Exploring the gut-brain-immune axis in neurodegeneration

Neurodegenerative diseases (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), represent a growing global health burden, particularly in aging populations. While traditional research has focused on neuronal mechanisms like protein misfolding and oxidative stress, recent evidence underscores the critical role of the gut-brain-immune axis in disease pathogenesis. This review synthesizes current knowledge on how gut microbiota dysbiosis influences neuroinflammation, blood-brain barrier (BBB) integrity, and immune homeostasis through microbial-derived metabolites, including short-chain fatty acids (SCFAs), lipopolysaccharides (LPS), and bacterial amyloids. We explore the communication pathways linking the gut, immune system, and central nervous system (CNS), and highlight disease-specific mechanisms and therapeutic opportunities. Despite promising preclinical findings, significant challenges remain in establishing causality and translating these insights into clinical practice.

Introduction

The rising prevalence of NDs and the limited efficacy of neuron-centric therapies have prompted a paradigm shift toward a systems biology approach. The gut-brain-immune triad offers a holistic framework to understand neurodegeneration, integrating signals from the gut microbiota, immune responses, and CNS function. This review aims to unify recent discoveries and emphasize the translational potential of microbiome-targeted and immunomodulatory interventions.

Toward a systems biology framework for NDs

Moving beyond reductionist models, a systems perspective acknowledges the contributions of glial dysfunction, chronic neuroinflammation, and metabolic dysregulation. This approach may reveal novel therapeutic targets and explain the failure of neuron-focused treatments.

Gut microbiota as a neuroregulatory hub

The gut microbiome, often termed the "second brain," regulates brain function through neural, endocrine, immune, and metabolic pathways. Dysbiosis can disrupt these pathways, leading to systemic inflammation and CNS dysfunction, positioning the gut as a central modulator of neurodegeneration.

Communication pathways in the gut–brain–immune triad

Bidirectional communication occurs via:

• Neural pathways: Vagus nerve and enteric nervous system.

• Endocrine signals: Gut hormones like GLP-1 and ghrelin.

• Immune mechanisms: Cytokine signaling and immune cell trafficking.

• Metabolic routes: Microbial metabolites such as SCFAs and tryptophan catabolites.
  These pathways collectively influence neuroinflammation, synaptic function, and neuronal survival.

Dysregulation of the gut–brain–immune axis in NDs

• AD: Gut dysbiosis promotes amyloid-β aggregation and tau hyperphosphorylation via LPS and reduced SCFA production.

• PD: α-Synuclein aggregation originates in the gut and propagates to the brain via the vagus nerve, exacerbated by SCFA depletion and immune activation.

• ALS: Altered Firmicutes/Bacteroidetes ratio and reduced butyrate producers correlate with neuroinflammation and motor neuron loss.

• MS: Dysbiosis drives Th17/Treg imbalance and molecular mimicry, fostering autoimmunity and demyelination.

Neuroinflammation: A converging mechanism

Neuroinflammation serves as a central integrator of gut-brain-immune crosstalk. Microbial metabolites, immune cell infiltration, and epigenetic modifications (e.g., miRNA regulation) sustain inflammatory cycles, contributing to synaptic dysfunction and neuronal damage.

Limitations of the study

Key challenges include:

• Establishing causality from correlation.

• Interindividual variability in microbiome composition.

• Methodological inconsistencies in microbiome research.

• Overreliance on cross-sectional and preclinical data.

• Bidirectional feedback loops complicating therapeutic targeting.

Significance of the review

This review integrates overlooked elements such as epigenetic regulation, non-GLP-1 gut hormones, and bidirectional gut-brain feedback. It advocates for a multidisciplinary approach to develop personalized, mechanism-based therapies.

Future directions

Priority areas include:

• Longitudinal human studies with multi-omics integration.

• Development of brain-gut organoid models.

• Standardization of microbiome research protocols.

• Exploration of vagal and epigenetic mechanisms.

• Clinical trials of probiotics, postbiotics, and dietary interventions.

Conclusions

The gut-brain-immune triad is a pivotal, though underrecognized, axis in ND pathophysiology. Microbial metabolites, particularly SCFAs, play key roles in modulating neuroinflammation and BBB integrity. While microbiome-based interventions hold promise, their clinical translation requires robust, longitudinal studies and personalized approaches. A systems-level understanding of this triad is essential for advancing ND prevention and treatment.