Beyond the Axis: Understanding the Brain-Gut-Microbiome System

By Eugene Capitano, MSc Psychology & Neuroscience of Mental Health, King’s College London

The way scientists describe the connection between our gut and brain has changed dramatically over the last three decades. What started as a simple two-way street is now recognized as a complex, interconnected biological network that influences everything from our mood and metabolism to our risk for neurological disease. This article, based on a comprehensive 2024 review by Dr. Tien Dong and Dr. Emeran Mayer in Cellular and Molecular Gastroenterology and Hepatology, explores this evolution in thinking, from a linear "axis" to a dynamic "system", and breaks down how this intricate network functions.

The Evolution of a Concept: From Axis to Integrated System

1990s–2000s: The “Gut–Brain Axis” (GBA)Early research identified a direct line of communication between the brain and the gut. Known as the Gut–Brain Axis, this model focused on the autonomic nervous system (including the vagus nerve) and the gut’s own “second brain,” the enteric nervous system. The emphasis was on how these nerve signals controlled motility, secretion, and sensation. At this stage, the trillions of gut microbes were not yet considered part of the picture.

2010s: The “Microbiota–Gut–Brain Axis” (MGB)With the rise of microbiome science, fueled by new sequencing technology, the gut’s microbial residents were formally added to the model. This expanded Microbiota–Gut–Brain Axis recognized that microbes produce neuroactive metabolites (SCFAs, GABA, serotonin precursors), modulate the immune system, and influence gut barrier integrity. While this was a leap forward, the communication was still viewed as a linear axis, just with more players.

2020s to Today: The “Brain–Gut–Microbiome (BGM) System”Recent breakthroughs in sequencing, metabolomics, and brain imaging revealed that an “axis” no longer captured the full complexity. The Brain–Gut–Microbiome (BGM) System, as described by Dong & Mayer, reframes the connection as a multi-directional network, integrating the brain, the gut connectome, the gut-associated immune system, and the microbiome. This model also accounts for external inputs like diet, stress, trauma, and individual genetic risks. Communication happens simultaneously across neuronal, hormonal, immune, and microbial pathways in constant feedback loops.

How the Gut Talks to the Brain: The Key Pathways

The BGM system relies on multiple overlapping communication channels.

The Gut's Sensory System: Enteroendocrine Cells (EECs)Deep within the gut lining are specialized sensory cells, including enterochromaffin cells (ECCs), that act as critical translators between the microbiome and the brain. They constantly monitor the gut environment, detecting nutrients and microbial metabolites. In response, they release powerful messenger molecules:

• Serotonin (5-HT): ECCs produce the vast majority of the body's serotonin, which regulates gut motility, secretion, and immune responses, while also signaling to the brain via the vagus nerve to influence mood.  
• Satiety Hormones: Molecules like cholecystokinin (CCK) and glucose-dependent insulinotropic polypeptide (GIP) are released to control appetite and blood sugar.  

Recent studies show microbes directly trigger these cells. For instance, specific bacterial metabolites like isovalerate can activate ECCs to release serotonin. Other metabolites from tryptophan can stimulate EECs via the Trpa1 receptor, a process that directly activates vagal nerve pathways to the brain. When this system is overstimulated, it can lead to the visceral pain seen in Irritable Bowel Syndrome (IBS) and contribute to anxiety-like behaviors.

A Chemical Factory: Neurotransmitters and Metabolites: Gut microbes produce a vast array of chemicals that can influence brain function:

• Neurotransmitters: Certain bacterial strains can synthesize neurotransmitters directly, such as GABA from Bifidobacterium (which calms neuronal activity) and others that produce dopamine and norepinephrine.  
• Short-Chain Fatty Acids (SCFAs): Metabolites like butyrate, acetate, and propionate, produced from dietary fiber, can reduce neuroinflammation, promote neuronal growth, and enhance synaptic plasticity. However, their effect can depend on genetics; in mouse models of Alzheimer's with the ApoE4 gene, SCFAs were found to worsen pathology, showing context is critical.  
• Other Neuroactive Metabolites: Tryptophan metabolites like indoles can influence mood regulation. A newly identified metabolite, 4-ethylphenyl sulfate, was found to reduce the protective myelin coating on neurons, leading to anxiety-like behaviors in mice.  

The Neuroimmune Connection: The gut microbiome constantly communicates with the brain through the immune system.

• Protective Priming: Components from beneficial bacteria, like polysaccharide A from Bacteroides fragilis, can train immune cells to reduce autoimmune inflammation in animal models of multiple sclerosis. In another fascinating discovery, gut microbes were shown to "educate" IgA-secreting immune cells that then travel to the brain's protective lining (the meninges) to defend it from pathogens.  
• Inflammatory Signaling: Conversely, gut dysbiosis can trigger the release of pro-inflammatory cytokines that activate vagal pathways and impact the brain. This mechanism is implicated in conditions like chronic fatigue syndrome, long COVID, and some forms of depression.  

The Gatekeepers: Protective Barriers in Gut-Brain Signaling

For these signals to work properly, they must be regulated by a series of protective barriers. When these barriers are weakened, it can contribute to disease.

The Gut Epithelial Barrier (GEB): The gut lining is the first line of defense. If it becomes "leaky" (increased intestinal permeability), microbial components like lipopolysaccharides (LPS) can enter the bloodstream. This condition, known as metabolic endotoxemia, triggers systemic inflammation that can compromise other barriers and contribute to neurodegenerative and psychiatric disorders.

The Mucus Layer: This slimy layer protects intestinal cells and shapes the microbial community. Beneficial microbes like Akkermansia muciniphilacan help strengthen this layer by stimulating mucus production. Disruption of the mucus layer can weaken gut defenses and alter gut-brain signaling.

The Blood-Brain Barrier (BBB): The BBB is the brain's highly selective security system. Systemic inflammation originating from the gut can weaken the BBB's tight junctions, allowing harmful molecules and immune cells to enter the brain. This can activate the brain's resident immune cells (glia), fueling the neuroinflammation seen in many psychiatric and neurologic disorders.

The Choroid Plexus Vascular Barrier (PVB): A more recently discovered barrier, the PVB also responds to gut inflammation. In animal studies, intestinal inflammation caused this barrier to "close," which was linked to impaired memory and anxiety-like behaviors, revealing another pathway for gut health to impact cognition.

The BGM System in Health and Disease

Dysregulation at any level of the BGM system can contribute to a wide range of disorders.

• Gastrointestinal & Metabolic Disorders: Conditions like IBS are now considered disorders of gut-brain interaction, driven by altered signaling, dysbiosis, and visceral hypersensitivity. In obesity and food addiction, distinct BGM signatures are linked to disrupted satiety signals and reward pathways. In metabolic-associated steatotic liver disease (MASLD), gut dysbiosis contributes directly to liver inflammation and fat accumulation.  
• Psychiatric & Neurological Disorders: 
• Depression & Anxiety: Studies show microbiota from depressed patients can induce depressive behaviors in mice. Dysbiosis is linked to altered serotonin and tryptophan metabolism, systemic inflammation, and even changes in estrogen metabolism in women.  
• Parkinson’s Disease: Evidence suggests the disease's hallmark protein, α-synuclein, may originate in the gut and travel to the brain via the vagus nerve. Gut symptoms like constipation often precede motor symptoms by years.  
• Alzheimer’s Disease: Gut dysbiosis has been shown to accelerate amyloid and tau pathology in animal models, with effects strongly influenced by a person's ApoE genotype.  
• Neurodevelopmental Disorders: In Autism Spectrum Disorder (ASD), individuals often have altered gut microbiota. However, recent research suggests these differences may be more related to restricted dietary preferences common in ASD rather than a direct cause of the condition, highlighting the complexity of these associations.  

Conclusion: A New Era of Medicine

The shift from a simple "axis" to a complex "BGM system" represents a paradigm shift in medicine. It helps explain why our mental health is inseparable from our gut health and why diet, stress, and lifestyle have such a profound impact on our overall well-being. Understanding this intricate communication network opens the door to innovative new therapies—from next-generation probiotics to targeted dietary interventions—that could one day treat a vast range of human diseases by restoring balance to this fundamental system.

Reference

Dong, T. S., & Mayer, E. (2024). Advances in Brain–Gut–Microbiome Interactions: A Comprehensive Update on Signaling Mechanisms, Disorders, and Therapeutic Implications. Cellular and Molecular Gastroenterology and Hepatology, 18(1), 1–13. https://doi.org/10.1016/j.jcmgh.2024.01.024