Chronic Low-Grade Inflammation – A Common Ground for Modern Epidemics

Modern lifestyles, particularly in the “western world”, are clearly having an impact on human health. Chronic stress and anxiety are recurrent and have a highly deleterious effect, leading to the development of chronic diseases and to an earlier onset of many age-related conditions.

Our feeding habits have also changed rather significantly. Throughout evolution, humans were designed for feeding patterns that highly differ from those currently observed. Modern western diets rely heavily on high-energy, low-nutrient processed food, for which we are not optimised. These choices are not innocuous - nutrition is a fundamental element in our health and in our resistance to disease.

The steady rise in chronic conditions observed in the last decades is most likely a consequence of these lifestyle options. Today’s most prevalent chronic diseases have been found to share a common ground that can be attributed to modern environments and behaviours.

Diet may be the main cause of most of these problems – it affects our metabolism, and it affects the gut microbiota, which, as discussed in a previous article, is a central element in our physical health through its influence on the immune system, and also in our mental and cognitive health, through its influence on the gut-brain axis.

Inflammation – friend and foe

Inflammation is a response for injury or infection that is characterised by increased blood flow, infiltration of immune cells into tissues, and production of chemical mediators. These processes act together to eliminate threat and/or to repair damaged tissue. When it occurs as a response to injury or infection, inflammation is an essential process of our defence arsenal.

But a different type of inflammation was discovered in the 1990s. It was described as a prolonged and maladaptive inflammatory response first associated with obesity, and it was suggested to underlie the diseases associated with excessive weight. It differed from classical inflammation in that it was low-grade, with a much lower production of inflammatory mediators, it was persistent, and its effects were systemic rather than local. It was deemed chronic low-grade inflammation.

Unlike inflammation in reaction to injury or infection, chronic low-grade inflammation, also known as metaflammation due to its association to metabolism, is a pathological feature. Instead of protecting us from damage, chronic low-grade inflammation is itself a damaging process. Metaflammation is induced essentially by environmental, behavioural, and nutritional factors linked to modern lifestyles, such as, for example, poor nutrition, sedentarism, insufficient sleep, and stress.

Most modern chronic conditions, such as cardiovascular diseases, cancer, chronic respiratory problems, autoimmune diseases, neurodegenerative conditions, or metabolic disorders, are associated with such a chronic inflammatory state. In these contexts, inflammation does not occur as a defence response – it is most likely the driving force behind them.

Inflammation and the brain – behavioural and psychiatric effects

Inflammatory molecules are able to influence most of our physiological functions, even our cerebral functions and behaviour. That is well established in the context of high-grade inflammation, be it chronic or acute, but recently, this notion has extended to chronic low-grade inflammation.

Communication between the immune system and the central nervous system is actually a key part of the inflammatory response to infection, injury or disease. This communication drives some recognizable components of the inflammatory reaction that are controlled by the brain, including fever and behavioural changes, namely fatigue, decreased appetite, impaired sleep, concentration deficits, depression and mild cognitive impairment; this set of behavioural changes is known as “sickness behaviour”.

Development of sickness behaviour is a normal response to an infection, and it can also occur during chronic low-grade inflammation, but in this context, these responses are not necessarily meant to protect us. Molecules released during an inflammatory response can act on brain circuits, neurotransmitter production or neuroendocrine functions, for example. They can thus easily influence mood and behaviour.

Neuroendocrine alterations associated with mood and behavioural changes have actually been described for most chronic metabolic disorders. This is particularly relevant given the prevalence and the increasingly earlier onset of metabolic diseases that has been observed in the last decades.

Chronic low-grade inflammation in metabolic disorders

Metabolic disorders, such as diabetes, the metabolic syndrome or obesity, are an outstanding consequence of our feeding behaviours, and their incidence has been steadily rising in the last decades. And these disorders are more than meets the eye. They have insidious consequences that in the long run can be significantly damaging.

Metabolic disorders are examples of conditions entailing both a chronic low-grade inflammatory state and an increased prevalence of behavioural and psychiatric symptoms. The most commonly reported symptoms include depression, cognitive impairment, fatigue, sleep difficulties and pain. These are serious problems with a huge impact on our quality of life.

Patients suffering from obesity, type 2 diabetes or metabolic syndrome usually have higher levels of inflammatory markers. This chronic low-grade inflammatory state is believed to originate, at least partially, from the adipose tissue. Adipocytes, the fat-storing cells in adipose tissue, have the ability to produce and secrete inflammatory molecules. Changes in their functions are often associated with weight gain, which leads to an increased release of pro-inflammatory factors.

This metaflammation that characterizes obesity and related metabolic disorders can lead to changes in the central nervous system. In the brain, inflammatory molecules can be released by glial cells or by peripheral immune cells recruited as a consequence of high-fat diets.

Diet is most likely the main cause of chronic low-grade inflammation, either through a direct pro-inflammatory action of certain foods, through the increase in adipose tissue’s secretion of inflammatory mediators, or through alterations in the gut microbiota.

Inflammation – the link between metabolic disorders and behavioural changes

The prevalence of behavioural symptoms in patients with metabolic disorders is impressively high: estimates indicate that 5.3 – 23% show signs of cognitive impairment, 17.8 – 30% have depressive symptoms, around 60% have chronic fatigue, 57.8 – 83.4% have chronic pain, and 63.4 – 84.8% experience sleep alterations. Growing experimental evidence has been attributing these symptoms to a direct action of chronic low-grade inflammation.

The association between metabolic disorders and an increased risk of cognitive decline has been gaining awareness in the last years and has been increasingly regarded as a consequence of chronic low-grade inflammation. Among patients with the metabolic syndrome, those with the highest level of inflammation were those who exhibited the greatest risk of age-related cognitive decline. Interestingly, weight reduction in obese patients has actually been found to lead to significant improvements in cognitive performance, which may be due to a decrease in the production of inflammatory mediators by adipose cells.

Also, a correlation between the occurrence of depressive symptoms and an increase in inflammation has been found in patients with the metabolic syndrome, type 2 diabetes and obesity. Weight loss in obese patients has also been shown to lead to reduced inflammation along with a reduction in depressive symptoms.

Anxiety and stress may also be important factors. Increased anxiety can be induced by chronic inflammation through its effects on the brain. But the opposite may also be true - stress is known to be a major risk factor for depression and recent theories state that stress and anxiety can stimulate components of the immune system involved in inflammation, which in turn lead to depression and fatigue, among others.

According to those theories, inflammation may be regarded not only as a biological response to injury, but also as a response to actual or imagined physical or mental threat, including stress. Stress-associated inflammation could therefore be another factor contributing to the development of many modern chronic pathologies, including metabolic disorders.

Fatigue is actually a rather common nonspecific symptom of inflammation. Patients with inflammatory conditions often report signs of both physical and mental fatigue, and individuals with metabolic disorders show significant associations between fatigue or motivation scores and the levels of inflammatory molecules.

Sleep is actually another interesting player in this link between inflammation and disease. Sleep quality is paramount to physical and mental health. Compromised sleep can be not only a consequence but also a cause of many pathological conditions. Sleep loss can accelerate the aging process, increase the risk of depression, anxiety, pain and chronic diseases, and actively contribute to fatigue. Interestingly, inflammation has been proposed as a biological link between sleep and all these processes.

Fatigue, pain, sleep alterations, cognitive performance, depression and anxiety are symptoms that are commonly connected and that can easily arise as a consequence of one another. Therefore, it is not surprising that chronic low-grade inflammatory processes may account for the development of this set of behavioural and symptoms.

Credit

Sara Adaes is a biochemist with a PhD in neuroscience and with a keen enthusiasm for science communication.

Now read part 2 in this series: Diet and Chronic Low Grade Inflammation

References

Capuron L, Su S, Miller AH, Bremner JD, Goldberg J, et al (2008). Depressive symptoms and metabolic syndrome: is inflammation the underlying link? Biol Psychiatry 2008; 64: 896–900. doi:10.1016/j.biopsych.2008.05.019

Castanon N, Lasselin J, Capuron L (2014). Neuropsychiatric comorbidity in obesity: role of inflammatory processes. Front Endocrinol, 5:74. doi:10.3389/fendo.2014.00074

Cunningham C, Campion S, Lunnon K, Murray CL, Woods JFC, et al (2009). Systemic Inflammation Induces Acute Behavioral and Cognitive Changes and Accelerates Neurodegenerative Disease. Biol Psychiatry, 65(4): 304–312. doi:10.1016/j.biopsych.2008.07.024

Dantzer R, O'Connor JC, Freund GG, Johnson RW, Kelley KW (2008). From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci, 9(1):46-56. doi:10.1038/nrn2297

Gregor MF, Hotamisligil GS (2011). Inflammatory mechanisms in obesity. Annu Rev Immunol. 2011;29:415-45. doi:10.1146/annurev-immunol-031210-101322

Guarner V, Rubio-Ruiz ME (2015). Low-grade systemic inflammation connects aging, metabolic syndrome and cardiovascular disease. Interdiscip Top Gerontol, 40:99-106. doi:10.1159/000364934

Hotamisligil GS (2006) Inflammation and metabolic disorders. Nature 444(7121), 860–867. doi:10.1038/nature05485

Irwin MR (2014). Sleep and inflammation in resilient aging. Interface Focus, 4(5):20140009. doi:10.1098/rsfs.2014.0009

Lasselin J, Capuron L (2014). Chronic low-grade inflammation in metabolic disorders: relevance for behavioral symptoms. Neuroimmunomodulation, 21(2-3):95-101. doi:10.1159/000356535.

Lasselin J, Laye S, Dexpert S, Aubert A, Gonzalez C, et al (2012): Fatigue symptoms relate to systemic inflammation in patients with type 2 diabetes. Brain Behav Immun 26(8):1211–1219. doi:10.1016/j.bbi.2012.03.003

Mayeda ER, Whitmer RA, Yaffe K (2015). Diabetes and cognition. Clin Geriatr Med, 31(1):101-15. doi:10.1016/j.cger.2014.08.021

Nguyen JC, Killcross AS, Jenkins TA (2014). Obesity and cognitive decline: role of inflammation and vascular changes. Front Neurosci, 8:375. doi:10.3389/fnins.2014.00375

Slavich GM, Irwin MR (2014). From stress to inflammation and major depressive disorder: a social signal transduction theory of depression. Psychol Bull, 140(3):774-815. doi:10.1037/a0035302.

Teeling JL, Felton LM, Deacon RM, Cunningham C, Rawlins JN, Perry VH (2007). Sub-pyrogenic systemic inflammation impacts on brain and behavior, independent of cytokines. Brain Behav Immun, 21(6):836-50. doi:10.1016/j.bbi.2007.01.012