Impact of Epigenetics, Diet, and Nutrition-Related Pathologies on Wound Healing

Abstract

Chronic wounds pose a significant challenge to healthcare. Stemming from impaired wound healing, the consequences can be severe, ranging from amputation to mortality. This comprehensive review explores the multifaceted impact of chronic wounds in medicine and the roles that diet and nutritional pathologies play in the wound-healing process. It has been well established that an adequate diet is crucial to proper wound healing. Nutrients such as vitamin D, zinc, and amino acids play significant roles in cellular regeneration, immune functioning, and collagen synthesis and processing. Additionally, this review discusses how patients with chronic conditions like diabetes, obesity, and nutritional deficiencies result in the formation of chronic wounds. By integrating current research findings, this review highlights the significant impact of the genetic make-up of an individual on the risk of developing chronic wounds and the necessity for adequate personalized dietary interventions. Addressing the nutritional needs of individuals, especially those with chronic conditions, is essential for improving wound outcomes and overall patient care. With new developments in the field of genomics, there are unprecedented opportunities to develop targeted interventions that can precisely address the unique metabolic needs of individuals suffering from chronic wounds, thereby enhancing treatment effectiveness and patient outcomes.

Keywords: chronic wounds; diabetes; diet; epigenetics; genomics; nutrition; obesity; socioeconomics; wound healing.

Figure 2

Principle of a genome-wide association study (GWAS) in wound healing research. GWAS is a hypothesis-free way of identifying genome regions associated with a trait and requires data on genetics and a trait of interest for individuals with healing wounds vs. nonhealing chronic ulcers from a population. GWASs consist of single-variant association tests for variants across the genome, but a significant association only means that a proxy for a causal variant was found. ① GWAS can confirm prior and identify novel associations, and post-GWAS analyses can determine how the regions affect the rate of healing of wounds. The typical pipeline of GWAS consists of ② the identification of a statistically significant variant, ③ testing if the associated variant is causal or just a proxy, and ④ displaying the GWAS findings with respect to their genomic positions, highlighting signals of known or novel association to a particular disease type using Manhattan plots. ⑤ Finally, additional strategies such as fine-mapping, functional confirmation, and meta-analysis are performed for bias-free identification of causal variants and to search for additional susceptibility variants. The following sources are acknowledged: Bailey Harrington (Creator) Nima Vaezzadeh, Visscher, et al. [42], and McCarthy et al. [43]. Created with BioRender.com.

Figure 1

The social determinants of health and the biology of adversity. (A) Social determinants of health encompass an individual’s economic stability, neighborhood and built environment, education access, healthcare access, and social and community relationships. (B) These areas can be sources of chronic psychosocial stressors to individuals who suffer from low socioeconomic status, unsafe housing, neighborhood violence, limited access to healthcare, early childhood adversity, discrimination, increased noised exposure, food insecurity, and decreased sleep quality, among others. (C) Pathway to chronic inflammation: The biologic consequence of adversity promotes pathways to chronic inflammation. Sympatho-adrenomedullary (SAM) axis and hypothalamic-pituitary-adrenal (HPA) axis: the SAM axis and the HPA axis are activated by psychosocial stress and regulate the production of catecholamines (dopamine, norepinephrine, and epinephrine) and glucocorticoids, respectively. Glucocorticoid and catecholamine signaling under chronic stress: (1) Glucocorticoid receptor (GR) shows impaired nuclear translocation and decreased anti-inflammatory gene transcription in chronic stress, and (2) β-Adrenergic receptors (ARs) have been found to alter their gene signaling to a noncanonical pathway (via β-arrestin 2 scaffolding) that increases production of inflammatory cytokines, which also upregulate NLRP3 (NLR family pyrin domain-containing 3) inflammasome activity. β3 Receptors have also been found to play a role in clonal hematopoiesis, which may contribute to atherosclerotic plaque formation. Neurohematopoietic axis: Chronic amygdalar activation has been linked to clonal hematopoiesis, possibly by direct sympathetic nervous system (SNS) innervation of the bone marrow; stress-induced leukopoiesis has been directly linked to atherosclerotic plaques. (D) SDoH-influenced chronic inflammation often results in the accumulation of pathological epigenetic modifications and shorting of telomere length. (E) All of these inflammatory processes lead to increased cardiovascular disease (CVD) risk factors, such as obesity, hypertension, diabetes, and atherosclerosis, ultimately contributing to major adverse cardiac events (MACE) and CVD mortality. ACTH indicates adrenocorticotropic hormone; AP-1, activating protein-1; CREB, cAMP response element-binding protein; CRH, corticotropin-releasing hormone; MAPK, mitogen-activated protein kinases; NF-κB, nuclear factor κ-light-chain-enhancer of activated B cells; and SNS, sympathetic nervous system. Reproduced under the terms of the Creative Commons CC BY license published by Wolters Kluwer. The following original report is credited: Tiffany M Powell-Wiley et al. [14].

Figure 3

Phases of Wound Healing and Nutrient Requirements in Different Phases. Wound healing is a complex, well-orchestrated process occurring in four distinct yet overlapping phases. The process commences with ① bleeding and hemostasis, where the injury occurs, clot formation and platelet activation halt blood loss. Following this, ② inflammation sets in, combating infections and clearing debris. ③ The proliferation phase ensues, involving fibroblast activation, angiogenesis, and granulation tissue formation. ④ Lastly, remodeling occurs, where the extracellular matrix is restructured, and the tissue regains its tensile strength with the scar tissue formation. Understanding the nutritional requirements of these biological events is pivotal for developing effective wound management strategies. Adequate nutrition via sufficient macromolecule intake is necessary to meet the metabolic requirements of different phases of the healing tissue. In obese and diabetic individuals, general nutritional deficiencies have been seen due to poor-quality diets, higher intake needs, and altered cell-signaling and metabolic pathways. Created with BioRender.com.