Advancing Precision Nutrition in Endometriosis Care: The Role of Nutrigenomics and Nutrigenetics

Endometriosis, Nutrigenomics, Nutrigenetics, Personalized Diet, Precision Nutrition, Artificial Intelligence, Direct to Consumer Genetic Testing https://doi.org/10.62186/001c.124784 Academic Medicine & Surgery Endometriosis is a gynecological disorder that affects 10-15% of women of reproductive age. It is characterized as a chronic, inflammatory, and hormone-dependent disease in which the endometrial tissue is present on the external uterine lining, resulting in infertility and pelvic pain. Some research studies stated that about 97% of human diseases are monogenic diseases associated with genes. Thus, modifying dietary intake (personalized diet) can potentially prevent monogenic diseases. Nutrigenomics and nutrigenetics have garnered substantial interest among researchers as potential avenues for managing chronic conditions like diabetes, cancer, obesity, and cardiovascular disorders. Nutrigenomics ascertains the effects of food and ingested nutrients on gene expression and regulation, tailoring nutritional needs to an individual’s genetic makeup, thereby facilitating personalized diets. On the other hand, nutrigenetics investigates how an individual’s genetic composition influences their response to dietary elements. Both fields could be beneficial in modifying various disease conditions. Furthermore, it explores the effects of precision nutrition, direct-to-consumer genetic testing, and the role of artificial intelligence in the nutrigenetics and nutrigenomics approach to managing endometriosis. This review aims to provide a comprehensive overview of potential treatment modalities for endometriosis through the lenses of nutrigenomics and nutrigenetics. It highlights the interplay between dietary interventions and gene expression, elucidating how personalized approaches could potentially modify the course of endometriosis. 1. INTRODUCTION Endometriosis is a gynecological disorder in which the en- dometrial tissue is developed in the external uterine cavity, resulting in infertility and pelvic pain.1‑3 Endometriosis is often characterized as a chronic, inflammatory, and hor- mone-dependent debilitating disease.4 Endometriosis af- fects approximately 10-15% of women in their reproductive years, with about 70% of these women experiencing on- going pelvic discomfort.5‑7 The disease etiology is multi- faceted and complicated involving hormonal, genetic, im- munological, and environmental factors.8 Frequent indicators encompass intense pelvic discomfort, dysmenor- rhea, dyspareunia, fertility challenges, fatigue, lower back pain, bloating, constipation, and diarrhea. Due to the po- tential lack of specific symptoms, diagnosis often faces de- lays.9 The delay in treatment may cause a decrease in fer- tility and reproductive function. Medical therapy aims to hormonally alter the menstrual cycle, inducing a pseudo- pregnancy, pseudo-menopause, or maintaining an anovu- latory state. As of now, there are no definitive cures for endometriosis. The standard clinical approaches usually in- volve using hormonal therapies to inhibit estrogen produc- tion, employing small-molecule drugs to alleviate pain, and conducting laparoscopic surgeries to eliminate endometri- otic lesions.2 However, hormonal therapy causes some se- vere side effects due to which some of the hormones like methyltestosterone and estrogen are phased out from the market. One extensively researched method involves ad- ministering estroprogestins and progestins for contracep- tion, which has also been explored for delivering specific drugs targeting endometriosis.10 Various clinical strategies used for the treatment of vaginal infections include tablets, creams, vaginal rings, and vaginal suppositories.11 Long- acting contraceptives that can be implanted, like Nex- planon®, and injectables such as Depo-Provera®, have been utilized in the treatment of endometriosis.12 Likewise, extended-release GnRH products like Lupron Depot® are employed in the treatment of endometriosis. Endometriosis exhibits characteristics such as oxidative stress, angiogen- esis, and matrix degradation. Consequently, directing drug therapy toward these specific targets may enhance ther- apeutic outcomes compared to presently employed meth- ods.13 Diet is believed to influence the development of en- dometriosis, potentially impacting its onset and progres- Etekochay MO, Muraleedharan D, Majumdar S, Nsengiyumva M. Advancing Precision Nutrition in Endometriosis Care: The Role of Nutrigenomics and Nutrigenetics. Academic Medicine & Surgery. Published online October 26, 2024. doi:10.62186/001c.124784 sion. Research suggests that certain dietary elements may contribute to an individual’s risk of developing this con- dition.14 Moreover, Various lifestyle factors may affect en- dometriosis risk by potentially reducing inflammation. Physical activity and omega-3 fatty acids in the diet might lower levels of inflammatory markers e.g., interleukin6 (IL-6) and tumor necrosis factor-alpha (TNFα). Although the relationship between physical activity and endometrio- sis is not entirely clear, higher consumption of long-chain omega-3 fatty acids has been linked to a decreased risk of endometriosis.15 Some research studies stated that about 97% of human diseases are monogenic diseases associated with genes. Thus, monogenic diseases can potentially be prevented by modifying dietary intake (personalized diet) (Gaboon, 2011). The research-focused approach of nutrigenetics and nu- trigenomics emerges as a pivotal domain within precision nutrition, offering pathways to advance personalized nutri- tional interventions.16 They have garnered substantial in- terest among researchers as potential avenues for manag- ing chronic conditions like diabetes, cancer, obesity, and cardiovascular disorders (Gaboon 2011). Nutrigenomics as- certains the effects of food and ingested nutrients on gene expression and regulation, tailoring nutritional needs to an individual’s genetic makeup, and thereby facilitating per- sonalized diets.17 On the other hand, nutrigenetics inves- tigates how an individual’s genetic composition influences their response to dietary elements (Gaboon, 2011). Both fields could be beneficial in modifying various disease con- ditions, for example, fish oil inhibits colonic tumor growth. The exploration of a link between dietary factors and the onset of endometriosis has garnered significant interest, primarily driven by the observation that both normal bodily functions and the disease’s pathological processes can be impacted by diet (Parrazzani, 2013). Here, in this review, we summarized the role of nutrigenetics, nutrigenomics, and precision nutrition in endometriosis treatment. 2. NUTRIGENOMICS AND NUTRIGENETICS IN ENDOMETRIOSIS Sufficient and appropriate nutrient intake plays a vital role in averting the onset of chronic diseases.18 Dietary inter- ventions have shown potential in both preventing and man- aging endometriosis as well as alleviating the associated pain.9 Maintaining an optimal equilibrium between the overall oxidation status and the body’s antioxidant re- sponse is crucial for a balanced genomic system. Employing a nutrigenomic strategy involves bolstering the body’s an- tioxidant levels by supplementing deficient antioxidants in individuals affected by such diseases.19 Nutrigenetics and nutrigenomics can be regarded as two distinct methodolo- gies within the field of nutritional genomics.20 Nutrigenet- ics examines the influence of genetic diversity, particularly in the form of a single-nucleotide polymorphism (SNP), on an individual reaction to dietary consumption e.g. An in- dividual reaction to caffeine differs due to genetic varia- tions in the CYP1A2 gene. This gene produces an enzyme in the liver responsible for breaking down caffeine, and certain gene variants metabolize caffeine at different rates (Sadeghi et al., 2019). In essence, nutrigenetics explores how an individual’s genetic makeup impacts their physical response to dietary consumption.20 Figure 1 depicts how dietary nutrition and nutrigenomics/nutrigenetics impact the overall health of an individual. Several nutritional elements, such as folate, choline, me- thionine, selenium, and retinoic acid, have demonstrated the ability to influence alterations in DNA methylation pat- terns.21 Nutrigenomics and nutrigenetics play an evolving role in understanding endometriosis. They explore how individ- ual genetic variations and dietary components interact, po- tentially influencing the development and progression of endometriosis. These fields examine how specific nutrients and dietary patterns might impact gene expression and bi- ological pathways involved in the condition, offering in- sights into potential personalized dietary interventions or preventive strategies (Otero BMC and Bernolo LF, 2023). Nutrients significantly influence the vaginal microbiome diversity. Lacking of vitamins e.g., D, E, C, and A, in diet and high in sugar and fats may contribute to the infection of the vagina. Also, the presence of folate, calcium, and β-carotene in diet may decrease the chances of infection. These infections are associated with adverse outcomes like human immunodeficiency virus (HIV) transmission risk, preterm birth, high susceptibility to infection of human pa- pillomavirus (HPV), as well as higher probabilities of devel- oping cervical, endometrial, and ovarian cancers as shown in Figure 1 (Ciberia et al., 2021). The different types of di- etary supplements and their role in endometriosis are sum- marized in Table 1. In cases of endometriosis, CpG hypomethylation may re- sult in the overexpression of steroidogenic factor 1 (SF1) or estrogen receptor β (ER-β). This overexpression can sub- sequently elevate the levels of estradiol and prostaglandin E2 (PGE2), promoting inflammation and facilitating cell growth. When diets lack these nutrients, it can lead to changes in lipid metabolism, increased oxidative stress, and abnormalities in epigenetic processes. Thus, giving proper food, diets, and nutrition can prevent the chances of en- dometriosis as discussed in Table 2.22 A growing body of evidence indicates that extra virgin olive oil is rich in un- saturated fatty acids and phytochemicals could be used po- tentially for cardiovascular protection, cancer prevention, and anti-inflammatory properties.23 Dietary elements could potentially impact the advance- ment and onset of endometriosis by influencing steroid hormone metabolism, the menstrual cycle, regulation of inflammation, oxidative stress, and muscle contraction.24 Furthermore, incorporating nutrients possessing anti-in- flammatory and antiestrogenic properties, such as antiox- idants like curcumin, epigallocatechin gallate, quercetin, resveratrol, and inositol has been proposed to alleviate en- dometriosis-associated pain.24,25 The impacts of diet and nutrients on endometriosis and related symptoms e.g., pelvic pain and infertility, etc., are summarized herein and in Table 2 and Figure 2. Advancing Precision Nutrition in Endometriosis Care: The Role of Nutrigenomics and Nutrigenetics Academic Medicine & Surgery 2 Figure 1. Diet and its Impact on vaginal microbiome. Deficiency of vitamins e.g., E,D,C, and A, and folate, calcium, and β-carotene in the diet but having high sugars and fats may alter vaginal microbiota and enhances the possibilities of bacterial vaginosis, and infections e.g., transmission risk of the human immunodeficiency virus (HIV), human papillomavirus (HPV), preterm birth, and cancer etc. Reproduced from an open-access journal under the term of Creative Commons Attribution (Ciberia et al., 2021). https://doi.org/10.1038/ s44222-023-00040-w. A meta-analysis conducted by Arab et al. in 2022 aimed to consolidate findings regarding the correlation between dietary intake of specific food groups and nutrients and the risk of developing endometriosis. Their research high- lighted potential associations suggesting that an optimal intake of total dairy products, along with reduced consump- tion of red meat, trans fatty acids (TFA), and saturated fatty acids (SFA), might be linked to a decreased risk of develop- ing endometriosis.14 A comprehensive review was conducted involving women diagnosed with endometriosis and those considered healthy. The aim was to investigate the potential correla- tion between diet and endometriosis. Ten studies were an- alyzed in total. The findings indicated that the intake of non-cruciferous vegetables, fruits, potatoes, legumes, dairy products, fish, vitamins (B12, C, D, and A), fatty acids- mono and polyunsaturated, as well as minerals like magne- sium, calcium, potassium, appeared to lower the risk of de- veloping endometriosis.26 2.1. MEDITERRANEAN DIET The Mediterranean diet, abundant in fruits, vegetables, whole grains, nuts, legumes, and olive oil has demonstrated multiple advantages for overall human health (Ciberia et al., 2021). Adopting a preconception Mediterranean diet by couples undergoing IVF/ICSI treatment contributes posi- tively to the success of achieving pregnancy as evidenced by Vujkovic and associates (Vujkovic et al., 2010; Ciberia et al., 2021). A single-arm study conducted in Austria investi- gated the impact of the Mediterranean diet on pain associ- Figure 2. Dietary nutrition and Nutrigenetics/ Nutrigenomics impacts on overall health. ated with endometriosis. A particular dietary regimen com- prising fresh vegetables, fruits, white meat, fatty fish, soy products, whole grain foods, magnesium-rich food sources, and cold-pressed oils was given to patients. The study re- vealed a notable alleviation in overall pain, including dys- menorrhea, dyspareunia, and dyschezia, along with en- hancements in the general condition among participants.27 In a case-control study conducted in Mexico, 82 infertile patients diagnosed with rASRM stages I–II endometriosis were randomly divided into two groups. One group adhered to a normal diet, while the other followed a high-antiox- idant diet (HAD) for 4 months, tailored to each patient’s energy requirements. Both groups demonstrated strong ad- Advancing Precision Nutrition in Endometriosis Care: The Role of Nutrigenomics and Nutrigenetics Academic Medicine & Surgery 3 Figure 3. Nutrition and Endometriosis Risk. herence, with 91.4% in the HAD group and 91.9% in the normal diet group completing the study. After 2 months of the intervention, the HAD group exhibited increased con- centrations of vitamins (serum retinol, alpha-tocopherol, leukocyte, and plasma ascorbate), heightened activity of antioxidant enzymes (superoxide dismutase and glu- tathione peroxidase), and decreased levels of oxidative stress markers (malondialdehyde and lipid hydroperox- ides).27. 2.2. DAIRY PRODUCTS A cohort prospective study conducted by MD Nodler and associates among adolescent patients in Mexican female suggested that consuming dairy products, especially yogurt and ice cream, during adolescence might decrease the risk of being diagnosed with endometriosis later in life28 as shown in Figure 3. A case-control study carried out among Iranian women between 2015-2016, involving 206 women without en- dometriosis and 207 with confirmed endometriosis through laparoscopy, revealed notable findings. The study suggested that the intake of green vegetables, red meat, dairy prod- ucts (such as milk and cheese), fresh fruit, grains, and legumes lowers the risk of developing endometriosis. How- ever, the consumption of carrots, green tea, fish, eggs, and oil did not show a significant relationship with the risk of endometriosis (M.D. Ashrafi et al., 2020). A randomized controlled study was carried out by Sesti and associates in patients treated with hormones and di- etary supplements. The study demonstrated that both hor- monal suppression therapy and dietary supplementation have similar effectiveness in reducing non-menstrual pelvic pain.29 2.3. FATS Studies focusing on specific nutrients did not establish a significant association between saturated fat and animal fat intake and the risk of developing endometriosis.8 Long-chain polyunsaturated fatty acids (LC-PUFA) have positive effects on various physiological processes such as growth, neurological development, accumulation of lean and fat mass, reproduction, as well as both innate and ac- quired immunity. Additionally, they impact the occurrence and severity of nearly all chronic and degenerative dis- eases, encompassing cancer, atherosclerosis, stroke, arthri- tis, diabetes, osteoporosis, neurodegenerative conditions, inflammatory diseases, and skin disorders (Gaboon, 2011). In xenograft models, dietary n-3 PUFAs effectively inhib- ited the growth of endometrial cancer cells (zheng et al., 2014). Omega-3 supplementation has demonstrated the potential to decelerate the expansion of endometrial im- plants, alleviate pain and inflammation, and enhance the quality of life for women diagnosed with stage III and IV endometriosis.22 2.4. MULTIVITAMINS AND MINERALS Selenium regulates the functions of numerous regulatory proteins involved in signal transduction, offering advan- tages in managing inflammatory diseases. Lowered sele- nium levels have been observed in both acute and chronic inflammatory conditions. In a study involving patients with endometriosis, simultaneous administration of vitamins E, C, selenium, and zinc showed an inverse correlation with the severity of the disease. Increased disease severity was noticed with reduced oral intake of antioxidant nutrients.21 Vitamin D might contribute to both the prevention and treatment of endometriosis. A meta-analysis conducted in 2020 revealed a correlation between low levels of vitamin D and a higher likelihood of being diagnosed with en- dometriosis, as well as a greater severity of symptoms.9 Four human studies, four animal studies, and four in vitro studies were done to assess the role of Vitamin D on endometriosis. While in vitro and animal studies indicated a potential regression of endometriotic implants and a re- duction in invasion and proliferation following vitamin D supplementation, these outcomes were not mirrored in the findings of the meta-analysis.30 In a significant and large cohort study, the correlation between vitamin consumption (C,E,B) and the occurrence of endometriosis was determined. Dietary habits were eval- uated using a questionnaire of food frequency. Throughout a follow-up period encompassing 735,286 persons/years, 1,383 new cases of laparoscopically-confirmed endometrio- sis were identified among 70,617 women. The study con- firmed an inverse relationship of vitamin C, E thiamine, and folate consumption with endometriosis.31 2.5. PROBIOTICS Probiotics have been suggested as a potential strategy to improve reproductive health and mitigate the risk of dis- eases.32 Probiotic microorganisms like Lactobacillus reuteri and Lactobacillus Plantarum, naturally produce vitamin B (). They play a crucial role in endometriosis patients as vi- tamin B levels are often found to be lesser in the general population. Also, they enhance the effectiveness of the im- mune system and stimulate vitamin and mineral absorp- tion. Additionally, these probiotic microorganisms might have the capability to generate specific enzymes such as es- terase, lipase, coenzymes A, Q, NAD, and NADP.21,33 Advancing Precision Nutrition in Endometriosis Care: The Role of Nutrigenomics and Nutrigenetics Academic Medicine & Surgery 4 Table 1. Different types of dietary supplements and their role in endometriosis treatment. Nutrients Role References Long-chain polyunsaturated fatty acids Helpful in chronic and degenerative diseases e.g., skin diseases, atherosclerosis, cancer, diabetes, osteoporosis, neurodegenerative and inflammatory conditions Gaboon, 2011 Omega-3 supplements Enhance life quality in women diagnosed with stage III and IV endometriosis Halpern et al., 2015 Notable improvements in pain symptoms linked to endometriosis, including dyspareunia, dysmenorrhea, and chronic pelvic pain Yalcin Bahat et al.21 Zinc, Selenium Shows inverse relationship with severity of endometriosis Yalcin Bahat et al.21 Probiotics influence the microbial makeup of the human body Thanaboonyawat et al.34; Feng and Liu.32 Lactobacilli Protects the vaginal environment Thanaboonyawat et al.34 Lactobacillis plantarum Actively prevent the presence of sperm-agglutinating Escherichia coli (E. coli) bacteria Yalcin Bahat et al.21 Lactobacillus rhamnosus GR-1 and Lactobacillus fermentum RC-14 Help sustain and reestablish a healthy vaginal microbial balance in cases of vaginal dysbiosis Yang et al.35 Vitamin D Reduces pelvic pain and endometriosis risk by increasing antioxidant levels. Barnard et al.9 Zinc, Magnesium, Vitamin C and E Can improve endometriosis risk as evidence from animal and human studies. Yalcin Bahat et al.21 Curcumin In vitro, animal, and human studies evince a decrease in endometriotic lesion size preventing the recurrence of disease. Yalcin Bahat et al.,21; Kizilay et al.36; Jelodar et al.37 Not only factors directly related to endometriosis but also individual patient factors can influence the choice of dietary interventions beneficial for women with en- dometriosis. For instance, in individuals diagnosed with ir- ritable bowel syndrome (IBS), adopting a low-FODMAP diet has demonstrated efficacy in alleviating symptoms such as abdominal pain and bloating (Black et al., 2021). Conse- quently, for women dealing with both endometriosis and concurrent IBS, considering a low-FODMAP diet as a pri- mary intervention might be advisable before exploring other dietary approaches (Black et al., 2021). 2.6. DIRECT-TO-CONSUMER NUTRIGENETICS TESTING Genomic data holds a unique significance as it encompasses not just our genetic makeup but also that of our family and future generations, including our children. Lately, nu- merous companies have begun marketing DNA testing kits directly to consumers through the Internet to provide ge- netic testing to customers without medical oversight, offer- ing predictions about personal risks for prevalent diseases like cancer, autoimmune conditions, or cardiovascular dis- eases.38,39 Generally, “direct-to-consumer genetic testing” is abbreviated as DTC-GT.39 DTC-GT assesses inherited dis- ease risks and has received recent approvals from the Food and Drug Administration as depicted in Figure 5.40 DTC-GT usually employs a technique known as SNP- chip genotyping, which examines specific variants across the genetic code, such as particular single nucleotide poly- morphisms (SNPs) or small insertions or deletions. SNP- Figure 4. Health benefits and limitations of (DTC-GT). chip genotyping is proficient at identifying common ge- netic variants. However, when it comes to detecting extremely rare variants, SNP chips often produce false pos- itives, indicating the presence of variants that are not pre- sent in the individual’s DNA. Another increasingly em- ployed method in DTC genetic tests is genome sequencing, which scrutinizes nearly the entire genetic code to identify its variants.41 The Food and Drug Administration (FDA), Medicare Centers, and Medicaid Services (CMS) offer some regulation of DTC-GT, but most genetic tests lack compre- hensive federal oversight. Figure 4 shows the health-related information/benefits and limitations of DTC-GT. Advancing Precision Nutrition in Endometriosis Care: The Role of Nutrigenomics and Nutrigenetics Academic Medicine & Surgery 5 A study conducted by McGuire and associates among 1087 social networkers for their interest in personal genome testing (PGT) reported that about 6% of networkers have used PGT, 64% have an interest in its use, and 30% have no interest in attaining knowledge about diseases in their family.42 It is remarkable to observe an increasing number of pa- tients feeling empowered to make decisions regarding their reproductive choices and seeking support to achieve their family-building goals because of DTC testing. It was noticed that some individuals have already chosen a particular treatment, such as oocyte or embryo cryopreservation or IVF, relying on the interpretation of DTC results.43 Thus, DTC testing could be an efficient approach to the diagnosis and treatment of endometriosis and related disorders. As the demand for reproductive medicine rises and we grapple with a flood of misinformation from various media and online sources concerning fertility and reproductive health, it is crucial to ensure ethical and prudent practice of assisted reproductive technologies. Hence, we must receive education regarding the drawbacks of DTC testing, enabling us to offer optimal guidance and support to our patients on their reproductive journeys. 2.7. ARTIFICIAL INTELLIGENCE IN NUTRIGENETICS AND NUTRIGENOMICS Experts anticipate that artificial intelligence (AI), deep and machine learning (ML) holds promise for diagnosing, man- aging, and treating an extensive range of medical condi- tions.44 The most prevalent application of classical ma- chine learning in healthcare is precision medicine, which forecasts the treatment procedures most likely to be effec- tive for a patient by considering various patient character- istics and the context of the therapy (Kharb and Joshi). Few AI or machine learning applications aimed at enhancing women’s health are currently in clinical practice, especially during pregnancy.45 Leveraging a digital twin alongside AI provides the chance to create tailored and highly accurate recommendations that align with the patient’s real-world circumstances. These recommendations can empower clin- icians to make more precise, personalized, and effective de- cisions.44,46,47 Davidson and associates conducted a study on novel

e.g., artificial intelligence (AI), deep learning, and machine learning (ML) to improve pregnancy outcomes. Among 129 studies the prominent areas within the realm of pregnancy where AI and ML methods have seen extensive use comprise prenatal care, involving aspects such as fetal anomalies and placental functioning (73 instances); peri- natal care, encompassing birth and delivery (20 instances); and addressing preterm birth (13 instances). Initiatives aimed at applying AI to clinical practice involve the devel- opment of clinical decision support systems (24 instances) and the creation of mobile health applications (9 in- stances).48

The major limitation is the integration of AI/ML into rou- tine clinical practice, particularly concerning the regulation of these technologies.44 3. PRECISION/PERSONALIZED NUTRITION The ultimate objective of precision nutrition (PN) is to cre- ate personalized nutritional recommendations or prevent metabolic disorders by considering a blend of an individual genetic makeup, environmental influences, and lifestyle factors.49‑51. To achieve this objective, as depicted in the precision nutrition plate (Figure 4), factors extending be- yond nutritional or genetic aspects-such as lifestyle choices like metabolomics, physical activity (PA) patterns, or gut microbiomics are increasingly recognized as substantial in- fluencers deserving attention within the realm of precision nutrition.50 The microbiota plays a crucial role in various biological functions of the host, including the development of the immune system, protection from harmful microor- ganisms, food breakdown during digestion, and production of micronutrients and bioactive compounds. Tailored inter- vention strategies could be formulated to “rebalance” an imbalanced microbiota or enhance the reaction to a par- ticular diet. Probiotics, prebiotics, synthetic stools, and fe- cal transplantation have shown effectiveness in reducing weight in experimental obesity models, indicating the need for additional studies on human subjects.52 For an ideal as- sessment of the type, quantity, and frequency of food in- take, real-time monitoring would be preferable over meth- ods such as 24-hour dietary recalls or short-term measurements of food consumption. Table-embedded scales, automatic ingestion monitors with sensors, hand gestures, accelerometers, smartphone camera apps em- ploying deep learning algorithms, and tooth-mounted sen- sors capable of recording various nutrients are devices de- signed to offer a more precise method for tracking and adjusting food consumption compared to dietary re- calls.52‑55 Improving the translation of PN (Precision Nutrition) science into products and services can be optimized by evaluating the equilibrium between advantages and draw- backs for both consumers and patients. Benefits encompass potential enhancements in specific health outcomes, the ease of utilizing user-friendly digital tools, and the effec- tiveness of a more tailored approach. Conversely, risks may stem from the expensive nature of recurrent omic testing, the time commitment required by intricate programs, and discrepancies between the scientific foundation and prod- uct assertions. These risks also involve apprehensions re- lated to trust, privacy, and the management of data.56 Fig- ure 5 represents the precision nutrition plate where multifaceted aspects involved in tailoring personalized nu- trition is summarized. As per the Nutrigenetics/Nutrigenomics International Society (ISNN) three key dimensions should be addressed for the future direction of precision nutrition57: Advancing Precision Nutrition in Endometriosis Care: The Role of Nutrigenomics and Nutrigenetics Academic Medicine & Surgery 6 Figure 5. Precision Nutrition Plate represents the multifaceted aspects involved in tailoring personalized nutrition. Reproduced from an open-access journal under the term of Creative Commons Attributions. 50 DOI: 10.3390/nu9080913. In extensive studies, self-administered Food Frequency Questionnaires (FFQs) are typically favored for assessing food intake. However, all these methods demand thorough preparation before implementation, thus utilization of high-throughput omics tools facilitates a comprehensive and integrated exploration of nutrition.58 3.1. MULTI-OMICS TECHNOLOGY “Omics” encompasses scientific disciplines focused on high-throughput measurements of biological molecules, including DNA, RNA, proteins, and metabolites.59 Several -omics technologies have been utilized in analyzing mater- nal urine and blood for pregnancy monitoring to identify potential diagnostic markers. However, these markers have not yet been integrated into clinical protocols. For example, the plasma concentration of ADAM-12 (A Disintegrin and Metalloproteinase-12) has exhibited changes in various pregnancy-related disorders. However, the effectiveness of ADAM-12 as a reliable marker for adverse outcomes re- mains uncertain.59 Presently, many omics technologies offer comprehensive readouts at singular levels such as genomic, epigenomic, transcriptomic, proteomic, or metabolomic. Multi-omics, on the other hand, involves integrating two or more omics datasets for comprehensive data analysis, visualization, and interpretation. This approach aims to grasp the un- derlying biological mechanisms in various disease states. As multi-omics technologies advance, extensive genomic data, even at the single-cell level, is increasingly accessible (Atherine et al., 2022). Functional genomic data, when combined with other omics data such as proteomics and metabolomics, provides a more comprehensive understanding of endometriosis. This integrated approach helps identify essential pathways and molecular signatures associated with the condition, offering potential benefits in diagnosis and the design of targeted therapies. CA-125, miRNA-200 family, miR-200b, HE4 (Human Epididymis Protein 4), and Circulating cell- free DNA are some key genetics and epigenetics biomarkers in endometriosis that affect the disease progression.60 3.2. DIGITAL/ VIRTUAL TWIN TECHNOLOGY In recent years, there has been an increasing demand for precise disease diagnosis and personalized treatment. The healthcare system is striving to tailor treatments to indi- vidual patients, aiming to maximize both effectiveness and efficiency.61 Digital twin technology is rapidly emerging as a game-changer in healthcare systems, fundamentally al- tering the delivery of patient care.62 Digital twins serve as a tool for patients to take an active role in their healthcare.63 Also, digital twins have been employed in the industry since 2002 to enhance manufacturing processes and manage the entire product life cycle more effectively.64 Through real- time monitoring of vital signs, physiological parameters, and other health-related data, digital twins possess the ca- pability to detect early signs of deterioration or anomalies. This proactive identification allows healthcare providers to intervene early, preventing complications and fine-tuning treatment plans for optimal efficacy. Furthermore, digital twins foster communication and collaboration between pa- tients and healthcare providers, fostering shared decision- making and a patient-centered approach to care. The concept of a “virtual digital twin” aims to offer the most suitable, adaptable, efficient, and cost-effective di- etary and lifestyle recommendations to an individual based on lifelong model and AI-driven models.46,52,65 Moztarzadeh and associates introduce machine learning (ML)-driven methodologies for digitally replicating cancer, acknowledging certain constraints. The proposed methods encompass Decision Tree Regression (DTR), ML Linear Re- gression (ML LR), Gradient Boosting Algorithm (GBA), and Random Forest Regression (RFR). These technologies en- able the system to process extensive patient data, con- structing precise cancer progression models while effec- tively distinguishing between affected and healthy individuals. Leveraging a credible dataset, numerous ma- chine-learning techniques have been created and simulated for breast cancer to illustrate the simplicity and feasibility of digital twin technology. This approach facilitates the simulation of cancer diagnosis and progression, providing insights into its future behavior. Such insights are invalu- able in devising novel treatments, anticipating potential complications, and proactively addressing them.65 A randomized controlled trial was conducted by Merlot and associates to assess the immediate and lasting effects, up to 4 hours, of a single 20-minute use of a digital thera- peutic (DTx - Endocare) on pain levels in women enduring pelvic pain associated with endometriosis. Following treat- ment, both the Endocare and control groups exhibited a 1. Refining conventional nutritional guidelines by seg- menting them into population subgroups based on factors like gender, age, and social determinants. 2. Implementing individualized techniques derived from detailed and comprehensive phenotyping. 3. Integrating genetic-informed nutrition strategies that focus on rare genetic variations Advancing Precision Nutrition in Endometriosis Care: The Role of Nutrigenomics and Nutrigenetics Academic Medicine & Surgery 7 significant reduction in clustered post-treatment pain com- pared to pre-treatment levels. Endocare consistently and significantly decreased pain perception up to 4 hours post- treatment, whereas the control group did not show signif- icant differences. The mean perceived pain relief was no- tably higher for Endocare at 28% compared to the control group across all post-treatment assessments.66 MAJOR CHALLENGES (i) The data gathered and employed in crafting digital twins are presumed to be accurate and devoid of contradictions. However, one prevalent concern regarding data accuracy re- volves around completeness, as incomplete data might in- troduce bias in predictions when utilized in the digital twin framework. (ii) Patient preferences often grapple with the balance between the quantity and quality of life. In certain scenarios, extended survival might coincide with a decline in the quality of life. Some patients prioritize a high quality of life even if it means acknowledging the potential short- ening of their lifespan. (iii) A blending of real-world evi- dence and results sourced from randomized clinical trials. (iv) In healthcare, safeguarding data privacy and protec- tion remains a critical concern, despite employing various forms of data encryption to manage data transfers.46 Sci- entists are creating diets that might enhance how patients respond to cancer treatment by utilizing machine learning and genotyping to reveal the nutritional weaknesses of tu- mors thus paving new pathways for the treatment of dis- ease using digital/ artificial technology.67 4. PROSPECTS, CHALLENGES AND CONCLUSION Endometriosis continues to be a substantial source of mor- bidity, significantly impacting the quality of life for women in their reproductive years.68 Studies concluded a connec- tion between genetic variations and endometriosis. How- ever, the specific molecular pathways through which these variations impact disease onset and progression remain un- clear.60 The integration of nutritionists into these teams might play a significant role in preventive and therapeutic out- comes in the future, contributing to the fight against en- dometriosis. Food and nutrients can impact both the de- velopment and advancement of the disease, opening the possibility of alternative or supplementary treatments for individuals affected by endometriosis. Further investiga- tion is necessary to unravel the mechanisms of Nutritional genomics in improving the diagnosis of endometriosis. It is fundamental to design cost-effective interventional and clinical studies for PN, nutritional genomics, and AI/ML. Moreover, to attain the trust of policymakers and health professionals it is mandatory to design regulatory embod- ies.58 A prominent limitation of Precision Nutrition (PN) is that most studies are observational rather than stemming from randomized controlled trials (RCTs) with evaluated clinical endpoints. Moreover, there is uncertainty about whether PN strategies can lead to improved endometrio- sis.58 This review delves into various dietary supplements, nu- tritional genomics, and their influence on endometriosis and associated symptoms. Additionally, it elaborates on precision/personalized nutrition and the application of dig- ital/virtual technology in addressing the progression of the disease. Furthermore, it explores the effects of direct-to- consumer genetic testing and the role of artificial intelli- gence in the nutrigenetics and nutrigenomics approach to managing endometriosis. Besides, more clinical approaches and research are needed to establish the accuracy and effi- cacy of this approach. Moreover, a nutritional approach to endometriosis management could be helpful for poor surgi- cal candidates. As all are not easy to handle and operative procedure, nutritional approach can be a good alternative. Submitted: September 03, 2024 EDT, Accepted: October 14, 2024 EDT This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CCBY-4.0). View this license’s legal deed at http://creativecommons.org/licenses/by/4.0 and legal code at http://creativecom- mons.org/licenses/by/4.0/legalcode for more information. Advancing Precision Nutrition in Endometriosis Care: The Role of Nutrigenomics and Nutrigenetics Academic Medicine & Surgery 8

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