The Vicious Cycle

Depression and anxiety aren’t just “in the mind.” They are often the result of a powerful loop between your brain, stress hormones, and your gut. The hypothalamus-pituitary-adrenal (HPA) axis and the gut-brain axis (GBA) interact in a complex, two-way system that is central to both mental and physical well-being. When stress hormones run high, they disrupt gut balance; when the gut is out of balance, it sends distress signals back to the brain. This self-perpetuating cycle drives stress, inflammation, and neurochemical changes that can fuel low mood, fatigue, anxiety, and the persistence of depression — but understanding it opens the door to new, more effective ways of healing.

The HPA axis is the body's primary system for regulating its response to stress. In individuals with MDD and anxiety disorders, this system is often hyperactive.

• Activation and Dysfunction: In response to stress, the hypothalamus releases hormones that ultimately stimulate the adrenal glands to release cortisol. In a state of chronic stress, the negative feedback mechanism that normally suppresses cortisol becomes impaired, leading to chronically elevated levels, or hypercortisolism (Bertollo et al., 2025).  
• Neurotoxic Effects: Prolonged exposure to high cortisol has damaging effects on the brain. It can lead to atrophy of the hippocampus and prefrontal cortex—regions crucial for mood regulation and memory. Furthermore, it can cause the amygdala, the brain's emotional processing center, to become hyperactive, exacerbating symptoms of both anxiety and emotional reactivity (Bertollo et al., 2025).  
• Impaired Neuroplasticity: Elevated cortisol interferes with synaptic plasticity—the brain's ability to adapt and form new connections. It suppresses brain-derived neurotrophic factor (BDNF), a protein essential for neuron survival and growth. Low BDNF levels are strongly associated with hippocampal atrophy and depressive symptoms (Bertollo et al., 2025).  

The GBA is a communication network linking the central nervous system and the gastrointestinal tract, with the gut microbiota playing a central role.

• Neurotransmitter Production: The gut is a major site of neurotransmitter synthesis. Approximately 90% of the body's serotonin, a key mood-regulating neurotransmitter, is produced in the gut. The gut microbiota also influences the production of other neuroactive substances, including GABA (gamma-aminotobutyric acid), which helps modulate anxiety (Bertollo et al., 2025).  
• Gut Dysbiosis and Neuroinflammation: An imbalance in the gut microbiota, or dysbiosis, is consistently linked to depression and anxiety. Dysbiosis can increase intestinal permeability, allowing inflammatory molecules and bacterial components like lipopolysaccharides (LPS) into the bloodstream. This triggers a systemic, low-grade inflammatory response. These molecules can cross the blood-brain barrier and induce neuroinflammation—inflammation within the brain itself. This process damages neurons, compromises synaptic plasticity, and disrupts neurotransmitter function, directly exacerbating depressive and anxious symptoms (Bertollo et al., 2025).  

The HPA and gut-brain axes continuously influence each other, creating a pathological loop. Chronic stress activates the HPA axis, and the resulting high cortisol levels disrupt the gut by altering the microbiota and damaging the intestinal barrier. This dysbiosis and inflammation then send signals back to the brain that perpetuate the stress response. Inflammatory molecules from the gut can further activate the HPA axis and lead to glucocorticoid resistance, where the brain's receptors for cortisol become desensitized, locking the HPA axis into a state of hyperactivity (Bertollo et al., 2025).

This vicious cycle establishes a feedback loop where stress-induced HPA hyperactivity disrupts gut health, and the resulting gut dysbiosis fuels the neuroinflammation that drives symptoms of depression and anxiety (Bertollo et al., 2025).

This holistic understanding suggests that effective treatments should integrate approaches that target both systems.

• Top-Down Regulation: Strengthening the Prefrontal Cortex Top-down treatments focus on strengthening the regulatory capacity of the prefrontal cortex (PFC) to reduce hyperactivity in lower cortical areas like the amygdala. Interventions such as cognitive-behavioral therapy (CBT) and mindfulness-based stress reduction enhance the PFC's ability to modulate emotional responses, thereby regulating the body’s stress response and calming the over-activation of the HPA axis (Bertollo et al., 2025).  
• Bottom-Up Regulation: Targeting the Gut Microbiome Bottom-up strategies target the gut to influence brain health through dietary and lifestyle changes. A balanced diet rich in fiber promotes beneficial bacteria, while a Western diet high in processed foods can induce dysbiosis. Supplementation with specific probiotics (Lactobacillus, Bifidobacterium) and prebiotics can help restore microbiota balance and reduce cortisol levels. For treatment-resistant conditions, emerging therapies like fecal microbiota transplantation (FMT) are also being explored (Bertollo et al., 2025). 

The impact of the HPA-GBA connection extends far beyond depression and anxiety. The same mechanisms of stress, dysbiosis, and neuroinflammation are implicated in a wide range of other neurological and psychiatric disorders.

• Dementia and Neurodegeneration: The GBA dysfunction and associated neuroinflammation are linked to neurodegenerative diseases. Research has specifically pointed to the gut microbiota's neuroinflammatory implications in Alzheimer's disease, suggesting a connection between gut health and the processes that lead to dementia (Bertollo et al., 2025).  
• Other Psychiatric and Neurological Conditions: The article broadly connects GBA dysfunction to "various neurological and psychiatric disorders, including neurodevelopmental conditions...and psychiatric illnesses" (Bertollo et al., 2025). This highlights the HPA-GBA axis as a foundational pathway in overall brain health.  
• Irritable Bowel Syndrome (IBS) and Endocrine Disorders: The microbiome’s impact on neurochemicals has been linked to conditions like IBS, which often co-occurs with mood disorders. Furthermore, imbalances in the gut microbiota are connected to endocrine system diseases like polycystic ovary syndrome (PCOS) and endometriosis (Bertollo et al., 2025).  

By addressing both the brain's top-down control systems and the gut's bottom-up influences, a multidisciplinary approach may hold the key to more effectively managing a wide array of debilitating mental and physical health conditions (Bertollo et al., 2025).

Bertollo, A. G., Santos, C. F., Bagatini, M. D., & Ignácio, Z. M. (2025). Hypothalamus-pituitary-adrenal and gut-brain axes in biological interaction pathway of the depression. Frontiers in Neuroscience, 19, 1541075. https://doi.org/10.3389/fnins.2025.1541075