscientists, microbiologists, gastroenterologists, and clinicians alike, while fostering new collaborations aimed at unraveling the complex neurobiology connecting the gut and the brain and accelerating translation from mechanistic discovery to clinical application.

Author Contributions

Gerard Clarke: conceptualization, writing – original draft, writing – review and editing.

Conflicts of Interest

G.C. has received honoraria from Janssen, Probi, Apsen, Heel Pharmaceuticals, and Boehringer Ingelheim as an invited speaker; is or has previously been in receipt of research funding from Pharmavite, Fonterra, Reckitt, Tate and Lyle, and Nestle; and is or has been a paid consultant for Yakult, Heel Pharmaceuticals, Bayer Healthcare, and Zentiva; this support neither influenced nor constrained the contents of this review.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.