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Understanding Depression

Through the Gut

The Gut-Brain Axis

The gut-brain axis is a complex, two-way communication system linking the gastrointestinal tract and the brain, primarily via the vagus nerve. It integrates multiple systems, including:

  • The central nervous system (CNS)

  • The enteric nervous system (ENS)

  • The Hypothalamus-Pituitary-Adrenal (HPA) axis

  • The gut microbiome

Together, these systems regulate digestion, immune responses, hormone secretion, and neurochemical balance.

Communication Pathways

  1. Neural: Approximately 500 million neurons in the gut communicate with the brain through the vagus nerve, influencing mood, pain perception, and stress responses.

  2. Immune: Gut microbes interact with immune cells, modulating inflammation and neuroimmune signaling. Dysregulation can contribute to neuroinflammation and altered brain function.

  3. Endocrine: The gut produces hormones and neurotransmitters including serotonin, tryptophan, and cortisol, that affect emotional regulation, stress resilience, and cognitive function.

When Communication Breaks Down

Disruptions in the gut-brain axis often due to gut dysbiosis (imbalanced microbiota) have been linked to:

  • Metabolic disorders

  • Mood and anxiety disorders

  • Autoimmune conditions

  • Neurodegenerative diseases

Maintaining a healthy gut microbiome is essential for preserving the integrity of this axis and supporting mental and physical health.

How the Gut Influences Brain Function

The connection between the gut and brain extends far beyond anatomy. The gut microbiota (a vast ecosystem of trillions of microorganisms) plays a pivotal role in regulating brain function, behaviour, and stress responses. With microbial genes outnumbering human genes by over 100 to 1, this complex system supports digestion, immunity, energy metabolism, and neurocognitive health.

The gut-brain axis (GBA) is regulated by the central and enteric nervous systems, the vagus nerve, and the immune and endocrine systems. Gut microbes influence the brain through:

  • Neurotransmitter production: Microbes synthesize compounds like serotonin, dopamine, and GABA, which affect mood and cognition.

  • Short-chain fatty acids (SCFAs): These microbial by-products such as butyrate, acetate, and propionate modulate neuroinflammation, synaptic plasticity, and stress responses.

  • Immune signaling: Microbial interactions with immune cells can influence brain function via cytokine release and inflammation regulation.

  • Vagal pathways: The vagus nerve transmits microbial signals directly to the brain, bypassing the blood-brain barrier.

Disruptions in gut microbial composition have been linked to conditions such as anxiety, depression, and autism spectrum disorder (ASD). Notably, up to 90% of children with ASD experience persistent gastrointestinal symptoms, which are associated with behavioural and mood challenges. These findings underscore the importance of gut health in neurodevelopment and emotional regulation.

 

Depression

Depression is a complex mood disorder that affects cognitive function, emotional regulation, and daily activities. It manifests through persistent low mood, changes in behaviour, sleep disturbances, appetite shifts, and impaired concentration. While traditionally linked to imbalances in neurotransmitters such as serotonin, dopamine, and norepinephrine, current neuroscience recognises a broader interplay of biological systems.

Neurochemical Imbalances

  • Serotonin regulates mood, sleep, and appetite. Low levels are associated with increased risk of suicide and emotional instability.

  • Dopamine influences motivation, reward, and perception. Deficiencies are linked to anhedonia (inability to feel pleasure) and, in severe cases, psychosis.

  • Norepinephrine affects alertness and stress responses. Dysregulation may contribute to fatigue, anxiety, and poor concentration.

Gut-Brain Axis and Inflammation

Approximately 90–95% of the body’s serotonin is produced in the gut, primarily by enterochromaffin cells. While this serotonin doesn’t cross the blood-brain barrier, it influences mood via the vagus nerve and immune signaling.

Disruptions in gut microbiota can increase intestinal permeability, allowing endotoxins to enter circulation and trigger neuroinflammation, which is implicated in depressive symptoms.

Research shows a two-way link between gut health and depression, though it's still unclear whether gut imbalances cause depression or result from it.

Genetics and Neuroplasticity

  • Genetic predisposition affects how individuals experience depression and respond to treatment. Variants in serotonin transporter genes and stress-related pathways may increase vulnerability.

  • Depression is not caused by a single chemical imbalance. Changes in nerve cell function, growth, and synaptic connectivity, collectively known as neuroplasticity, are increasingly recognised as central to its cause.

 

Gut-Brain Axis and Depression

The gut microbiota is essential for maintaining effective communication between the gut and the brain. This communication happens through several key pathways:

  • Tryptophan metabolism, which helps produce serotonin

  • Neural signals, sent through the gut’s own nervous system and the vagus nerve

  • Microbial by-products, like short-chain fatty acids, which affect hormones, immunity, and brain chemistry

Early Life Microbiota Development

The composition of an individual’s gut microbiota is largely established within the first three years of life. Key influencing factors include:

  • Mode of delivery (vaginal birth vs. C-section)

  • Breastfeeding and maternal diet

  • Medication exposure

  • Environmental factors and genetics

Despite containing approximately 8 million protein-coding genes, the human gut microbiome is dominated by a few bacterial clusters, known as enterotypes, which shape metabolic and immunological profiles

Gut Imbalance and Mental Health

Dysbiosis, or gut microbial imbalance, is associated with:

  • Digestive disorders: IBS, IBD, leaky gut, and bacterial overgrowth

  • Mood disorders: Depression, anxiety, and emotional dysregulation

  • Disruption of the GBA, particularly in brain-to-gut signaling seen in IBS

Interruptions in gut-brain-axis can alter gut motility and trigger immune and hormonal changes. Rodent studies show that gut bacteria influence emotions, stress response, and brain development. Lack of proper colonisation leads to reduced neurotransmitter levels and impaired gut function.

A well-balanced gut microbiota is associated with reduced anxiety and improved emotional regulation. Preclinical studies suggest that the severity of depression may depend on the extent to which gut microbes influence emotional behaviour.

Emerging research suggests that gut microbiota may contribute to the pathogenesis of neuropsychiatric disorders, not just their gastrointestinal symptoms. Many individuals with conditions such as depression, anxiety, and autism spectrum disorder also report significant gut-related issues.

 

Key Takeaways

  • Depression is multifactorial: It involves neurochemical imbalances, immune responses, genetics, and gut health, not just brain chemistry alone.

  • Gut-brain axis matters: The gut and brain communicate through neural (nerves), hormonal, and immune pathways, with gut microbes playing a central role in mood regulation.

  • Microbiota influences mental health: A balanced gut microbiome supports emotional resilience, while dysbiosis is linked to depression, anxiety, and cognitive decline.

  • Early-life factors shape gut health: Birth method, breastfeeding, maternal diet, and environment influence microbiota development and long-term mental health outcomes.

  • Systems-level care is essential: Supporting gut health through nutrition and lifestyle may offer new, accessible pathways to improve mental wellbeing, especially where traditional psychiatric care is limited.

October 2025

Sources

Breit, S., Kupferberg, A., Rogler, G. and Hasler, G., 2018. Vagus nerve as modulator of the brain–gut axis in psychiatric and inflammatory disorders. Frontiers in Psychiatry, 9, p.44.

Jarčušková, D., Tkáč, I., Hlaváčová, N., Stančáková Yaluri, A., Kozárová, M., Habalová, V., Klimčáková, L., Židzik, J., Javorský, M., & Bednářová, A. (2024). Serotonin transporter 5-HTTLPR polymorphism and escitalopram treatment response in patients with major depressive disorder. BMC Psychiatry, 24, Article 690.

Kim, Y.-K. and Shin, C., 2018. The microbiota-gut-brain axis in neuropsychiatric disorders: Patho-physiological mechanisms and novel treatments. Current Neuropharmacology, 16(5), pp.559–573.

Martin, C.R., Osadchiy, V., Kalani, A. and Mayer, E.A., 2018. The brain-gut-microbiome axis. Cell Molecular Gastroenterology and Hepatology, 6(2), pp.133–148.

Mohajeri, M.H., La Fata, G., Steinert, R.E. and Weber, P., 2018. Relationship between the gut microbiome and brain function. Nutrition Reviews, 76(7), pp.481–496.

Mörkl, S., Wagner-Skacel, J., Lahousen, T., Lackner, S., Holasek, S.J., Bengesser, S.A., Painold, A., Holl, A.K. and Reininghaus, E., 2020. The role of nutrition and the gut-brain axis in psychiatry: A review of the literature. Neuropsychobiology, 79(1), pp.80–88.