{"paper_id":"348a0c30-7de6-4206-9796-d7d95449aa1d","body_text":"Review \nAdvancing Precision Nutrition in Endometriosis Care: The Role of          \nNutrigenomics and Nutrigenetics    \nMaudlyn O Etekochay, MPH1\n, Devika Muraleedharan, MD2\n, Subhasree Majumdar, PhD3\n,\nMugisha Nsengiyumva, MPH4\n1 Inova Health System, Fairfax, Virginia, USA, 2 Ivane Javakhishvili Tbilisi State University, Tbilisi, Georgia, 3 Zoology, Sonamukhi College, Sonamukhi, \nWest Bengal, India, 4 Public Health and Scientific Research Center, Kigali, Rwanda \nKeywords: Endometriosis, Nutrigenomics, Nutrigenetics, Personalized Diet, Precision Nutrition, Artificial Intelligence, Direct to Consumer Genetic \nTesting \nhttps://doi.org/10.62186/001c.124784 \nAcademic Medicine & Surgery \nEndometriosis is a gynecological disorder that affects 10-15% of women of reproductive \nage. It is characterized as a chronic, inflammatory, and hormone-dependent disease in \nwhich the endometrial tissue is present on the external uterine lining, resulting in \ninfertility and pelvic pain. Some research studies stated that about 97% of human \ndiseases are monogenic diseases associated with genes. Thus, modifying dietary intake \n(personalized diet) can potentially prevent monogenic diseases. \nNutrigenomics and nutrigenetics have garnered substantial interest among researchers \nas potential avenues for managing chronic conditions like diabetes, cancer, obesity, and \ncardiovascular disorders. Nutrigenomics ascertains the effects of food and ingested \nnutrients on gene expression and regulation, tailoring nutritional needs to an \nindividual’s genetic makeup, thereby facilitating personalized diets. On the other hand, \nnutrigenetics investigates how an individual’s genetic composition influences their \nresponse to dietary elements. Both fields could be beneficial in modifying various disease \nconditions. Furthermore, it explores the effects of precision nutrition, \ndirect-to-consumer genetic testing, and the role of artificial intelligence in the \nnutrigenetics and nutrigenomics approach to managing endometriosis. This review aims \nto provide a comprehensive overview of potential treatment modalities for endometriosis \nthrough the lenses of nutrigenomics and nutrigenetics. It highlights the interplay \nbetween dietary interventions and gene expression, elucidating how personalized \napproaches could potentially modify the course of endometriosis. \n1. INTRODUCTION \nEndometriosis is a gynecological disorder in which the en-\ndometrial tissue is developed in the external uterine cavity, \nresulting in infertility and pelvic pain.1‑3 Endometriosis is \noften characterized as a chronic, inflammatory, and hor-\nmone-dependent debilitating disease.4 Endometriosis af-\nfects approximately 10-15% of women in their reproductive \nyears, with about 70% of these women experiencing on-\ngoing pelvic discomfort.5‑7 The disease etiology is multi-\nfaceted and complicated involving hormonal, genetic, im-\nmunological, and environmental factors.8 Frequent \nindicators encompass intense pelvic discomfort, dysmenor-\nrhea, dyspareunia, fertility challenges, fatigue, lower back \npain, bloating, constipation, and diarrhea. Due to the po-\ntential lack of specific symptoms, diagnosis often faces de-\nlays.9 The delay in treatment may cause a decrease in fer-\ntility and reproductive function. Medical therapy aims to \nhormonally alter the menstrual cycle, inducing a pseudo-\npregnancy, pseudo-menopause, or maintaining an anovu-\nlatory state. As of now, there are no definitive cures for \nendometriosis. The standard clinical approaches usually in-\nvolve using hormonal therapies to inhibit estrogen produc-\ntion, employing small-molecule drugs to alleviate pain, and \nconducting laparoscopic surgeries to eliminate endometri-\notic lesions.2 However, hormonal therapy causes some se-\nvere side effects due to which some of the hormones like \nmethyltestosterone and estrogen are phased out from the \nmarket. One extensively researched method involves ad-\nministering estroprogestins and progestins for contracep-\ntion, which has also been explored for delivering specific \ndrugs targeting endometriosis.10 Various clinical strategies \nused for the treatment of vaginal infections include tablets, \ncreams, vaginal rings, and vaginal suppositories.11 Long-\nacting contraceptives that can be implanted, like Nex-\nplanon®, and injectables such as Depo-Provera®, have \nbeen utilized in the treatment of endometriosis.12 Likewise, \nextended-release GnRH products like Lupron Depot® are \nemployed in the treatment of endometriosis. Endometriosis \nexhibits characteristics such as oxidative stress, angiogen-\nesis, and matrix degradation. Consequently, directing drug \ntherapy toward these specific targets may enhance ther-\napeutic outcomes compared to presently employed meth-\nods.13 \nDiet is believed to influence the development of en-\ndometriosis, potentially impacting its onset and progres-\nEtekochay MO, Muraleedharan D, Majumdar S, Nsengiyumva M. Advancing Precision\nNutrition in Endometriosis Care: The Role of Nutrigenomics and Nutrigenetics.\nAcademic Medicine & Surgery. Published online October 26, 2024.\ndoi:10.62186/001c.124784\n\nsion. Research suggests that certain dietary elements may \ncontribute to an individual’s risk of developing this con-\ndition.14 Moreover, Various lifestyle factors may affect en-\ndometriosis risk by potentially reducing inflammation. \nPhysical activity and omega-3 fatty acids in the diet might \nlower levels of inflammatory markers e.g., interleukin6 \n(IL-6) and tumor necrosis factor-alpha (TNFα). Although \nthe relationship between physical activity and endometrio-\nsis is not entirely clear, higher consumption of long-chain \nomega-3 fatty acids has been linked to a decreased risk of \nendometriosis.15 Some research studies stated that about \n97% of human diseases are monogenic diseases associated \nwith genes. Thus, monogenic diseases can potentially be \nprevented by modifying dietary intake (personalized diet) \n(Gaboon, 2011). \nThe research-focused approach of nutrigenetics and nu-\ntrigenomics emerges as a pivotal domain within precision \nnutrition, offering pathways to advance personalized nutri-\ntional interventions.16 They have garnered substantial in-\nterest among researchers as potential avenues for manag-\ning chronic conditions like diabetes, cancer, obesity, and \ncardiovascular disorders (Gaboon 2011). Nutrigenomics as-\ncertains the effects of food and ingested nutrients on gene \nexpression and regulation, tailoring nutritional needs to an \nindividual’s genetic makeup, and thereby facilitating per-\nsonalized diets.17 On the other hand, nutrigenetics inves-\ntigates how an individual’s genetic composition influences \ntheir response to dietary elements (Gaboon, 2011). Both \nfields could be beneficial in modifying various disease con-\nditions, for example, fish oil inhibits colonic tumor growth. \nThe exploration of a link between dietary factors and the \nonset of endometriosis has garnered significant interest, \nprimarily driven by the observation that both normal bodily \nfunctions and the disease’s pathological processes can be \nimpacted by diet (Parrazzani, 2013). Here, in this review, we \nsummarized the role of nutrigenetics, nutrigenomics, and \nprecision nutrition in endometriosis treatment. \n2. NUTRIGENOMICS AND NUTRIGENETICS IN \nENDOMETRIOSIS \nSufficient and appropriate nutrient intake plays a vital role \nin averting the onset of chronic diseases.18 Dietary inter-\nventions have shown potential in both preventing and man-\naging endometriosis as well as alleviating the associated \npain.9 Maintaining an optimal equilibrium between the \noverall oxidation status and the body’s antioxidant re-\nsponse is crucial for a balanced genomic system. Employing \na nutrigenomic strategy involves bolstering the body’s an-\ntioxidant levels by supplementing deficient antioxidants in \nindividuals affected by such diseases.19 Nutrigenetics and \nnutrigenomics can be regarded as two distinct methodolo-\ngies within the field of nutritional genomics.20 Nutrigenet-\nics examines the influence of genetic diversity, particularly \nin the form of a single-nucleotide polymorphism (SNP), on \nan individual reaction to dietary consumption e.g. An in-\ndividual reaction to caffeine differs due to genetic varia-\ntions in the CYP1A2 gene. This gene produces an enzyme \nin the liver responsible for breaking down caffeine, and \ncertain gene variants metabolize caffeine at different rates \n(Sadeghi et al., 2019). In essence, nutrigenetics explores \nhow an individual’s genetic makeup impacts their physical \nresponse to dietary consumption.20 Figure 1 depicts how \ndietary nutrition and nutrigenomics/nutrigenetics impact \nthe overall health of an individual. \nSeveral nutritional elements, such as folate, choline, me-\nthionine, selenium, and retinoic acid, have demonstrated \nthe ability to influence alterations in DNA methylation pat-\nterns.21 \nNutrigenomics and nutrigenetics play an evolving role \nin understanding endometriosis. They explore how individ-\nual genetic variations and dietary components interact, po-\ntentially influencing the development and progression of \nendometriosis. These fields examine how specific nutrients \nand dietary patterns might impact gene expression and bi-\nological pathways involved in the condition, offering in-\nsights into potential personalized dietary interventions or \npreventive strategies (Otero BMC and Bernolo LF, 2023). \nNutrients significantly influence the vaginal microbiome \ndiversity. Lacking of vitamins e.g., D, E, C, and A, in diet \nand high in sugar and fats may contribute to the infection \nof the vagina. Also, the presence of folate, calcium, and \nβ-carotene in diet may decrease the chances of infection. \nThese infections are associated with adverse outcomes like \nhuman immunodeficiency virus (HIV) transmission risk, \npreterm birth, high susceptibility to infection of human pa-\npillomavirus (HPV), as well as higher probabilities of devel-\noping cervical, endometrial, and ovarian cancers as shown \nin Figure 1 (Ciberia et al., 2021). The different types of di-\netary supplements and their role in endometriosis are sum-\nmarized in Table 1. \nIn cases of endometriosis, CpG hypomethylation may re-\nsult in the overexpression of steroidogenic factor 1 (SF1) \nor estrogen receptor β (ER-β). This overexpression can sub-\nsequently elevate the levels of estradiol and prostaglandin \nE2 (PGE2), promoting inflammation and facilitating cell \ngrowth. When diets lack these nutrients, it can lead to \nchanges in lipid metabolism, increased oxidative stress, and \nabnormalities in epigenetic processes. Thus, giving proper \nfood, diets, and nutrition can prevent the chances of en-\ndometriosis as discussed in Table 2.22 A growing body of \nevidence indicates that extra virgin olive oil is rich in un-\nsaturated fatty acids and phytochemicals could be used po-\ntentially for cardiovascular protection, cancer prevention, \nand anti-inflammatory properties.23 \nDietary elements could potentially impact the advance-\nment and onset of endometriosis by influencing steroid \nhormone metabolism, the menstrual cycle, regulation of \ninflammation, oxidative stress, and muscle contraction.24 \nFurthermore, incorporating nutrients possessing anti-in-\nflammatory and antiestrogenic properties, such as antiox-\nidants like curcumin, epigallocatechin gallate, quercetin, \nresveratrol, and inositol has been proposed to alleviate en-\ndometriosis-associated pain.24,25 The impacts of diet and \nnutrients on endometriosis and related symptoms e.g., \npelvic pain and infertility, etc., are summarized herein and \nin Table 2 and Figure 2. \nAdvancing Precision Nutrition in Endometriosis Care: The Role of Nutrigenomics and Nutrigenetics\nAcademic Medicine & Surgery 2\n\nFigure 1. Diet and its Impact on vaginal microbiome. Deficiency of vitamins e.g., E,D,C, and A, and folate,                 \ncalcium, and β-carotene in the diet but having high sugars and fats may alter vaginal microbiota and enhances                   \nthe possibilities of bacterial vaginosis, and infections e.g., transmission risk of the human immunodeficiency               \nvirus (HIV), human papillomavirus (HPV), preterm birth, and cancer etc. Reproduced from an open-access               \njournal under the term of Creative Commons Attribution (Ciberia et al., 2021).             https://doi.org/10.1038/\ns44222-023-00040-w.  \nA meta-analysis conducted by Arab et al. in 2022 aimed \nto consolidate findings regarding the correlation between \ndietary intake of specific food groups and nutrients and \nthe risk of developing endometriosis. Their research high-\nlighted potential associations suggesting that an optimal \nintake of total dairy products, along with reduced consump-\ntion of red meat, trans fatty acids (TFA), and saturated fatty \nacids (SFA), might be linked to a decreased risk of develop-\ning endometriosis.14 \nA comprehensive review was conducted involving \nwomen diagnosed with endometriosis and those considered \nhealthy. The aim was to investigate the potential correla-\ntion between diet and endometriosis. Ten studies were an-\nalyzed in total. The findings indicated that the intake of \nnon-cruciferous vegetables, fruits, potatoes, legumes, dairy \nproducts, fish, vitamins (B12, C, D, and A), fatty acids- \nmono and polyunsaturated, as well as minerals like magne-\nsium, calcium, potassium, appeared to lower the risk of de-\nveloping endometriosis.26 \n2.1. MEDITERRANEAN DIET \nThe Mediterranean diet, abundant in fruits, vegetables, \nwhole grains, nuts, legumes, and olive oil has demonstrated \nmultiple advantages for overall human health (Ciberia et \nal., 2021). Adopting a preconception Mediterranean diet by \ncouples undergoing IVF/ICSI treatment contributes posi-\ntively to the success of achieving pregnancy as evidenced \nby Vujkovic and associates (Vujkovic et al., 2010; Ciberia et \nal., 2021). A single-arm study conducted in Austria investi-\ngated the impact of the Mediterranean diet on pain associ-\nFigure 2. Dietary nutrition and Nutrigenetics/   \nNutrigenomics impacts on overall health.      \nated with endometriosis. A particular dietary regimen com-\nprising fresh vegetables, fruits, white meat, fatty fish, soy \nproducts, whole grain foods, magnesium-rich food sources, \nand cold-pressed oils was given to patients. The study re-\nvealed a notable alleviation in overall pain, including dys-\nmenorrhea, dyspareunia, and dyschezia, along with en-\nhancements in the general condition among participants.27 \nIn a case-control study conducted in Mexico, 82 infertile \npatients diagnosed with rASRM stages I–II endometriosis \nwere randomly divided into two groups. One group adhered \nto a normal diet, while the other followed a high-antiox-\nidant diet (HAD) for 4 months, tailored to each patient’s \nenergy requirements. Both groups demonstrated strong ad-\nAdvancing Precision Nutrition in Endometriosis Care: The Role of Nutrigenomics and Nutrigenetics\nAcademic Medicine & Surgery 3\n\nFigure 3. Nutrition and Endometriosis Risk.     \nherence, with 91.4% in the HAD group and 91.9% in the \nnormal diet group completing the study. After 2 months of \nthe intervention, the HAD group exhibited increased con-\ncentrations of vitamins (serum retinol, alpha-tocopherol, \nleukocyte, and plasma ascorbate), heightened activity of \nantioxidant enzymes (superoxide dismutase and glu-\ntathione peroxidase), and decreased levels of oxidative \nstress markers (malondialdehyde and lipid hydroperox-\nides).27. \n2.2. DAIRY PRODUCTS \nA cohort prospective study conducted by MD Nodler and \nassociates among adolescent patients in Mexican female \nsuggested that consuming dairy products, especially yogurt \nand ice cream, during adolescence might decrease the risk \nof being diagnosed with endometriosis later in life28 as \nshown in Figure 3. \nA case-control study carried out among Iranian women \nbetween 2015-2016, involving 206 women without en-\ndometriosis and 207 with confirmed endometriosis through \nlaparoscopy, revealed notable findings. The study suggested \nthat the intake of green vegetables, red meat, dairy prod-\nucts (such as milk and cheese), fresh fruit, grains, and \nlegumes lowers the risk of developing endometriosis. How-\never, the consumption of carrots, green tea, fish, eggs, and \noil did not show a significant relationship with the risk of \nendometriosis (M.D. Ashrafi et al., 2020). \nA randomized controlled study was carried out by Sesti \nand associates in patients treated with hormones and di-\netary supplements. The study demonstrated that both hor-\nmonal suppression therapy and dietary supplementation \nhave similar effectiveness in reducing non-menstrual pelvic \npain.29 \n2.3. FATS \nStudies focusing on specific nutrients did not establish a \nsignificant association between saturated fat and animal fat \nintake and the risk of developing endometriosis.8 \nLong-chain polyunsaturated fatty acids (LC-PUFA) have \npositive effects on various physiological processes such as \ngrowth, neurological development, accumulation of lean \nand fat mass, reproduction, as well as both innate and ac-\nquired immunity. Additionally, they impact the occurrence \nand severity of nearly all chronic and degenerative dis-\neases, encompassing cancer, atherosclerosis, stroke, arthri-\ntis, diabetes, osteoporosis, neurodegenerative conditions, \ninflammatory diseases, and skin disorders (Gaboon, 2011). \nIn xenograft models, dietary n-3 PUFAs effectively inhib-\nited the growth of endometrial cancer cells (zheng et al., \n2014). Omega-3 supplementation has demonstrated the \npotential to decelerate the expansion of endometrial im-\nplants, alleviate pain and inflammation, and enhance the \nquality of life for women diagnosed with stage III and IV \nendometriosis.22 \n2.4. MULTIVITAMINS AND MINERALS \nSelenium regulates the functions of numerous regulatory \nproteins involved in signal transduction, offering advan-\ntages in managing inflammatory diseases. Lowered sele-\nnium levels have been observed in both acute and chronic \ninflammatory conditions. In a study involving patients with \nendometriosis, simultaneous administration of vitamins E, \nC, selenium, and zinc showed an inverse correlation with \nthe severity of the disease. Increased disease severity was \nnoticed with reduced oral intake of antioxidant nutrients.21 \nVitamin D might contribute to both the prevention and \ntreatment of endometriosis. A meta-analysis conducted in \n2020 revealed a correlation between low levels of vitamin \nD and a higher likelihood of being diagnosed with en-\ndometriosis, as well as a greater severity of symptoms.9 \nFour human studies, four animal studies, and four in \nvitro studies were done to assess the role of Vitamin D on \nendometriosis. While in vitro and animal studies indicated \na potential regression of endometriotic implants and a re-\nduction in invasion and proliferation following vitamin D \nsupplementation, these outcomes were not mirrored in the \nfindings of the meta-analysis.30 \nIn a significant and large cohort study, the correlation \nbetween vitamin consumption (C,E,B) and the occurrence \nof endometriosis was determined. Dietary habits were eval-\nuated using a questionnaire of food frequency. Throughout \na follow-up period encompassing 735,286 persons/years, \n1,383 new cases of laparoscopically-confirmed endometrio-\nsis were identified among 70,617 women. The study con-\nfirmed an inverse relationship of vitamin C, E thiamine, and \nfolate consumption with endometriosis.31 \n2.5. PROBIOTICS \nProbiotics have been suggested as a potential strategy to \nimprove reproductive health and mitigate the risk of dis-\neases.32 Probiotic microorganisms like Lactobacillus reuteri \nand Lactobacillus Plantarum, naturally produce vitamin B \n(). They play a crucial role in endometriosis patients as vi-\ntamin B levels are often found to be lesser in the general \npopulation. Also, they enhance the effectiveness of the im-\nmune system and stimulate vitamin and mineral absorp-\ntion. Additionally, these probiotic microorganisms might \nhave the capability to generate specific enzymes such as es-\nterase, lipase, coenzymes A, Q, NAD, and NADP.21,33 \nAdvancing Precision Nutrition in Endometriosis Care: The Role of Nutrigenomics and Nutrigenetics\nAcademic Medicine & Surgery 4\n\nTable 1. Different types of dietary supplements and their role in endometriosis treatment.            \nNutrients Role References \nLong-chain \npolyunsaturated fatty acids \nHelpful in chronic and degenerative diseases e.g., skin diseases, \natherosclerosis, cancer, diabetes, osteoporosis, neurodegenerative and \ninflammatory conditions \nGaboon, 2011 \nOmega-3 supplements Enhance life quality in women diagnosed with stage III and IV \nendometriosis \nHalpern et al., 2015 \nNotable improvements in pain symptoms linked to endometriosis, \nincluding dyspareunia, dysmenorrhea, and chronic pelvic pain \nYalcin Bahat et al.21 \nZinc, Selenium Shows inverse relationship with severity of endometriosis Yalcin Bahat et al.21 \nProbiotics influence the microbial makeup of the human body Thanaboonyawat et \nal.34; Feng and \nLiu.32 \nLactobacilli Protects the vaginal environment Thanaboonyawat et \nal.34 \nLactobacillis plantarum Actively prevent the presence of sperm-agglutinating Escherichia coli \n(E. coli) bacteria \nYalcin Bahat et al.21 \nLactobacillus rhamnosus \nGR-1 and Lactobacillus \nfermentum RC-14 \nHelp sustain and reestablish a healthy vaginal microbial balance in \ncases of vaginal dysbiosis \nYang et al.35 \nVitamin D Reduces pelvic pain and endometriosis risk by increasing antioxidant \nlevels. \nBarnard et al.9 \nZinc, Magnesium, Vitamin C \nand E \nCan improve endometriosis risk as evidence from animal and human \nstudies. \nYalcin Bahat et al.21 \nCurcumin In vitro, animal, and human studies evince a decrease in endometriotic \nlesion size preventing the recurrence of disease. \nYalcin Bahat et \nal.,21; Kizilay et al.36; \nJelodar et al.37 \nNot only factors directly related to endometriosis but \nalso individual patient factors can influence the choice of \ndietary interventions beneficial for women with en-\ndometriosis. For instance, in individuals diagnosed with ir-\nritable bowel syndrome (IBS), adopting a low-FODMAP diet \nhas demonstrated efficacy in alleviating symptoms such as \nabdominal pain and bloating (Black et al., 2021). Conse-\nquently, for women dealing with both endometriosis and \nconcurrent IBS, considering a low-FODMAP diet as a pri-\nmary intervention might be advisable before exploring \nother dietary approaches (Black et al., 2021). \n2.6. DIRECT-TO-CONSUMER NUTRIGENETICS TESTING \nGenomic data holds a unique significance as it encompasses \nnot just our genetic makeup but also that of our family \nand future generations, including our children. Lately, nu-\nmerous companies have begun marketing DNA testing kits \ndirectly to consumers through the Internet to provide ge-\nnetic testing to customers without medical oversight, offer-\ning predictions about personal risks for prevalent diseases \nlike cancer, autoimmune conditions, or cardiovascular dis-\neases.38,39 Generally, “direct-to-consumer genetic testing” \nis abbreviated as DTC-GT.39 DTC-GT assesses inherited dis-\nease risks and has received recent approvals from the Food \nand Drug Administration as depicted in Figure 5.40 \nDTC-GT usually employs a technique known as SNP-\nchip genotyping, which examines specific variants across \nthe genetic code, such as particular single nucleotide poly-\nmorphisms (SNPs) or small insertions or deletions. SNP-\nFigure 4. Health benefits and limitations of (DTC-GT).       \nchip genotyping is proficient at identifying common ge-\nnetic variants. However, when it comes to detecting \nextremely rare variants, SNP chips often produce false pos-\nitives, indicating the presence of variants that are not pre-\nsent in the individual’s DNA. Another increasingly em-\nployed method in DTC genetic tests is genome sequencing, \nwhich scrutinizes nearly the entire genetic code to identify \nits variants.41 The Food and Drug Administration (FDA), \nMedicare Centers, and Medicaid Services (CMS) offer some \nregulation of DTC-GT, but most genetic tests lack compre-\nhensive federal oversight. Figure 4 shows the health-related \ninformation/benefits and limitations of DTC-GT. \nAdvancing Precision Nutrition in Endometriosis Care: The Role of Nutrigenomics and Nutrigenetics\nAcademic Medicine & Surgery 5\n\nA study conducted by McGuire and associates among \n1087 social networkers for their interest in personal \ngenome testing (PGT) reported that about 6% of networkers \nhave used PGT, 64% have an interest in its use, and 30% \nhave no interest in attaining knowledge about diseases in \ntheir family.42 \nIt is remarkable to observe an increasing number of pa-\ntients feeling empowered to make decisions regarding their \nreproductive choices and seeking support to achieve their \nfamily-building goals because of DTC testing. It was noticed \nthat some individuals have already chosen a particular \ntreatment, such as oocyte or embryo cryopreservation or \nIVF, relying on the interpretation of DTC results.43 Thus, \nDTC testing could be an efficient approach to the diagnosis \nand treatment of endometriosis and related disorders. \nAs the demand for reproductive medicine rises and we \ngrapple with a flood of misinformation from various media \nand online sources concerning fertility and reproductive \nhealth, it is crucial to ensure ethical and prudent practice of \nassisted reproductive technologies. Hence, we must receive \neducation regarding the drawbacks of DTC testing, enabling \nus to offer optimal guidance and support to our patients on \ntheir reproductive journeys. \n2.7. ARTIFICIAL INTELLIGENCE IN NUTRIGENETICS AND \nNUTRIGENOMICS \nExperts anticipate that artificial intelligence (AI), deep and \nmachine learning (ML) holds promise for diagnosing, man-\naging, and treating an extensive range of medical condi-\ntions.44 The most prevalent application of classical ma-\nchine learning in healthcare is precision medicine, which \nforecasts the treatment procedures most likely to be effec-\ntive for a patient by considering various patient character-\nistics and the context of the therapy (Kharb and Joshi). Few \nAI or machine learning applications aimed at enhancing \nwomen’s health are currently in clinical practice, especially \nduring pregnancy.45 Leveraging a digital twin alongside AI \nprovides the chance to create tailored and highly accurate \nrecommendations that align with the patient’s real-world \ncircumstances. These recommendations can empower clin-\nicians to make more precise, personalized, and effective de-\ncisions.44,46,47 \nDavidson and associates conducted a study on novel \nmethods e.g., artificial intelligence (AI), deep learning, and \nmachine learning (ML) to improve pregnancy outcomes. \nAmong 129 studies the prominent areas within the realm of \npregnancy where AI and ML methods have seen extensive \nuse comprise prenatal care, involving aspects such as fetal \nanomalies and placental functioning (73 instances); peri-\nnatal care, encompassing birth and delivery (20 instances); \nand addressing preterm birth (13 instances). Initiatives \naimed at applying AI to clinical practice involve the devel-\nopment of clinical decision support systems (24 instances) \nand the creation of mobile health applications (9 in-\nstances).48 \nLIMITATIONS \nThe major limitation is the integration of AI/ML into rou-\ntine clinical practice, particularly concerning the regulation \nof these technologies.44 \n3. PRECISION/PERSONALIZED NUTRITION \nThe ultimate objective of precision nutrition (PN) is to cre-\nate personalized nutritional recommendations or prevent \nmetabolic disorders by considering a blend of an individual \ngenetic makeup, environmental influences, and lifestyle \nfactors.49‑51. To achieve this objective, as depicted in the \nprecision nutrition plate (Figure 4), factors extending be-\nyond nutritional or genetic aspects-such as lifestyle choices \nlike metabolomics, physical activity (PA) patterns, or gut \nmicrobiomics are increasingly recognized as substantial in-\nfluencers deserving attention within the realm of precision \nnutrition.50 The microbiota plays a crucial role in various \nbiological functions of the host, including the development \nof the immune system, protection from harmful microor-\nganisms, food breakdown during digestion, and production \nof micronutrients and bioactive compounds. Tailored inter-\nvention strategies could be formulated to “rebalance” an \nimbalanced microbiota or enhance the reaction to a par-\nticular diet. Probiotics, prebiotics, synthetic stools, and fe-\ncal transplantation have shown effectiveness in reducing \nweight in experimental obesity models, indicating the need \nfor additional studies on human subjects.52 For an ideal as-\nsessment of the type, quantity, and frequency of food in-\ntake, real-time monitoring would be preferable over meth-\nods such as 24-hour dietary recalls or short-term \nmeasurements of food consumption. Table-embedded \nscales, automatic ingestion monitors with sensors, hand \ngestures, accelerometers, smartphone camera apps em-\nploying deep learning algorithms, and tooth-mounted sen-\nsors capable of recording various nutrients are devices de-\nsigned to offer a more precise method for tracking and \nadjusting food consumption compared to dietary re-\ncalls.52‑55 \nImproving the translation of PN (Precision Nutrition) \nscience into products and services can be optimized by \nevaluating the equilibrium between advantages and draw-\nbacks for both consumers and patients. Benefits encompass \npotential enhancements in specific health outcomes, the \nease of utilizing user-friendly digital tools, and the effec-\ntiveness of a more tailored approach. Conversely, risks may \nstem from the expensive nature of recurrent omic testing, \nthe time commitment required by intricate programs, and \ndiscrepancies between the scientific foundation and prod-\nuct assertions. These risks also involve apprehensions re-\nlated to trust, privacy, and the management of data.56 Fig-\nure 5 represents the precision nutrition plate where \nmultifaceted aspects involved in tailoring personalized nu-\ntrition is summarized. \nAs per the Nutrigenetics/Nutrigenomics International \nSociety (ISNN) three key dimensions should be addressed \nfor the future direction of precision nutrition57: \nAdvancing Precision Nutrition in Endometriosis Care: The Role of Nutrigenomics and Nutrigenetics\nAcademic Medicine & Surgery 6\n\nFigure 5. Precision Nutrition Plate represents the      \nmultifaceted aspects involved in tailoring personalized       \nnutrition. Reproduced from an open-access journal       \nunder the term of Creative Commons Attributions.      50  \nDOI: 10.3390/nu9080913.   \nIn extensive studies, self-administered Food Frequency \nQuestionnaires (FFQs) are typically favored for assessing \nfood intake. However, all these methods demand thorough \npreparation before implementation, thus utilization of \nhigh-throughput omics tools facilitates a comprehensive \nand integrated exploration of nutrition.58 \n3.1. MULTI-OMICS TECHNOLOGY \n“Omics” encompasses scientific disciplines focused on \nhigh-throughput measurements of biological molecules, \nincluding DNA, RNA, proteins, and metabolites.59 Several \n-omics technologies have been utilized in analyzing mater-\nnal urine and blood for pregnancy monitoring to identify \npotential diagnostic markers. However, these markers have \nnot yet been integrated into clinical protocols. For example, \nthe plasma concentration of ADAM-12 (A Disintegrin and \nMetalloproteinase-12) has exhibited changes in various \npregnancy-related disorders. However, the effectiveness of \nADAM-12 as a reliable marker for adverse outcomes re-\nmains uncertain.59 \nPresently, many omics technologies offer comprehensive \nreadouts at singular levels such as genomic, epigenomic, \ntranscriptomic, proteomic, or metabolomic. Multi-omics, \non the other hand, involves integrating two or more omics \ndatasets for comprehensive data analysis, visualization, \nand interpretation. This approach aims to grasp the un-\nderlying biological mechanisms in various disease states. \nAs multi-omics technologies advance, extensive genomic \ndata, even at the single-cell level, is increasingly accessible \n(Atherine et al., 2022). \nFunctional genomic data, when combined with other \nomics data such as proteomics and metabolomics, provides \na more comprehensive understanding of endometriosis. \nThis integrated approach helps identify essential pathways \nand molecular signatures associated with the condition, \noffering potential benefits in diagnosis and the design of \ntargeted therapies. CA-125, miRNA-200 family, miR-200b, \nHE4 (Human Epididymis Protein 4), and Circulating cell-\nfree DNA are some key genetics and epigenetics biomarkers \nin endometriosis that affect the disease progression.60 \n3.2. DIGITAL/ VIRTUAL TWIN TECHNOLOGY \nIn recent years, there has been an increasing demand for \nprecise disease diagnosis and personalized treatment. The \nhealthcare system is striving to tailor treatments to indi-\nvidual patients, aiming to maximize both effectiveness and \nefficiency.61 Digital twin technology is rapidly emerging as \na game-changer in healthcare systems, fundamentally al-\ntering the delivery of patient care.62 Digital twins serve as a \ntool for patients to take an active role in their healthcare.63 \nAlso, digital twins have been employed in the industry since \n2002 to enhance manufacturing processes and manage the \nentire product life cycle more effectively.64 Through real-\ntime monitoring of vital signs, physiological parameters, \nand other health-related data, digital twins possess the ca-\npability to detect early signs of deterioration or anomalies. \nThis proactive identification allows healthcare providers to \nintervene early, preventing complications and fine-tuning \ntreatment plans for optimal efficacy. Furthermore, digital \ntwins foster communication and collaboration between pa-\ntients and healthcare providers, fostering shared decision-\nmaking and a patient-centered approach to care. \nThe concept of a “virtual digital twin” aims to offer the \nmost suitable, adaptable, efficient, and cost-effective di-\netary and lifestyle recommendations to an individual based \non lifelong model and AI-driven models.46,52,65 \nMoztarzadeh and associates introduce machine learning \n(ML)-driven methodologies for digitally replicating cancer, \nacknowledging certain constraints. The proposed methods \nencompass Decision Tree Regression (DTR), ML Linear Re-\ngression (ML LR), Gradient Boosting Algorithm (GBA), and \nRandom Forest Regression (RFR). These technologies en-\nable the system to process extensive patient data, con-\nstructing precise cancer progression models while effec-\ntively distinguishing between affected and healthy \nindividuals. Leveraging a credible dataset, numerous ma-\nchine-learning techniques have been created and simulated \nfor breast cancer to illustrate the simplicity and feasibility \nof digital twin technology. This approach facilitates the \nsimulation of cancer diagnosis and progression, providing \ninsights into its future behavior. Such insights are invalu-\nable in devising novel treatments, anticipating potential \ncomplications, and proactively addressing them.65 \nA randomized controlled trial was conducted by Merlot \nand associates to assess the immediate and lasting effects, \nup to 4 hours, of a single 20-minute use of a digital thera-\npeutic (DTx - Endocare) on pain levels in women enduring \npelvic pain associated with endometriosis. Following treat-\nment, both the Endocare and control groups exhibited a \n1. Refining conventional nutritional guidelines by seg-\nmenting them into population subgroups based on \nfactors like gender, age, and social determinants. \n2. Implementing individualized techniques derived \nfrom detailed and comprehensive phenotyping. \n3. Integrating genetic-informed nutrition strategies \nthat focus on rare genetic variations \nAdvancing Precision Nutrition in Endometriosis Care: The Role of Nutrigenomics and Nutrigenetics\nAcademic Medicine & Surgery 7\n\nsignificant reduction in clustered post-treatment pain com-\npared to pre-treatment levels. Endocare consistently and \nsignificantly decreased pain perception up to 4 hours post-\ntreatment, whereas the control group did not show signif-\nicant differences. The mean perceived pain relief was no-\ntably higher for Endocare at 28% compared to the control \ngroup across all post-treatment assessments.66 \nMAJOR CHALLENGES \n(i) The data gathered and employed in crafting digital twins \nare presumed to be accurate and devoid of contradictions. \nHowever, one prevalent concern regarding data accuracy re-\nvolves around completeness, as incomplete data might in-\ntroduce bias in predictions when utilized in the digital twin \nframework. (ii) Patient preferences often grapple with the \nbalance between the quantity and quality of life. In certain \nscenarios, extended survival might coincide with a decline \nin the quality of life. Some patients prioritize a high quality \nof life even if it means acknowledging the potential short-\nening of their lifespan. (iii) A blending of real-world evi-\ndence and results sourced from randomized clinical trials. \n(iv) In healthcare, safeguarding data privacy and protec-\ntion remains a critical concern, despite employing various \nforms of data encryption to manage data transfers.46 Sci-\nentists are creating diets that might enhance how patients \nrespond to cancer treatment by utilizing machine learning \nand genotyping to reveal the nutritional weaknesses of tu-\nmors thus paving new pathways for the treatment of dis-\nease using digital/ artificial technology.67 \n4. PROSPECTS, CHALLENGES AND CONCLUSION \nEndometriosis continues to be a substantial source of mor-\nbidity, significantly impacting the quality of life for women \nin their reproductive years.68 Studies concluded a connec-\ntion between genetic variations and endometriosis. How-\never, the specific molecular pathways through which these \nvariations impact disease onset and progression remain un-\nclear.60 \nThe integration of nutritionists into these teams might \nplay a significant role in preventive and therapeutic out-\ncomes in the future, contributing to the fight against en-\ndometriosis. Food and nutrients can impact both the de-\nvelopment and advancement of the disease, opening the \npossibility of alternative or supplementary treatments for \nindividuals affected by endometriosis. Further investiga-\ntion is necessary to unravel the mechanisms of Nutritional \ngenomics in improving the diagnosis of endometriosis. It \nis fundamental to design cost-effective interventional and \nclinical studies for PN, nutritional genomics, and AI/ML. \nMoreover, to attain the trust of policymakers and health \nprofessionals it is mandatory to design regulatory embod-\nies.58 \nA prominent limitation of Precision Nutrition (PN) is \nthat most studies are observational rather than stemming \nfrom randomized controlled trials (RCTs) with evaluated \nclinical endpoints. Moreover, there is uncertainty about \nwhether PN strategies can lead to improved endometrio-\nsis.58 \nThis review delves into various dietary supplements, nu-\ntritional genomics, and their influence on endometriosis \nand associated symptoms. Additionally, it elaborates on \nprecision/personalized nutrition and the application of dig-\nital/virtual technology in addressing the progression of the \ndisease. Furthermore, it explores the effects of direct-to-\nconsumer genetic testing and the role of artificial intelli-\ngence in the nutrigenetics and nutrigenomics approach to \nmanaging endometriosis. Besides, more clinical approaches \nand research are needed to establish the accuracy and effi-\ncacy of this approach. Moreover, a nutritional approach to \nendometriosis management could be helpful for poor surgi-\ncal candidates. As all are not easy to handle and operative \nprocedure, nutritional approach can be a good alternative. \nSubmitted: September 03, 2024 EDT, Accepted: October 14, \n2024 EDT \nThis is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License \n(CCBY-4.0). View this license’s legal deed at http://creativecommons.org/licenses/by/4.0 and legal code at http://creativecom-\nmons.org/licenses/by/4.0/legalcode for more information. \nAdvancing Precision Nutrition in Endometriosis Care: The Role of Nutrigenomics and Nutrigenetics\nAcademic Medicine & Surgery 8\n\nREFERENCES \n1. Becker K, Heinemann K, Imthurn B, et al. Real \nworld data on symptomology and diagnostic \napproaches of 27,840 women living with \nendometriosis. Sci Rep. 2021;11(1):20404. \ndoi:10.1038/s41598-021-99681-3 \n2. Zondervan KT, Becker CM, Koga K, et al. \nEndometriosis. Nat Rev Dis Primers. 2018;4:9. \ndoi:10.1038/s41572-018-0008-5 \n3. Horne AW, Missmer SA. Pathophysiology, \ndiagnosis, and management of endometriosis. BMJ. \n2022;379:e070750. doi:10.1136/bmj-2022-070750 \n4. Gallagher CS, Mäkinen N, Harris HR, et al. \nGenome-wide association and epidemiological \nanalyses reveal common genetic origins between \nuterine leiomyomata and endometriosis. 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