What Is Inflammation?
Inflammation is a normal component of host defence and is essential to survival. Acute inflammation is a healthy response to an injury that normally has a rapid onset but disappears within hours or days as the inflammation subsides.
Chronic inflammation is a low-grade inflammatory response of prolonged duration due to the cause of inflammation persisting. The inflammatory process causes tissue damage and is accompanied by simultaneous attempts at healing and repair. The nature, extent and time course of chronic inflammation is variable, and depends on the balance between the causative agent and attempts by the body to remove it.
Important environmental components that can negatively affect the healing process include age (healing slows with age), nutritional deficiencies (specifically vitamin C, protein, zinc, fatty acids), metabolic diseases and some drugs.
Polymorphisms have been identified in several genes that result in higher basal levels of proinflammatory agents. Nutritional and lifestyle interventions aim to either directly affect the gene expression to reduce cytokine levels, or to address the secondary features of the inflammatory response.
Acute Verse Chronic Inflammation
To understand inflammation better, it is helpful to go back to the basics of acute inflammation physiology. Acute inflammation occurs when there is a sudden injury to the body such as a cut, or splinter. The below diagram starts to give us a picture of the inflammatory process.
Chronic Inflammation Pathway
The displayed image illustrates the effects of chronic low-grade inflammation from environmental triggers including obesity and a high lipid diet. The image highlights that oxidative stress, the secretion of pro-inflammatory cytokines, the inflammasome platform, and the NF-kB pathway are all implicated in the manifestation and continued cycle of low-grade inflammation. The effects of chronic, low-grade inflammation may manifest in a number of diseases of lifestyle. This particular example is highlighting the relationship to the metabolic syndrome and insulin resistance.
“Insulin resistance and the role of inflammation. Overnutrition leads to high levels of lipids and glucose and overtime development of obesity and metabolic syndrome (MetS), ultimately causing chronic low-grade inflammation. High nutrients can modulate insulin resistance by altering the insulin-signalling cascade through changes in IRS1, PI3K, and AKT phosphorylation. High lipids can also promote inflammation through generation of ceramide, and high glucose increases overall oxidative stress. During T2DM progression the insulin resistant tissues promote the exhaustion of insulin secreting ?-cells, which activates defensive mechanisms leading to lower insulin release.”
Keane K. Molecular Events Linking Oxidative Stress and Inflammation to Insulin Resistance and ?-Cell Dysfunction. Oxidative medicine and cellular longevity. 2015 Jun 10;2015:15.
Low Grade Chronic Inflammation
Chronic inflammation is an unhealthy response to an assault on the body, from pathogens it can’t break down, an overactive immune response or oxidative stress, and has a slower onset and can continue for days, to months to years. Considering that optimal health could be viewed as the ability to adequately adapt to everyday stressors, or challenges, the presence of low-grade inflammation would alter this ability, leading to an abnormal, or less optimal response.
Low-grade, chronic, systemic inflammation has become a well-known pathological feature of a wide range of chronic diseases of lifestyle. It can be defined as a 2- to 3- fold increase in circulating inflammatory mediators, usually associated with the innate arm of the immune system, often in the absence of any overt symptoms, and is a state that develops slowly – in contrast to an acute inflammatory response. Biomarkers of inflammation include the pro-inflammatory cytokines, interleukin (IL)-6, IL-1 and tumour necrosis factor alpha (TNFA), and their respective soluble receptors, the acute phase protein, C-reactive protein (CRP) – which can be measured as a standard laboratory test, as well as fibrinogen and leukocyte count.
Although these biomarkers cannot be directly related to a specific disease state, taking these measures into account, together with other genotypic and phenotypic factors, insight to the risk for diseases of lifestyle, due to chronic, low-grade inflammation, can be attained. Major modifiers of low-grade inflammation and its relevant biomarkers include age, diet, body fatness, physical fitness and genetics, and the gut microbiome as well as exposure to oxidative stress. It may also be clinically useful to test some of the above mentioned biomarkers of inflammation, or the concentration change, in response to a challenge, such as an oral glucose or fat load, or acute exercise.
Important contributors that are thought to play major roles in the onset and maintenance of low-grade inflammation include cell senescence, the nuclear factor kappa B (NF-kB) pathway and the inflammasome platform. Of course, other significant factors that can contribute and continue to drive inflammation include genetics, co-morbidity, altered gut microbiota (dysbiosis), and environmental factors such as medication use and poor nutrition.
Cell senescence can be viewed as a cell-cycle arrest mechanism and is synonymous with the aging process. Senescent cells are normal cells that cease to divide due to a DNA damage response, or in response to a high level of oxidative stress. Even though these cells no longer divide, they tend to take on a secretory phenotype (known as the senescence-associated secretory phenotype – or SASP), which entails the production of numerous inflammatory mediators including IL-6, IL-1B, IL-8, other chemokines, matrix metalloproteinases, as well as nitric oxide and reactive oxygen species (ROS). SASP has been shown to be involved in development and wound healing and is protective for individuals at a younger age, however, this changes in later life due to their ability to constantly produce the above-mentioned inflammatory mediators.
The NF-kB pathway plays an integral role in inflammation, regulating gene expression associated with inflammation, cell survival, cell proliferation, invasion, angiogenesis, and metastasis. NF-kB is a transcription factor that modulates gene expression of over 400 genes by binding to parts of DNA known as kB response elements in the gene promotors and enhancers. Activation of NF-kB can be achieved via numerous (>150) different stimuli, including bacterial antigens, cytokines such as TNFA, IL-1 and IL-6, as well as products of oxidative stress or oxidised molecules such as oxidised low density lipoprotein (LDL). Chronic activation of this pathway occurs when the assaulting stimulus is not removed, activating NF-kB, thus increasing oxidative stress markers, which in turn leads to increased production of proinflammatory mediators, encouraging chronic, low-grade inflammation.
Inflammasomes are cytoplasmic platforms that are an essential part of the innate immune system and for the clearance of pathogens and damaged cells. Inflammasomes trigger the maturation and release of pro-inflammatory cytokines including IL-1B and IL-18, and induce a type of cell death called pyroptosis, assisting in host defence. However, overt, or dysregulated, inflammasome activation has been implicated as a major driver of autoimmune and metabolic disorders, neurodegenerative disorders and certain cancers. The activation of the inflammasome platform and its functions require controlled regulation in order to avoid unintended host tissue damage, while still allowing for pathogen-killing inflammatory response.
Effects of Chronic Inflammation
Low-grade, chronic inflammation is associated with obesity and visceral fat deposition, insulin resistance and the metabolic syndrome, type 2 diabetes, atherosclerosis and other cardiovascular diseases, sarcopenia and osteoporosis, neurodegenerative diseases, major depression, and cancer.
Personalised lifestyle and nutrition interventions for improving inflammation and decreasing risk for associated diseases of lifestyle will be given according to genotype. It is, however, important to take the full panel into account to ensure a holistic, personalised plan is provided.
General Lifestyle Recommendations For Improved Inflammation
Manage weight, and lose weight if overweight. A 10% reduction in body weight over one year can be considered a significant clinical outcome for decreasing risk of morbidities associated with low-grade inflammation. It is also important to maintain a healthy body fat percentage, as excess adipose tissue triggers the activation of inflammatory pathways.
Increase physical activity. Physical activity has been shown to increase production of the myokine from skeletal muscle, IL-6, leading to the secretion of anti-inflammatory cytokines, which, in turn, prevent the release of the proinflammatory TNFA and IL-1. Physical activity and exercise training also increase energy expenditure and reduce body fat, which is beneficial in controlling the levels of pro-inflammatory cytokines produced by adipose tissue. Physical activity on a regular basis as also associated with improved anti-oxidant capacity.
Dietary Recommendations For Improved Inflammation
- Calorie restriction
- Avoidance of AGE’s
- Avoidance of the Modern Western Diet, and increased adherence to the Mediterranean diet, with a reduced animal protein, higher plant-based diet, has been shown to be beneficial in improving markers of inflammation.
- Decrease intake of refined sugar
- Fatty acids and Omega-3 fatty acids
- Vitamin E
- Vitamin D
Inflammation PowerPoint Presentation
Inflammation and Oxidative Stress: The Molecular Connectivity between
Insulin Resistance, Obesity, and Alzheimer’s Disease
Verdile et al, 2015
Nutrients and Oxidative Stress: Friend or Foe?
Ling Tang et al, 2018