Inflammation
What is inflammation?
The word “inflammation” comes from the Latin word “inflammare” which means “to kindle or set on fire”. The inflammatory response consists of redness, heat, and swelling, either internal or external, and is the normal response of living tissue to injury or infection.[1]
Inflammation is a complicated process involving more than just the activation of the immune response. It has a diverse effect on many organs of the body, including the brain.[2]
Inflammation and mental health
The association between the immune system and mental health has been formally acknowledged since at least the 1970s and is an area of increasing research.
The term ‘psycho-neuroimmunology’ was developed in the 1970s to describe the association between the brain, behaviour and the immune system.
The term is increasingly relevant, as it examines mental health issues from the perspective of the immune system, the gut, and the nervous system, as well as looking at other organs in the body.
Many diseases, from rheumatoid arthritis and diabetes to cancer and heart disease are caused by, or correlated with inflammation. Often the exact cause of inflammation is difficult to isolate.[3]
There is growing evidence that inflammation also plays an important role in mood disorders and other mental health conditions,[4] possibly through its activation of the immune system.
The underlying process for this is often some form of neuro-inflammation – which is an immune-related process that occurs within the brain, creating inflammation there.[5]
- Brain fog
- Poor attention and concentration
- Poor memory
- Depression
- Mood swings
- Anxiety
- Poor sleep
- Addiction
- Exhaustion
- Aches and pains
- Stiffness (when joints and muscles are affected)
- Heat and swelling
- Redness
- Change in bowel movements (when digestion is affected)
- Headaches (common in chronic inflammation)
Neuro-inflammation can be caused by traumatic brain injuries (for example in a car accident) or are correlated with brain infections or autoimmune disease.
In these circumstances, activated central nervous system (CNS) immune cells and the blood-brain barrier (BBB) coordinate the production of cytokines — chemicals involved in inflammation, and other chemical messengers — which directly influence brain function and act on specific receptors of the brain.[6]
Neuro-inflammation is implicated in various psychiatric disorders such as:
- Depression
- Bipolar disorder
- Schizophrenia
- Obsessive-compulsive disorder
- Parkinson’s disease
Chronic neuro-inflammation, is implicated in neurodegenerative disease such as Alzheimer’s disease and declines in cognitive function.
There is strong evidence linking depression to inflammation, [7] though it’s not clear whether inflammation contributes to depression, or whether depression contributes to inflammation.
- Studies demonstrate that, when compared to non-depressed patients, depressed patients consistently demonstrate all the cardinal features of inflammation [8]
- There is a strong association between inflammatory markers and individual depressive symptoms such as fatigue, cognitive dysfunction, and impaired sleep
Lypopolysaccharides (LPS) which are components of bacteria in the gut, are one of the major causes of inflammation. LPS can get into the bloodstream when there is leaky gut, and can cause systemic inflammation, where it can cause behavioural symptoms overlapping with those of major depression [9]
There is also a link between depression, inflammation and oxidative pathways. Inflammation and oxidation are often seen as ‘essential partners’ in mental health issues.[10]
- Depression is associated with a chronic, low-grade inflammatory response [11], [12]
- Depression is associated with elevated cytokines which mediate the body’s innate immunity and their receptors in blood and cerebrospinal fluid (CSF) [13]
- There is a link between depression and premature mortality in chronic diseases such as cancer and heart disease [14]
- Depression is associated with an increase in inflammatory markers such as acute phase proteins, chemokines, adhesions molecules and anti-inflammatory mediators such as prostaglandins [15]
- Depression activates cell-mediated immunity (the part of the immune system not associated with antibodies and which is known as the body’s adaptive immunity) [16]
- Activation of cell-mediated immunity refers to activation of the T-cells of the immune system [17], [18]
- Depression is associated with activation of the compensatory anti-inflammatory reflex system (CIRS)
- CIRS is a system that controls acute inflammation and limits an overzealous acute inflammatory response
- This is achieved by a number of methods, and includes dampening cytokine activity and therefore reducing inflammation
Research has provided evidence for depression-inflammation relationships developing early in life. There appears to be a circular relationship between depression and inflammation in children.
- Children with higher inflammatory cytokine levels were more likely to be depressed at age 18 compared with those with lower cytokine levels [19]
- In a different study, involving children aged 9, 11 or 13 years, depression predicted the subsequent level of C -reactive protein (CRP)
- C -reactive protein is a marker of inflammation and is raised in infection or inflammation in the body [20]
- Evidence shows inflammatory markers were higher in about a third of depressed patients compared to the majority of non-depressed subjects [21]
- An experiment which involved injecting Lipopolysaccharides (LPS) into animal bodies led to severe learning deficits
- These deficits were accompanied by an increase in beta-amyloid plaque in their hippocampus, and beta-amyloid plaque is a marker for Alzheimer’s disease
Behaviour and mood are heavily influenced by neurotransmitters and brain networks.
Cytokines, both pro-inflammatory and anti-inflammatory cytokines, are small proteins released by cells which have a specific effect on the interactions and communications with cells. [22]
Cytokines have been shown to interact with virtually every physiological process relevant to depression, including the processing and function of neurotransmitters.
- In research, administering cytokines profoundly affected the production, uptake and release of key neurotransmitters for mood and behaviour, serotonin, noradrenaline and dopamine [23]
Increased cytokines levels were shown to lead to:
- Reduced serotonin levels (the neurotransmitter which regulates our moods, appetite and sleep)
- Indeed cytokines are involved in the breakdown of serotonin
- Decreased dopamine uptake (the pleasure and reward neurotransmitter)
- Reduced GABA levels (the calming and focus neurotransmitter)
- Reduced levels of acetylcholine (the neurotransmitter involved in memory and stress) [24]
There seems to be a symbiotic relationship between inflammation and stress hormones in that inflammatory cytokines can trigger the release of stress hormones; and conversely, elevated stress hormones can trigger inflammation.
Meanwhile, there is a correlation between high levels of stress hormones, inflammation and depression:
- The administration of inflammatory cytokines acutely impact the HPA axis, which is activated during the stress response [25]
- Cytokines stimulate the release of hormones involved in the stress response such as corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and cortisol
- All these stress hormones are increased in patients with depression [26]
- Conversely, impairment in the HPA axis activity due to chronic stress and the associated rise in cortisol can cause enhanced susceptibility to inflammation [27]
- Chronic stress causes the activation of the HPA axis, and of inflammtory cytokines which can lead to suppressed immunity [28]
Autoimmune disease occurs when the body’s immune system attacks the body’s own cells and tissues. Therefore it involves an inflammatory response.
Types of autoimmune disease include:
- Rheumtaoid arthritis
- Systemic lupus erythematosus (SLE)
- Multiple sclerosis (MS)
- Psoriasis
- Crohn’s disease
- Hashimoto’s thyroiditis
The cause of autoimmune disease in many cases is unknown. There are many factors implicated:
- Autoimmune conditions are more common in females suggesting a hormonal component
- They can run in families, suggesting a genetic component
- There is a theory that they are caused by gut issues such as leaky gut or gluten intolerance
[29]
There is a correlation between autoimmune disease and mental health issues:
- Autoimmune disease and severe infections are risk factors for schizophrenia and other mental illness [30]
- A range of psychiatric disorders including psychosis has been observed to occur more frequently alongside autoimmune diseases
- In some studies, a prior autoimmune disease increased the risk of depression by 45% [31]
Brain-reactive antibodies (antibodies which only affect brain tissue) and inflammation are the key factors implicated in the link between autoimmunity and mental health problems.
Brain-reactive antibodies are present in about 2-3% of the population and normally cause no harm.
Brain-reactive antibodies have been implicated in:
- Autism
- Obsessive-compulsive disorder
- Schizophrenia
These conditions are believed to originate during pregnancy in the developing foetus:
- Elevated levels of antibodies have been found at the end of pregnancy in mothers of children who later develop schizophrenia
- Elevated brain-reactive antibodies have been found in pregnant mothers and their children who later develop autism [32]
In response to infection and/or inflammation, the release of inflammatory cytokines stops the development of new nerve cells in the brain known as “neurogenesis” or “neuroplasticity”.
Evidence indeed shows that infection and inflammation, which activate the release of cytokines, affect behaviour and cognitive functions such as memory.[33]
Just as inflammation and inflammatory cytokines can reduce neurogenesis, inflammation is also implicated in neurodegenerative diseases such as Alzheimer’s disease.
The chemical markers associated with inflammation are consistently raised in Alzheimer’s and can be used to predict cognitive decline and the development of dementia.[34]
During any physical illness, the immune system communicates with the brain through the secretion of cytokines.[35]
Due to the interaction between the immune system and the brain, non-neurological infections such as pneumonia and urinary tract infection (UTI) can be accompanied by acute syndromes of brain dysfunction [36] characterised by delirium and confusion. [37]
[38]
There is strong evidence associating infectious agents with mental health issues.
Infectious agents include:
- Bacteria
- Viruses
- Parasites
- Fungi
- Prions
These infectious agents can cause mental health issues, including cognitive, psychotic and mood disorders.
Viruses and bacteria
Viruses and bacteria can act as endocrine disruptors, disturbing hormonal balance. They can also create an inflammatory-immune response.
- Epstein barr [39]
- Cytomegalovirus
Prenatal infections in the mother are increasingly recognized as playing a role in the development of various brain disorders in the offspring such as:
- Depression
- A prior history of hospitalization with infection increased the risk of depression by 62% [40]
- Schizophrenia
- Autism
- Bipolar disorder
- Mental retardation
- Cerebral palsy
HIV has been associated with a large number of psychiatric illnesses from depression to substance abuse.
Impaired cognition has been associated with several infections including:
- Herpes
- Herpes simplex virus type 1 (HSV-1) causes cold sores, eye infection and encephalitis
- Exposure to HSV-1 has been associated with cognitive impairment (memory tests) as well as emotion processing in otherwise healthy individuals
- Hepatitis
- HIV
Patients affected with sepsis (sepsis occurs when infectious agents (or toxins) enter the bloodstream and tissue and can cause serious organ damage and ultimately death if not treated) and encephalitis have been shown to have cognition issues long after the infection has cleared.
Schizophrenia is highly disabling, and so far the following infectious agents have been implicated as potential causes:
- Herpes type 2
- Borna virus
- Chlamydia infections
- Toxoplasmosis
- Toxoplasmosis is a parasitic disease caused by ingesting food or drink contaminated with parasites shed from cats
- Toxoplasmosis infection has been associated with a wide range of psychiatric disorders including schizophrenia, personality disorders and obsessive compulsive disorders
Fungal infections and mental health
Candida albicans is a fungal infection.
- Candida albicans is a new candidate for studies in connection with mental health
- Candida albicans has been associated with reduced cognitive function and potentially schizophrenia
Parasites and mental health
- All parasites emit toxins known as the indole catabolites. These burden the liver and kidneys and can make you become fatigued, irritable and can cause weight gain.
- Parasites are known to be connected to immune dysfunction, chronic fatigue, sleep disturbances, teeth grinding, IBS, anemia, joint aches and pains, skin conditions and constipation
- Parasites affect everyone differently. One person can be affected by parasites and not have mood problems and another person may get depressed or have digestive problems
- The parasite toxoplasma (which causes toxoplasmosis) is known to be correlated with generalised anxiety disorder twice as frequently as other parasites
- A study in 2006 showed that women with high levels of toxoplasma were more likely to give birth to children who later became schizophrenic and had birth defects [41]
Causes of inflammation
An inflammatory response can be triggered by a number of factors. If these triggers continue over a period of time, inflammation can become chronic.
- Sugars and refined carbohydrates [42]
- Processed and fried foods which are high in salt, sugar and bad fats (trans fats and hydrogenated fats)
- Nutritional deficiencies [43]
- Alcohol [44]
- Often caused by food allergens such as gluten [45]
- Food allergies can be a major cause of brain inflammation [46]
Fewer than seven hours a night.[47]
Lack of oxygen which could be due to:
- Poor breathing habits
- Insufficient exercise
- Urban living and pollution
- Superficial breathing due to chronic stress
- Poor circulation
- Iron deficiency
Sedentary behaviour may contribute to negative mood by enhancing the inflammatory signaling pathway and increasing mood disturbance.[48]
Excessive exercise or exercise which is too intense may lead to an excess release of stress hormones, physical damage, free radical damage and inflammation. This in turn may contribute to the development of mental health disorders.
- Gut dysbiosis and Leaky gut (which allows inflammatory substances such as Lipopolysaccharides (LPS) to pass through the gut barrier into the bloodstream, contributing to inflammation)
- Poor digestion [49]
- Use of medicines such as antibiotics, NSAIDs (non-steroidal anti inflammatory drugs), proton pump inhibitors [50]
Toxins such as mercury and pesticides, are neurotoxins which can cause inflammation in the brain. [51]
Toxicity and then inflammation can also be triggered by certain pharmaceutical and recreational drugs such as alcohol, antibiotics, contraceptive pills, etc.
Low grade, hidden or chronic infections [52]
Stress, whether acute or chronic, can cause an inflammatory reaction in the body and the brain. [53]
Trauma, whether physical or psychological, can lead to inflammation.
Chronic childhood trauma such as abuse will tend to cause mental health issues, not just for psychological reasons, but also for biochemical ones — the stress to the system involved in chronic trauma can lead to inflammation, which in turn can lead to mental health issues.