Abstract
Aim and objective
Emerging translational evidence suggests that epigenetic alterations (DNA methylation, miRNA expression, and histone modifications) occur after external stimuli and may contribute to exacerbated inflammation and the risk of suffering several diseases including diabetes, cardiovascular diseases, cancer, and neurological disorders. This review summarizes the current knowledge about the harmful effects of high-fat/high-sugar diets, micronutrient deficiencies (folate, manganese, and carotenoids), obesity and associated complications, bacterial/viral infections, smoking, excessive alcohol consumption, sleep deprivation, chronic stress, air pollution, and chemical exposure on inflammation through epigenetic mechanisms. Additionally, the epigenetic phenomena underlying the anti-inflammatory potential of caloric restriction, n-3 PUFA, Mediterranean diet, vitamin D, zinc, polyphenols (i.e., resveratrol, gallic acid, epicatechin, luteolin, curcumin), and the role of systematic exercise are discussed.
Methods
Original and review articles encompassing epigenetics and inflammation were screened from major databases (including PubMed, Medline, Science Direct, Scopus, etc.) and analyzed for the writing of the review paper.
Conclusion
Although caution should be exercised, research on epigenetic mechanisms is contributing to understand pathological processes involving inflammatory responses, the prediction of disease risk based on the epigenotype, as well as the putative design of therapeutic interventions targeting the epigenome.
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Introduction
Inflammation encompasses a myriad of pathophysiological and immune responses to diverse environmental “insults”, such as toxins or pathogens, in order to facilitate tissue recovery and to maintain homeostasis [1]. These mitigation and reparation processes are mediated by the production and recruitment of cytokines, chemokines, adhesion molecules, and other autocrine/paracrine molecules focused on the local site of damage, thus inducing an acute inflammatory reaction [2]. However, when inflammation persists for a long time, it becomes a chronic condition, triggering a cascade of inflammatory events that eventually lead to durable cellular harms, permanent tissue injury, and organ dysfunction [3]. This state involves the induction of several pro-inflammatory mediators produced predominantly by activated macrophages, including Interleukin 1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), and interleukin 6 (IL-6) to perpetuate the inflammatory phenotype [4]. The inflammatory signaling is mediated by enzymes and adhesion molecules as well as the activation of nuclear factor kappa β (NF-κB) and other transcription factors as central regulators where the immune system and associated cells also play an orchestrated role [5]. The identification of factors involved in the onset and progression of inflammation is essential for the better understanding of inflammation-related disorders and the search for therapeutic targets.
Emerging evidence suggests that epigenetic processes affecting gene expression without changes in the nucleotide sequence may contribute to the pathophysiology of inflammatory processes [6]. In this context, it has been documented that epigenetic modifications (such as DNA methylation in CpG islands, chromatin remodeling by histone tail modifications, and non-coding RNA expression) occur after environmental stimuli and play a fundamental role in inflammatory gene transcription [7]. Indeed, integrative epigenome-wide association studies (EWAS) using large-scale bioinformatics analysis have reported different epigenetic marks related to several circulatory inflammation markers [8]. Therefore, epigenetic signature alterations may exacerbate inflammatory responses and influence the risk of chronic inflammatory disease, including diabetes, cardiovascular diseases, cancer, and neurological disorders [9]. However, elucidation of the specific epigenetic pathways involved in the modulation of the inflammasome and disease susceptibility remain largely unknown.
This review summarizes the current knowledge about the effects of obesity, infections (comprising bacterial and viral agents), smoking/excessive alcohol drinking, chronic stress, climate, pollution and other environmental factors including physical activity and the role of nutrients and dietary bioactive compounds on inflammation status through epigenetic mechanisms, and how these events may influence chronic disease development. This knowledge may allow the implementation of personalized nutrition based on inflammatory epigenetic signatures for the prevention and management of chronic inflammatory diseases.
Nutrition/dietary bioactive compounds
Nutritional factors have been related with a pro-inflammatory potential [10]. Particularly, the consumption of Western-type diets evokes a state of chronic metabolic inflammation “metainflammation” that contribute to the development of many prevalent non-communicable diseases [11]. In this context, complex interactions among food components and the epigenome modifications shape the cellular phenotype by a dynamic regulation of gene expression from some time ago [12]. Thus, epigenetic phenomena may account for the observed relationships between diet, inflammation, and diet‐related diseases [13].
Transgenerational animal studies have shown an increased inflammatory response after the consumption of high-fat/high calorie diets by altering miRNA expression and DNA methylation processes [65]. Together, these findings suggest that the impact of physical activity in inflammation is dependent of type, intensity, and clinical settings of exercise interventions [54].
Obesity and associated diseases
Obesity is a metabolic condition associated with adipose tissue dysfunction and low-grade systemic inflammation that causally contributes to the development of chronic disorders such as T2D and CVD, where epigenetic mechanisms may be involved [66]. Indeed, it has been reported that the alteration of the adipocyte physiology in obesity might be related to specific alterations in the expression pattern of miRNAs related to inflammatory processes [67]. Also, the adverse effects of the inflammatory state include insulin resistance in the adipose tissue and pancreatic β-cell dysfunction, which may induce epigenetic changes that perpetuate inflammation [68]. In consequence, the resulting hyperglycemia and hyperlipidemia conditions as well as persistent inflammation involving epigenomic deregulation could cause damage to the vasculature with putative risk to develop CVD [69]. In the same time, excessive adiposity negatively impacts immune function and host defense in obese individuals, increasing the susceptibility to infection and related morbidity and mortality [70].
Epigenetic mechanisms involved in obesity-related inflammation are summarized (Table 3). For example, global DNA hypermethylation has been positively associated with increased expression of specific pro-inflammatory genes (including the CCL2 gene) in adipocytes from obese individuals [71]. BMI-discordant twin pair analyses detected methylome deregulations of subcutaneous adipose tissue in obesity that trigger inflammation and may contribute to the development of unhealthy obesity outcomes [72]. Thus, methylation analyses in obese individuals showed significantly lower methylation of four CpGs in the first exon of the TLR4 gene, suggesting epigenetic regulation of inflammatory processes in obesity [73]. Moreover, it was reported that aberrant methylation of the IL6 gene promoter may play a role in the etiology and pathogenesis of excessive body weight in humans [74]. Findings from the Methyl Epigenome Network Association (MENA) project revealed associations between methylation sites in peripheral blood mononuclear cells (PBMCs) and waist circumference, which were located in genes related to inflammation and obesity [75]. Likewise, it was reported that DNA methylation in adipose-derived stem cells was significantly modified by an obese environment, affecting pathways involved in adipogenesis, inflammation, and immunosuppression [76]. Genome-wide DNA methylation analysis in visceral adipose tissue of severely obese men with and without metabolic syndrome detected differentially methylated regions mapped to genes related to inflammation and immunity [77].
Of note, the expression of the NNMT gene, a major methyltransferase enzyme, was positively correlated with markers of inflammation in adipose tissue samples from morbidly obese patients [78]. In addition, a higher expression of DNMT3b methyltransferase was found in adipose tissue macrophages isolated from obese mice, supporting a role for DNMT3b in regulation of macrophage polarization and inflammation in obesity [79]. In adipose tissue of obese mice, gene expression levels of the Dnmt3a methyltransferase were markedly increased, as were many inflammatory cytokines, suggesting that increased expression of Dnmt3a may contribute to obesity-related inflammation [80]. Remarkably, DNA methylation changes of the Klf14 gene (a master regulator of gene expression) provided prediction for chronic inflammation in the adipose tissue of mice suffering obesity and diabetes conditions [81]. Furthermore, altered gene methylation profiles on immune cells were related to impaired metabolism and inflammatory response in a porcine model of obesity [82].
In mice, diet-induced obesity led to hypermethylation of the Ankrd26 gene (previously associated with the development of obesity and T2DM), which in turn, contributed to enhanced secretion of pro-inflammatory mediators in white adipose tissue [83]. Consistently, epigenetic silencing of the ANKRD26 gene by increased promoter methylation correlated with a pro-inflammatory profile and the presence of cardio-metabolic risk factors in peripheral leukocytes from obese individuals [84]. Transgenerational studies detected DNA methylation changes of key inflammatory genes in monocytes from neonates born of obese mothers, underlying an intrauterine epigenetic programming of immune function by maternal obesity [85]. Accordingly, maternal pregravid obesity has been associated with epigenetic modifications altering the inflammatory program of the offspring’s monocytes at birth [86].
A bioinformatic approach identified a total of 23 active microRNAs (miRNAs) and transcription factor regulatory pathways significantly associated with obesity-related inflammation [87]. Also, a set of exosomal miRNAs differentially expressed in abdominal obesity was associated with inflammation [88]. Overweight and obesity led to deregulation of circulating inflammatory miRNAs, which may contribute to the heightened inflammatory state associated with these conditions [89]. In adipocytes and macrophages, inflammation boosted a specific miRNA pattern, with a negative impact on the physiopathology of obesity-induced inflammation [90].
Particularly, circulating miR-374a-5p was characterized as a potential modulator of the inflammatory response in obesity [91]. In vitro analyses unveiled a key role of miR-326 expression in mediating obesity-induced adipose tissue inflammation through regulating the differentiation toward Th17 cells [92]. Also, miR-30 was identified as an important regulator of macrophage polarization in mice, indicating that miR-30 could be a therapeutic target for obesity-induced metabolic inflammation [93]. Besides, adipocyte-secreted exosomal miR-34 was progressively increased with the development of dietary obesity, transmitting signals of nutrient overload to adipose-resident macrophages for exacerbation of obesity-induced systemic inflammation and associated metabolic complications [94]. In the same way, obesity induced an imbalance in macrophage polarization in adipose tissue through miR-155 up-regulation, thus causing chronic inflammation and insulin resistance [95]. Accordingly, obesity-associated inflammation induced miR-155 expression in adipocytes resulting in an increased inflammatory state in these cells [96]. Using an obese mice model, it was observed that the expression of miR-27a increased concomitantly with the activation of pro-inflammatory pathways [97]. Meanwhile, miR-130b contributed to obesity-associated adipose tissue inflammation and insulin resistance in diabetic rodents [98]. Endoplasmic reticulum stress and inflammatory markers were up-regulated in obese patients, showing positive correlations with miR-320 expression in adipose tissue [99]. miR-221 triggered white adipose tissue inflammation and insulin resistance in obesity partially through suppressing SIRT1 [100]. Visceral adipose miR-223 up-regulation modulated macrophage-mediated inflammation in human and murine obesity models [101]. miR-126 and miR-193b were further identified as important regulators of adipose inflammation in human obesity through effects on CCL2 production [102].
In contrast, the anti-inflammatory miR-1934, miR532-5p, and miR-146a were down-regulated in obesity, which promoted inflammation in adipose tissues [122]. In some cases, the immunological response to infection may be excessive, producing an inflammatory cytokine storm that eventually lead to extensive tissue damage and organ dysfunction [123].
For instance, it has been reported that inflammation triggered by Helicobacter pylori infection was related to differential DNA methylation patterns in human gastric mucosa [124]. Also, H. pylori-induced chronic inflammation played a direct role in the induction of aberrant DNA methylation, which correlated with gastric cancer risk [125]. In humans, the levels of methylation in gastric mucosae were associated with H. pylori virulence and measures of chronic inflammation [126]. During chronic H. pylori infection, inflammation-induced epigenetic silencing of miR-210 was identified as a mechanism of proliferation of gastric epithelium, with implications in gastric cancer development [127].
Experimental periodontitis using systemic microbial challenge (Porphyromonas gingivalis gavage) led to distinct patterns of inflammatory and epigenetic features [128]. miR-181a-5p and miR-21a-5p influenced the expression of inflammatory mediators in macrophages infected with Brucella abortus, thus contributing to bacterial control in host cells [129]. In addition, bacterial vaginosis predicted the length of gestation through miRNA-related epigenetic programming of the inflammatory response [130]. Furthermore, histone H3K14 hyperacetylation and differentially expressed miRNAs regulated the host inflammatory response during Staphylococcus aureus infection in mice mammary tissue [131]. Similarly, Escherichia coli infection in murine mammary tissue promoted histone hyperacetylation at genes related to the expression of inflammatory genes and drastic immune response [132].
Sepsis is defined as life-threatening organ dysfunction caused by a deregulated systemic immune response to infection. Interestingly, DNA methylation changes have been associated with sepsis in monocytes, which correlated with inflammatory signals [133]. Besides, chromatin modifications have been implicated in the regulation of the cellular immune/inflammatory responses in patients with sepsis [134].
Regarding viral infections, it was demonstrated that TLR3 activation increased HIV-1 transactivation in primary human macrophages via the inflammatory JNK and NFκB pathways and histone acetylation [135]. In vivo analyses revealed that respiratory syncytial virus infection induced the H3K4 demethylase KDM5B to promote an altered immune/inflammatory response that contributed to the development of chronic disease [136]. Human cytomegalovirus infection resulted in profound effects on the host cell DNA methylation machinery and was associated with inflammation in vivo [137]. Hypermethylation of PPAR gamma (PPARG) promoter was associated with liver inflammation and fibrosis in chronic hepatitis B virus infection [138]. An in vitro assay showed that loss of TIMP-3 by hypermethylation promoted chronic inflammation and tumor invasion during human papillomavirus infection [139]. miR-155, an indicator of inflammation-induced hepatocyte damage, was up-regulated both in monocytes and in the serum of patients with chronic hepatitis C infection [140]. Remarkably, DNA methyltransferase inhibition of regulatory T cells (Tregs) accelerated resolution of influenza-induced lung inflammation and related injury repair in mice [141].
Indeed, the development of immunomodulatory therapies targeting the epigenome during infectious diseases have emerged in the past years [142]. In this context, histone H3 modulation in macrophages was proposed as a strategy to attenuate the NF-κB/NLRP3-mediated inflammatory response during infection by the parasite Leishmania donovani [193]. Similarly, epigenetic programming of pro-inflammatory phenotype in the heart development and vulnerability to disease later in life were associated with fetal hypoxia in rats [194]. Furthermore, hypoxia drove cardiac miRNAs profiles and inflammation processes in the right and left ventricle in a murine model [195].
Concluding remarks
Obesity and unhealthy diet as well as adverse environmental stimuli including sleep deprivation, chemical exposure, alcohol abuse, smoking, and climate pollution promote inflammatory processes in the host through epigenetic alterations, involving predominantly DNA methylation modifications in animal studies (Table 4). However, further studies in humans focused on other epigenetic mechanisms, such as histone acetylation/deacetylation processes and miRNA regulation affecting pro-inflammatory gene expression are required.
Scientific advances concerning the epigenetic mechanisms underlying inflammation-related chronic diseases such as diabetes, cardiovascular diseases, cancer, and neurodegenerative disorders are providing a better understanding of the molecular bases for the implicated pathological processes, and the prediction of individual disease risk based on the epigenotype. Nevertheless, it is necessary to integrate this knowledge with other emerging factors influencing the susceptibility/resistance to inflammation including the genetic background, microbiota composition, and metabolomic profiles using systems biology and large-scale bioinformatics tools.
Also, the fact that diverse pathogens, including respiratory viruses, induce epigenome modifications to promote systemic infection, opens opportunities for the development of efficient medications for specific targets. This finding is of current relevance for emerging widespread viral infections such as SARS-CoV-2/COVID-19, with a common fatal inflammatory lung condition without current effective therapies or available vaccine. Moreover, the suppressive effect of obesity and other environmental mediators of the immune function also needs to be addressed.
Progress in the identification of epigenetically active dietary components and lifestyle factors will contribute to the design of therapeutic interventions alleviating persistent inflammation by targeting the epigenome. In this regard, dietary bioactive compounds (i.e. polyphenols), n-3 PUFA, and regular physical activity have demonstrated anti-inflammatory properties through epigenetic phenomena. Nevertheless, the heterogeneity of the existing literature and the scarcity of studies in humans makes it difficult to propose specific recommendations about the amounts of polyphenols and n-3PUFA consumptions as well as the type, intensity, or duration of exercise that could counteract inflammatory processes. However, current available knowledge highlights the importance of anti-inflammatory dietary and exercise patterns for health and evidence the need of performing more nutriepigenetic investigations through randomized controlled clinical trials in order to prescribe precision nutritional and lifestyle recommendations for specific population and diseased groups.
Although further scientific advances in these research areas are needed, these insights are paving the way for the design of innovative strategies aimed to the prevention, management, prognosis, and treatment of chronic inflammatory diseases through personalized approaches (including precision nutrition) based on inflammatory epigenetic signatures.
Conclusions
Obesogenic and health-damaging environments can drive persistent inflammation by modifying some specific epigenetic mechanisms and negatively impact the development of chronic inflammatory diseases. The prescription of nutritional therapies using epigenetically active nutrients and physical activities with anti-inflammatory properties may help to revert the adverse effects of chronic inflammation.
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Ramos-Lopez, O., Milagro, F.I., Riezu-Boj, J.I. et al. Epigenetic signatures underlying inflammation: an interplay of nutrition, physical activity, metabolic diseases, and environmental factors for personalized nutrition. Inflamm. Res. 70, 29–49 (2021). https://doi.org/10.1007/s00011-020-01425-y
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DOI: https://doi.org/10.1007/s00011-020-01425-y