Introduction and overview of the focus of the position paper
Inflammation is a central component of innate (non-specific) immunity. In generic terms, inflammation is a local response to cellular injury that is marked by increased blood flow, capillary dilatation, leucocyte infiltration, and the localised production of a host of chemical mediators, which serves to initiate the elimination of toxic agents and the repair of damaged tissue( 1 ). It is now clear that the termination (alternatively known as resolution) of inflammation is an active process involving cytokines and other anti-inflammatory mediators, particularly lipids, rather than simply being the switching off of pro-inflammatory pathways( 2 , 3 ).
Inflammation acts as both a ‘friend and foe’: it is an essential component of immunosurveillance and host defence, yet a chronic low-grade inflammatory state is a pathological feature of a wide range of chronic conditions, such as the metabolic syndrome (MetS), non-alcoholic fatty liver disease (NAFLD), type 2 diabetes mellitus (T2DM) and CVD( 4 , 5 ). Although the association between inflammation and chronic conditions is widely recognised, the issue of causality and the degree to which inflammation contributes and serves as a risk factor for the development of disease remain unresolved. As will be discussed, part of this uncertainty is due to a general lack of sensitive and specific biomarkers of low-grade chronic inflammation that can be used in human trials( 1 ).
Exploring the role of inflammation in health and chronic diseases
Low-grade inflammation in cardiometabolic disease
The role of inflammation in the early-stage pathophysiology of atherothrombotic events has been recognised for over 20 years. Leucocyte recruitment into the sub-endothelial compartment of damaged arteries initiates a cascade of events mediated by leucocyte-derived inflammatory mediators. In particular, chemokines and cytokines propagate atherosclerosis via (1) increased chemokine production and expression of endothelial adhesion molecules, stimulating further leucocyte recruitment, (2) promoting lipid-laden foam-cell formation, (3) initiating smooth muscle cell proliferation, and (4) inducing plaque instability and eventual rupture( 8 , 9 ). The ensuing thrombosis is also in large part dependent on the inflammatory status of the ruptured plaque.
In addition to a direct role on events within the arterial wall, inflammation is an important determinant of the multi-organ cardiometabolic dysfunction, and the increased risk of T2DM, NAFLD and CVD associated with obesity( 10 ). Adipose tissue hypertrophy is associated with immune cell infiltration, in particular that of macrophages and T cells, and a local pro-inflammatory milieu wherein key cytokines including TNF-α, IL-6 and IL-1β impede the insulin signalling cascade to induce insulin resistance( 11 , 12 ). This ultimately leads to a dysregulation of glucose and lipid metabolism in adipose tissue, skeletal muscle and liver. However, up to 30 % of obese individuals are considered metabolically healthy (MHO)( 13 ), and there is evidence to suggest that a lack of the typical elevation in the inflammatory profile associated with obesity may underlie this ‘protected’ MHO phenotype. For example, in morbidly obese individuals, Barbarroja and co-workers observed mean homeostatic model assessment for insulin resistance (HOMA-IR) scores (insulin sensitivity index) of 3·31 and 11·48 in subjects with MHO (BMI 55 kg/m2) or who were metabolically unhealthy obese (BMI 56 kg/m2), respectively, which was associated with a 2- to 4-fold greater adipose expression of inflammatory cytokines (TNF-α, IL-1β and IL-6) between the two obese groups( 14 ).
Inflammation plays a direct role in the progression of NAFLD, the most common liver disorder in Western countries. NAFLD comprises a spectrum of conditions ranging from benign steatosis to non-alcoholic steatohepatitis characterised by hepatocyte injury (hepatocyte ballooning and Mallory bodies) and necroinflammation, and potentially to progressive fibrosis that can lead to cirrhosis( 15 , 16 ). The pathological progression of NAFLD is considered to have a two-hit basis (Fig. 1). The first hit, hepatocyte accumulation of fat, is thought to arise due to an increased delivery of fatty acids to the hepatocyte, an increase in hepatocyte fatty acid and TAG synthesis, and decreased fatty acid oxidation. The resultant excess of fat may result in lipotoxicity and a pro-inflammatory and pro-oxidative state (the second hit), which ultimately induces cellular senescence, which, if unchecked, leads to fibrosis and cirrhosis. Hepatic inflammation is mediated via the activation of local macrophages called Kupffer cells. Currently, no medication or surgical procedure has been approved for treating NAFLD or non-alcoholic steatohepatitis with confidence. Considering the overall lack of success in curbing global trends in the prevalence of excess body weight, inflammatory processes are emerging as a strong therapeutic target to reduce the risk of T2DM, CVD and NAFLD in obese individuals.
Gut–systemic inflammatory associations
Increasing evidence indicates that the microbiota is significantly altered through the ageing process( 18 , 19 ) and in obesity( 18 ), with a deleterious decline in microbiota ‘richness’ and gene expression diversity evident in both situations( 18 ).
Gastrointestinal tract–microbiota interactions influence host health, and in particular immune function, by promoting the development and maintenance of the mucosal immune system, protecting against pathogen invasion and maintaining gastrointestinal tract barrier integrity( 20 ). Gut permeability to bacterial lipopolysaccharides (LPS), a potent inflammatory stimulant, appears to be an important trigger for low-grade systemic inflammation. LPS are found on the outer membrane of Gram-negative bacteria such as Proteobacteria (e.g. Escherichia coli), and serve as an endotoxin.
In addition to its role in low-grade inflammatory cardiometabolic conditions, emerging evidence is suggesting that the gut microbiota can influence the risk of high-grade autoimmune inflammatory conditions such as type 1 diabetes mellitus, coeliac disease, inflammatory bowel disease and rheumatoid arthritis( 25 – 27 ), the incidence of which has risen dramatically since the 1940s. These conditions are now thought to affect 5–10 % of those in Western societies( 28 ). Certain members of the gut microbiota have been shown to induce mimics of human antigens and trigger the production of autoantibodies responsible for aberrant immune responses to normal human proteins and hormones including leptin, peptide YY and ghrelin( 29 ). It is not unreasonable to speculate that the adverse impact of the energy-dense, nutrient-poor Western-style diet on human gut microbiota and immune system, which have both been finely tuned and honed by high-fibre, high-polyphenol traditional diets over the millennia, may therefore be an important contributor to the environmental stimuli that trigger and progress autoimmune conditions( 30 ).
Probiotic, fibre or polyphenol up-regulation of microbial activities that control both the quantity and profile of bile acids returning to the liver via the enterohepatic circulation with their subsequent regulation of farnesoid X receptor and TGR5 is also emerging as an important pathway linking the gut microbiota with extra-intestinal physiological/immune function( 33 , 36 , 37 ).
Low-grade systemic inflammation and neuroinflammation
Communication between the systemic immune system and the central nervous system (CNS) is a critical but often overlooked component of the inflammatory response to tissue injury, disease or infection. Activation of highly conserved neuronal and hormonal communication pathways in mammals drives diverse CNS-regulated components of the inflammatory response, including fever, neurogenic inflammation, descending anti-inflammatory mechanisms and a coordinated set of metabolic and behavioural changes, including fatigue, anhedonia, depression and mild cognitive impairment. These behavioural changes are collectively referred to as ‘sickness behaviour’( 38 – 40 ).
In a recent prospective clinical study, Alzheimer's disease patients were followed for 6 months and assessed for the presence of circulating cytokines, episodes of microbial infection and cognitive decline. Patients with both high levels of TNF-α (>4·2 pg/ml) at baseline and microbial infection during the assessment period showed a 4-fold greater cognitive decline, relative to patients with low levels of TNF-α ( < 2·4 ng/ml) at baseline and no infections. Raised serum levels of TNF-α and IL-6, but not CRP, are also associated with increased frequency of other common neuropsychiatric symptoms observed in Alzheimer's disease patients, including apathy, anxiety, depression and agitation( 47 ).
Dietary modulation of low-grade inflammation
There is a substantial amount of evidence to suggest that many foods, nutrients and non-nutrient food components modulate inflammation both acutely and chronically( 1 , 6 ). However, dietary studies have been typically limited to measuring a small number of blood markers of inflammation, often in the fasting state, and these may not necessarily reflect inflammation in tissue compartments or what happens in response to inflammatory challenges. This presents a significant limitation to our understanding of diet/nutrient–inflammation interactions. Previous ILSI Europe activities have dealt extensively with the food/nutrition–inflammation interaction( 6 , 7 ), and it is beyond the scope of the present review to provide a systematic or extensive coverage of this area. Instead, some specific examples will be discussed.
Dietary fats and inflammation
Dietary fatty acids may affect inflammatory processes through effects on body weight and adipose tissue mass and via an impact on membrane and lipid raft composition and function. Within the cell, membrane-derived fatty acids and their derivatives can influence inflammation by serving as modulators of NF-κB and PPAR-α/γ transcription factor pathways( 55 ), and as precursors for a host of eicosanoid and docosanoid oxidation products produced via the action of epoxygenases, lipoxygenases and cyclo-oxygenases( 56 ). Also, recent advances in the field have uncovered NLRP3 (NACHT, LRR and PYD domains-containing protein 3) inflammasome activation and IL-1β signalling as a key sensor of SFA-mediated metabolic stress in obesity and T2DM( 57 ) and EPA- and DHA-derived resolvins and protectins that actively ameliorate a pro-inflammatory state( 58 ). Obesity significantly reduced DHA-derived 17-hydroxydocosahexaenoic acid, a resolvin D1 precursor, and protectin D1 in adipose tissue, which may in turn have pro-inflammatory consequences( 59 ). Also, dietary EPA/DHA supplementation within an obesogenic dietary challenge restored endogenous adipose resolvin and protectin biosynthesis, concomitant with attenuated adipose inflammation and insulin resistance( 59 ). An elegant human study showed that a relatively high dose of LC n-3 PUFA augmented anti-inflammatory eicosanoid secretion and attenuated inflammatory gene expression in the subcutaneous adipose tissue of severely obese non-diabetic patients( 60 ).
As with other common phenotypes, there is evidence emerging that the associations between dietary fat composition and inflammation are influenced by common gene variants( 68 ). In the LIPGENE study, SNP in the genes encoding the anti-inflammatory peptide adiponectin (ADIPOQ) and its receptor (ADIPOR1) have been shown to interact with SFA to modulate the effect of dietary fat modification on insulin resistance( 69 ), and using a case–control approach, it was observed that a common SNP of the C3 gene was related to the risk of the MetS, but more importantly, the impact of this was greatly accentuated by high plasma levels of SFA( 70 ). Also, the combination of polymorphisms in genes encoding IL-6, lymphotoxin α (LTA) and TNF-α had an additive effect, which interacted with plasma fatty acid status to modulate the risk of the MetS( 71 ). Grimble et al. ( 72 ) demonstrated that the ability of LC n-3 PUFA to decrease TNF-α production is influenced by inherent TNF-α production and by polymorphisms in the TNF-α and LTA genes.
Dietary carbohydrates and inflammation
Besides postprandial lipaemia, postprandial glucose is an independent predictor of diabetes and CVD, an effect which may be mediated through oxidative stress and inflammation( 76 ). Importantly, there appears to be no glycaemic threshold for reduction of either microvascular or macrovascular complications. The progressive relationship between plasma glucose and the risk of CVD extends well below the diabetic threshold( 77 , 78 ).
Although mechanistic evidence indicates a positive correlation between the glycaemic index and load of the diet and low-grade inflammation, intervention studies, to date, do not convincingly support this.
Plant bioactive compounds and inflammation
Recent prospective cohort data suggest that improved cognitive function and a reduced risk of age-related neurodegenerative diseases, associated with increased fruit and vegetable intake( 85 – 87 ), may be in large part attributable to intake of specific flavonoids( 87 ), and may involve an effect on inflammatory processes (Table 1). In particular, increased consumption of total flavonoids was positively associated with episodic memory in middle-aged adults( 88 ) and with a reduced rate of cognitive decline in adults aged 70 years and over( 89 ).
Translating research into public health benefit and novel products
Biomarkers of inflammation in human nutrition studies
As explained previously, inflammation is a normal process, and there are a large number of cells and mediators involved; measurement of these is often used as a ‘biomarker’ of inflammation, i.e. an indicator that inflammation is occurring.
Currently, there is no consensus as to which markers best represent low-grade inflammation( 6 ), or differentiate between acute and chronic inflammation or between the various phases of inflammatory responses( 7 ).
One can question whether static measurements of single or complex biomarkers are truly informative about health status, reasoning from the concept that health is defined by the ability to adequately adapt to everyday challenges( 123 ). Measuring the concentration of inflammatory markers in the bloodstream under basal conditions is probably less informative and relatively insensitive compared with measurements of the concentration change in response to a challenge.
With the coming of age of the ‘omics’ technologies and bioinformatic tools, a large increase in the number, specificity and sensitivity of candidate biomarkers of inflammation can be expected in the next decade( 134 ). A screening of the ‘Thomson Reuters IntegritySM Biomarker Database’ reveals that as of May 2014, 945 candidate biomarkers of inflammation have been described, of which only seventeen, including CRP, TNF-α, serotransferrin and erythrocyte sedimentation rate, have been developed into biomarker assays approved and recommended by regulatory bodies for use in clinical studies.
Referência :
Br J Nutr. 2015 Oct 14;114(7):999-1012.
