Chronic Social Stress Activates the Immune System and Causes Depression
Stress levels around the world are surging, alongside the incidence of stress-related psychiatric disorders. Right alongside our increased stress levels, the human gut contains fewer bacterial species than ever before – with one important consequence being reduced stress resilience.
Preclinical and clinical evidence has shown how stress exposure can alter the gut microbiota and their metabolites and how stress-related shifts in the gut microbiota jeopardize tight junctions of the gut barrier. In this context, bacteria and bacterial products can translocate from the gut to the bloodstream, lymph nodes, and other organs, thereby modifying systemic inflammatory responses.
Heightened circulating inflammation can be a causative factor in stress-related psychiatric disorders, including depression.
In a recent scientific review published in the journal Biological Psychiatry, researchers detail preclinical and clinical evidence that traces these brain-to-gut-to-brain pathways that underlie stress-related psychiatric disorders, including depression. They also review evidence for interventions that modulate the gut microbiota (including probiotics and prebiotics) to reduce stress responses and psychiatric symptoms.
Extensive research over several decades has demonstrated that stress, including psychosocial stress (stress that arises from social interactions) is one of the most important risk factors for depression.
Great effort has therefore been devoted to research seeking to reveal precisely how stress perturbs the biology of the brain and other bodily systems to produce the diverse range of depression symptoms.
A new study appearing in the journal Nature shows how when someone is experiencing social stress, the functioning (or mis-functioning) of the body’s immune system can cause depression or increase its risk.
Psychosocial stress can affect the two-way communications between the Central Nervous System (CNS, which includes the brain) and the rest of the body. In people experiencing chronic stress, past research has shown that the innate immune system is activated, resulting in the mobilization of immune cells including white blood cells in peripheral organs and blood, as well as the production of tiny proteins called cytokines, which can trigger inflammation.
One intriguing discovery in psychiatry research has been that a subset of people with stress-related psychiatric disorders, including major depression, “display a state of chronic low-grade inflammation.”
It has also been shown that stress induces changes to the thin but vital membranes separating the brain and the rest of the body, the blood-brain barrier (BBB), as well as the blood-gut-barrier (BGB) that separates the intestinal compartment from the systemic circulation and the rest of the body. These barriers, which normally play a protective role, keeping toxins and microbes “in their place” are disrupted by stress-induced inflammation, allowing the entry of circulating proteins from the gut into the blood and from the blood into the brain. One region in the brain affected by such invasion, is the nucleus accumbens (NAc), which is central in the processing of rewards and also in the response to aversive stimuli, and implicated in depression.
The recent study in Nature reveals new details about mechanisms through which stress-induced immune changes can affect the function of the brain’s neurons and ultimately, behavior.
In the presence of stress, immune factors at work in the body’s periphery, such as a rise in the circulation of pro-inflammatory cytokines, likely have a direct impact on neurons—for example, by binding directly to receptors expressed in neurons. The new study demonstrates a distinct way in which stress promotes interactions of immune cells in the periphery with the brain—an indirect way that appears to result in adverse changes in social behavior.
The new research focuses on the role in this process of collagen-digesting enzymes called MMPs (matrix metalloproteinases) and in particular MMP8. This enzyme, like others in the MMP family, has roles in shaping and regulating the space between neurons, called extracellular space (ECS), as well as the extracellular matrix (ECM), which is a dense web-like material that individual neurons extend out into ECS.
The researchers showed how MMP8, which is released during chronic social stress by immune cells circulating in the body’s periphery, can invade the brain perhaps due to damage to the BBB, and alter the shape of ECS and ECM – leading to depression.
These two new studies can be summed up as…
- Stress disrupts microbiome balance and reduces gut integrity (i.e. increases gut “leakiness”)
- Leaky gut results in immune activation and pro-inflammatory state
- Increased cytokines exposure (e.g. MMP8) damages the BBB (aka “Leaky Brain”)
- Cytokines are causally linked to social-avoidance behavior (rodents) and depression (humans)
Circulating myeloid-derived MMP8 in stress susceptibility and depression
February 7, 2024
Stressed to the Core: Inflammation and Intestinal Permeability Link Stress-Related Gut Microbiota Shifts to Mental Health Outcomes
Biological Psychiatry https://doi.org/10.1016/j.biopsych.2023.10.014
Feb 15, 2024
