Foundational research demonstrates that spirituality may affect the way people with cancer experience pain. One potential route is through alterations in thoughts and beliefs, such as pain-related catastrophizing. The purpose of this study is to understand whether spirituality impacts pain experiences through pain-related catastrophizing.This explanatory sequential mixed methods study was informed by an adapted Theory of Unpleasant Symptoms. Data were collected via online surveys (N = 79) and follow-up qualitative interviews (N = 25). Phase 1 employed Empirical Bayesian analysis. Phase 2 used deductive content analysis. Phase 3 involved creating a mixed methods joint display to integrate findings and draw meta inferences.Results indicate that spirituality was directly negatively associated with pain-related catastrophizing, and indirectly negatively associated with the outcomes of pain interference, pain severity, and pain-related distress. Qualitative categories highlight the supportive role of spirituality when facing pain, while also shedding light on the limitations of spirituality in the context of some pain . Mixed methods findings reveal the importance of spirituality for some people as they face cancer and cancer-related pain, as well as the need for integrating spirituality as part of a larger pain management plan.This research advances supportive cancer care by exploring the complex role of spirituality in pain experiences. Findings will inform further exploration into the role of spirituality in supporting holistic symptom management in the context of cancer, as well as developing and testing interventions to enhance spirituality and address symptom-related suffering. Spirituality may be an important source of support when patients are faced with a life-threatening illness such as cancer . “SpiritPain-related catastrophizing includes negative cognitions and beliefs related to pain   and can We aimed to understand the role of spirituality and pain-related catastrophizing in experiences of pain  among adults with cancer. More specifically, we sought to 1) quantitatively examine relationships between spirituality and pain outcomes while testing the mediating role of pain-related catastrophizing, 2) qualitatively explore how spirituality and pain-related catastrophizing contribute to pain experiences, and 3) integrate and interpret quantitative and qualitative data to draw meta-inferences about the role of spirituality and pain-related catastrophizing.This explanatory sequential mixed methods study involved a quantitative phase, a qualitative phase, and a mixed methods phase. Phase 1 included a descriptive correlational analysis of quantitative cross-sectional survey data; phase 2 consisted of semi-structured qualitative interviews with deductive content analysis; and mixed methods data interpretation. Mixed methods integration was achieved in three main ways: 1) connecting ; 2) creAn adaptation of the Theory of Unpleasant Symptoms  informedParticipants were recruited though a local cancer clinic using mailings, phone calls, and in-person recruitment. Eligible participants were age ≥ 18 years, diagnosed with any type or stage of cancer, currently receiving disease-directed cancer treatment, reporting average pain intensity > 0 on a 0–10 scale in the past 7 days, and able to communicate in English. Exclusion criteria included any diagnosed mental illness or cognitive impairment that precluded ethical and safe participation in study procedures.Phase 1 involved sampling to enroll participants with various levels of pain . UsingIn Phase 1, study instruments were primarily completed via Qualtrics. For participants with technology limitations, paper surveys were provided. The following data were collected.Standard demographic and clinical characteristics were assessed to characterize the sample, including age, sex, gender, race, ethnicity, education, marital status, comorbidities, type and stage of cancer.To assess pain intensity and interference, the Brief Pain Inventory–Short Form (BPI–SF) was used . The BPISpirituality, operationalized as spiritual well-being, was assessed using the Functional Assessment of Chronic Illness Therapy–Spiritual Well-Being scale . This inPain-related catastrophizing was assessed using the Pain Catastrophizing Scale . This inA standardized questionnaire was used to elicit information about use of common medications which could influence the experience of pain.In Phase 2, semi-structured qualitative interviews were conducted. Interview guides were designed to elicit in-depth accounts of participants’ lived experiences with pain, spirituality, and pain-related beliefs and feelings . The PI (M.M.) conducted all interviews, primarily through secure Zoom calls, with options for interviewing in-person and via telephone, as needed. Interviews lasted approximately 60 minutes, and were recorded, de-identified, and transcribed.In Phase 1, data analysis was conducted in SPSS version 27 and Mplus Version 8.10. Descriptive statistics were generated for sample demographics and key variables. A test of joint significance  was emplspirituality, pain-related catastrophizing, pain outcomes, and relationships between these concepts) and was used to initially populate the categorization matrix. Engaging with an unconstrained categorization matrix allowed for nuanced findings to emerge from the data, expanding upon the initial matrix. Individual coding team members read each transcript multiple times to ensure a thorough understanding of content. The team then developed the unconstrained categorization matrix and re-examined each transcript line by line, coding data according to categories and subcategories (adding to the matrix as necessary), then organizing findings into meaningful statements exemplified by representative quotes. Maintaining analytic memos, collaborative analysis, and regular consensus-building meetings enhanced trustworthiness and rigor [In Phase 2, data were analyzed with deductive content analysis using standard procedures and an unconstrained categorization matrix  . An adapnd rigor .Phase 3 involved connection, integration and interpretation of mixed methods data through the creation of a novel joint display , 18. TheThe University of Wisconsin-Madison Institutional Review Board reviewed and approved study procedures before beginning (protocol #2021 – 0143). A detailed informed consent form was included at the start of the study survey, with options to consent and proceed, or to decline and end the survey. For completion of Phase 1, participants received $10 in compensation via a gift card. Those who completed Phase 2 received an additional $20 in compensation, also via a gift card. A team member was available to answer questions about the study during the consent process. Participants were assured they could end participation at any time with no adverse consequences to care received.Data were included from N = 77 quantitative surveys and N = 25 qualitative interviews. A study flow diagram is presented in EB analysis results  indicateThree discrete yet interconnected categories and nine sub-categories were identified in the qualitative analysis. These further clarify how spiritual well-being and pain-related catastrophizing contributed to experiences of pain. Categories and sub-categories are presented below. Category 1) Pain-related catastrophizing is a pervasive phenomenon, often marked by: a) Spirals of mental stress and fear related to pain, b) Anger and frustration with pain and its impacts on quality of life, and c) Hopelessness in the face of pain. This category illustrates the complex and pervasive role of pain-related catastrophizing in the lives of many participants who are facing pain. Findings reveal the interwoven, reciprocal experiences of catastrophizing and pain. Participants described their experiences with pain “spirals”, as well as the “mental anguish” they found hard to disentangle from the painful experience itself, bringing enhanced complexity to the understanding of suffering associated with cancer pain.Category 2) Spirituality can help patients transcend pain-related catastrophizing through: a) Inspiring faith and trust serving as motivation to continue amidst suffering, b) Helping provide meaning and a wider perspective around pain, and c) Offering emotional comfort through supportive beliefs and practices. Spirituality was found to provide a framework for interpreting and making meaning around experiences of pain. Participants described how their spirituality motivated and inspired them to keep caring for themselves despite their suffering. Engaging with spirituality also helped some participants hold a broader perspective around their pain experiences, often leading to intentionally focusing on gratitude amid pain and the ability to hold a “both/and” perspective . Spiritual beliefs and practices helped participants self-regulate and access feelings of calm when facing pain and the stress that comes with it. Overall, many participants described routes by which spirituality acted as an antidote to pain-related catastrophizing and altered the way they could relate to their pain experiences.Category 3) Spirituality has real limitations in the context of certain pain experiences, such as when pain is: a) Chronic, b) Neuropathic, and/or c) Especially intense/severe. It is especially relevant to note that some participants communicated the limitations they experienced when exploring how spirituality might impact their pain. For example, various participants were facing neuropathic pain and described how nothing else could be done to help. While spirituality may be supportive in some contexts, limitations must be recognized.A joint display was created  illustraThis mixed methods study highlights the supportive role of spirituality for some people with cancer pain. Findings align with professional recommendations stating the necessity of incorporating spirituality as part of serious illness care , 15. QuaFindings that spiritual well-being was directly negatively associated with pain-related catastrophizing, and was indirectly negatively associated with the selected pain outcomes , support hypothesized relationships identified through the theoretical framework .Findings extend previous work on the relationship between spirituality and pain, which have yielded mixed results. For example, a prior secondary analysis of spirituality and pain among women with breast cancer receiving foot reflexology found no significant relationship . HoweverWhile the relationship between spirituality and pain-related catastrophizing has not yet been explored among people with cancer, one recent study reported a significant relationship between faith and positive expectations  among people with cancer . Given tPrior qualitative studies have shown that spirituality is centrally important to many people when facing cancer , 28. SpiMixed methods findings centered on the importance of spirituality for some participants as they faced cancer and cancer-related pain, as well as the need for integrating spirituality as part of a larger pain management plan. Though spirituality can effectively reduce cancer pain , researcRecent research has revealed associations between engagement with spiritual care and less aggressive care at the end of life, more time between final treatment and death, and increased use of hospice services . These oEvidence-based spiritual screening tools have been developed for use in practice , and theFinally, most people with cancer experience more than one symptom , supportDespite the rigorous mixed methods approach, several limitations were identified. First, given the nature of cross-sectional data collection, this is an exploration of potential relationships, and is not able to prove causality. Additionally, many participants who had severe pain declined to participate in one or both phases, citing reasons such as being too busy or too sick. While the research team made conscious and earnest efforts to engage with a more diverse group of patients, the sample did not include any gender non-conforming individuals and does not represent the larger population in terms of race and ethnicity. Given that interviews and surveys were conducted in English, findings also do not represent those who speak other languages. The lack of diverse voices in this study, accompanied by the fact the research team only recruited the people most open to discussing their pain and spirituality, could have limited the inclusion of other relevant perspectives. Also, the overall small sample size made quantitative modeling challenging. Therefore, findings are limited in terms of generalizability and translatability. Finally, of participants who completed both the survey and the interview, some informally reported changes in their cancer treatments, pain experiences, and spirituality between Phases 1 and 2, which should be taken into consideration in the context of this mixed methods study.Given the need for holistic support in the management of pain among people with cancer, additional exploration into the role of spirituality is warranted. While spirituality can be unique to each person, aspects of connection and meaning can be relevant in the lives of patients across contexts. Findings from this mixed methods study support the idea that consciously engaging with spirituality can serve as a sustaining resource amidst challenges such as cancer, pain-related catastrophizing, and pain.


The evidence available to date suggests that copayment reductions/waivers provided to commercially insured populations, especially when applied in primary prevention and/or to brand drugs in therapy classes with generic alternatives, are unlikely to yield meaningful health improvements and may direct scarce resources away from financing therapy areas in which patients have no generic alternatives, such as biopharmaceuticals. The slow uptake of copayment reduction/waiver strategies among private payers is appropriate. Although Post-MI FREEE certainly represented a major step forward in a research field littered with studies that are weakly designed and/or nontransparently reported, its results suggest the need for continued caution in VBID adoption. The Post-MI FREEE trial report differed in important ways from the a priori analysis plan, and observed effect sizes were small. Until utilization analyses are reported, the Post-MI FREEE results have limited applicability to MCO costs, and even when fully reported, the Post-MI FREEE results should not be applied to primary prevention.


To determine whether menopause elevates the risk for developing diagnostic depression and anxiety. Menopause-associated vasomotor symptoms such as insomnia and hot flushes are well recognized, but no systematic review of the psychological consequences of menopause has been undertaken. Menopause can be a time of social change for women, confounding any correlation.Using PRISMA methodology, we conducted a systematic review of all published (in English) original data examining a relationship between menopause and depression and anxiety. We ranked the quality of all included studies using Grading of Recommendations, Assessment, Development and Evaluation (GRADE) criteria.Twenty-two selected studies were summarized and compared, being eight cross-sectional surveys; one retrospective cohort, and 13 prospective cohort studies. Depression and anxiety are common during menopause and the post-menopause, with vasomotor symptoms and a prior history of major depression elevating risk of menopausal associated depression. Psychosocial factors also may increase risk of depression during menopause.Menopause increases vulnerability to depression and anxiety, perhaps via estrogen fluctuations affecting serotonin and GABA. Underlying neuroticism and contemporaneous adverse life events are also risk factors for menopausal decompensation with depression. Most women reach menopause at an average age of 51–52 years.Menopause, or  Psychological symptoms include mood dyregulation, loss of libido, anxiety, irritability, sleeping difficulties, forgetfulness, and trouble concentrating or making decisions.Menopause occurs in three stages: perimenopause, menopause, and the post-menopause. A woman is “post-menopausal” after 12 months of no menstrual cycle or period.Perhaps surprisingly, no review of whether menopause elevates the risk of developing major depression and/or anxiety has previously been undertaken.We conducted a systematic review to determine the influence of the menopausal transition on mood and anxiety and provide guidance on the associated risks for menopause-related anxiety and depression.This systematic review is registered with PROSPERO (CRD 4202233498). The literature search was performed according to the PRISMA guidelines for systematic reviews. Two reviewers independently searched databases including PubMed, Cochrane library, Medline, Embase, PsychINFO, AMED, and Elsevier science from the earliest record to 10 December 2021.The following terms were used: “depression,” “depressive disorder,” “anxiety,” “mood disorder,” “menopause,” and “menopausal transition.” In addition, cross-references in the included studies were hand-searched to identify additional eligible original studies.Articles were selected based on a priori inclusion and exclusion criteria. A study was considered eligible if it included original data on women undergoing menopausal transition, with a clearly described measure of depression or an anxiety disorder.Studies that did not evaluate women’s mental state during menopause or enrolled fewer than 100 participants and did not assess the association between menopause and mental health were excluded from the study. Non-English language studies and opinion pieces or reviews were also excluded .Figure 1All eligible studies were independently reviewed by two authors and the studies that satisfied the inclusion criteria were summarized into a standardized table. Every included study was independently rated for quality, using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) criteria.7 and two cross-sectional surveys,9 found a significant association between the menopausal transition and depression and/or anxiety. Five other studies didn’t  but not for de novo MDD, relative to pre-menopause status. Being peri-menopausal compared to pre-menopausal more than doubled the risk of depression during follow-up.The Study of Women’s Health Across the Nation noted a four-fold increase in depression in women with no history of depression during their menopausal transition compared to their pre-menopausal status. Moreover, a diagnosis of MDD was more than twice likely to occur in women with no history of pre-menopausal depression.The Penn Ovarian Aging Study that being peri-menopausal was associated with a significantly increased risk of depressive symptoms relative to pre-menopause. Furthermore, being peri-menopausal was associated with an increased risk of depression and anxiety in women without history of probable depressive or anxiety disorder.The PATH project revealed found that pre-menopausal women with no lifetime history of MDD were nearly twice as likely to develop peri-menopausal depressive symptoms compared to women with no history of depression. The Melbourne women’s midlife health project (MWMHP) also found that women in the menopausal transition and early post-menopausal phase were at higher risk of depressive symptoms and low mood than the late post-menopause.The Harvard study showed that psychological symptoms were significantly elevated in peri-menopausal women compared to matched pre-menopausal women. Almeida et al. reported that reproductive status did not affect the prevalence of MDD, but when contrasted with pre-menopause, the peri-menopausal phase was associated with an elevated risk of developing depressive symptoms.Pimenta et al. from Italy showed that depressive symptoms were significantly higher in the post-menopausal compared to the pre-menopausal women.Five out of the twenty-two studies found a significant increased prevalence of depression and anxiety in post-menopausal women. A cross-sectional survey reported that significantly more post-menopausal than pre-menopausal women had depressive symptoms, and the PATH project revealed that being post-menopausal was associated with increased risk of anxiety symptoms compared to pre-menopause.Almeida et al. noted adverse psychological symptoms were significantly elevated in post-menopausal women compared to their pre-menopausal counterparts.Pimenta et al. being post-menopausal elevated the risk four-fold for major depressive relapse but did not significantly elevate risk for new MDD.In the Study of Women’s Health Across the Nation, documented that in women who reached menopause, symptoms of anxiety and depression decreased in the years after the final menstrual period or hysterectomy.By contrast, Gibson et al.20Biological risk factors have been shown in eleven studies here to play a role in the onset of depression and/or anxiety in the different menopausal stages. These biological factors include the vasomotor symptoms (VMS) of menopause, unrelated chronic medical diseases, and a history of premenstrual syndrome. Seven studies reported that depression and anxiety were strongly associated with VMS and related poor sleep. from New Jersey, USA, suggested that depressed women had more difficulty coping with the symptoms and physical changes of menopausal transition, and that those who experience more severe menopausal symptoms were more likely to have depressive symptoms during the menopausal transition.A prospective longitudinal study noted a significant relationship between depression and anxiety, and the presence of hot flushes (part of VMS) in both peri- and post-menopausal women. This association remained significant even after educational status and insomnia were controlled for.Juang et al.10 Having at least one chronic medical condition prior to study entry more than doubled the risk of depression. Impaired role functioning because of physical health problems increased the risk of developing depression by 88%.Chronic medical diseases and a decrease in physical health have also been associated with mood symptoms during menopause.22 a history of postpartum depression, and an adverse perception of menopause. A past history of depression or anxiety was also a significant predictor of the onset of depressive symptoms during the menopausal stages. Women with a history of depression or anxiety were more prone to develop mood symptoms during menopause.22 A history of anxiety also increased the risk of development of depressive symptoms during menopause.9Psychological factors that played a role in the onset of new mood disorder in menopause include a past history of depression and anxiety, demonstrated that neuroticism  at age 30 significantly predicted increased prevalence of major depression and anxiety disorders during menopause. Chou et al. demonstrated that regardless of age, neuroticism was found to be significantly associated with depressive symptoms during the menopause transition.The prospective long-term Zurich study23 These stressful life events included decreased sexual activity; and children failing to enter college or get a job.13 Anxiety and depression were also more severe in post-menopausal women from rural or low socio-economic areas.Numerous studies have demonstrated the relationship between social factors and mood disorders during menopause, such as age, stressful life events, marital status, low socio-economic or financial status, and lack of family or social support.This review revealed that during the menopausal transition, symptoms of anxiety and depression are common. We have ranked the main risk factors for depression and anxiety during menopause, as well as any protective factors in the table below.One of the biggest single risk factors for menopausal associated depression was a previous history of depressive illness, that is, a relapse of pre-existing depression. Vasomotor symptoms such as insomnia and hot flushes were highly correlated with both new incident depression and anxiety, and a relapse of prior depressive illness.Both contemporaneous adverse social factors or life events and an underlying predisposition to depression and anxiety (neuroticism) were also found to elevate the risk of developing depression during menopause.25 However, one study we included noted a decline in anxiety and depressive symptoms during the post-menopausal stage after bilateral oophorectomy .It has been suggested that changes in hormonal levels during the menopausal transition might influence the brain via hypothalamic and hippocampal function. Steroid hormones affect serotonin and GABA signaling, which along with fluctuating neuronal opioids during menopause have been associated with depression, irritability, and anxiety. Reduced estrogen levels and sleep disturbance are also similarly seen during post-natal depression.Menopausal vasomotor symptoms including hot flushes and sleep disturbance were found in this review to be associated with depression and anxiety during menopause, although the underlying mechanism remains unclear. Hot flushes are thought to occur as a result of the dysregulation in the thermoregulatory center in the hypothalamus, which happens during ovarian failure and estrogen withdrawal. These hot flushes are associated with sleep disturbance and can adversely affect mood.Compared to women with no previous depressive disorder, increased variability of follicle-stimulating hormone (FSH) and estrogen, and decreased levels of inhibin B and increased levels of luteinizing hormone are linked to depression in women with a previous history of depressive disorder. predicts depression during menopause. People with elevated neuroticism can find minor frustrations overwhelming. Furthermore, a negative perception towards menopause seems to play a significant role in predicting depression and anxiety during menopause. Stressful life events during menopause, such as illness, marital discord, and children leaving home or failing to enter college or getting a job, are all associated with depression and anxiety during menopause.Neuroticism, a trait disposition to experiencing negativity,Some of the included studies did not assess the presence of a past psychiatric history in women during menopause, which we found to be a major risk factor. Also, numerous studies had little or no data on anxiety during menopausal transition. Finally, almost all the cross-sectional studies assessed mood through self-report surveys or questionnaires, leading to potential bias or misattribution, and highlights concerns about the consistent diagnostic validity for major depressive disorder.The selected articles had a wide range of study methods, including cohort studies of several years’ duration originating from many countries, and included studies examined the influence of diverse biopsychosocial factors. Stringent inclusion and exclusion criteria and a quality ranking allowed focus on the highest quality data.Both the direct steroid hormone level fluctuations during menopausal transition and biopsychosocial factors during menopause are important in menopause-associated depression.There is less data on menopausal-incident anxiety, but we cautiously suggest an evidence-based link between VMS, sleep disturbances, and anxiety associated with menopause.Early screening and clinical intervention using the risks identified here could reduce the possibility of developing depressive symptoms during menopause.In conclusion, there is a “window of vulnerability” for depression and anxiety during the menopause.


Dynamic heterogeneity in lung ventilation is an important measure of pulmonary function and may be characteristic of early pulmonary disease. While standard indices like spirometry, body plethysmography, and blood gases have been utilized to assess lung function, they do not provide adequate information on regional ventilatory distribution nor function assessments of ventilation during the respiratory cycle. Emerging technologies such as xenon CT, volumetric CT, functional MRI and X-ray velocimetry can assess regional ventilation using non-invasive radiographic methods that may complement current methods of assessing lung function. As a supplement to current modalities of pulmonary function assessment, functional lung imaging has the potential to identify respiratory disease phenotypes with distinct natural histories. Moreover, these novel technologies may offer an optimal strategy to evaluate the effectiveness of novel therapies and therapies targeting localized small airways disease in preclinical and clinical research. In this review, we aim to discuss the features of functional lung imaging, as well as its potential application and limitations to adoption in research. Several pulmonary diseases can affect the lungs non-uniformly, particularly in the early stages of disease –5. This Spirometry, the most common test of lung function, often done with body plethysmography, quantifies global airflow and lung volumes, but is limited in detection of specific regional deficiencies –9. AlterXenon is an inert, noble gas that has been used as an inhalation contrast agent for functional lung imaging. Xenon-133 is advantageous because of its similar x-ray absorption characteristics as iodine, making it a useful inhalation contrast agent . AdditioXenon computed tomography was introduced in the 1980s as a functional imaging tool for measuring regional pulmonary ventilation. This imaging modality involves a wash-in phase, where the subject inhales a xenon and oxygen gas mixture over a short period of time. This is followed by a period of inhaling a high oxygen concentration while the radioisotope is exhaled or systemically absorbed, termed the washout phase. Xe CT scans can capture either at the beginning and end of the wash-in phase under a single-breath (static), or periodically over the course of multiple breaths throughout the wash-in and out phases (dynamic). Images are subsequently processed into a three-dimensional distribution map whereby areas of poor ventilation can be qualitatively and quantitatively assessed. Many variations of this procedure exist, and studies continue to optimize gas mixture concentrations and the timing of the wash-in and washout phases to better visualize regional ventilation, overall pulmonary function loss, and dynamic changes in the lung .Diverse methods for volumetric are described in the literature; however, this has broadly been described using either paired  breath-hold CT (BHCT) or 4-Dimensional CT (4DCT) and comprising three computational steps: (1) lung volume delineation (segmentation), (2) measurement of lung motion through deformable image registration (DIR) or non-DIR methods, and (3) algorithmic calculation of surrogate measures for regional ventilation.129Xe hyperpolarized MRI  and deformation vectors , although variants and other methods were also reported in the literature. These images are then reconstructed, pairing images from the inhalation and exhalation phase thereby producing measurements for lung volume and ventilation . Throughized MRI .With respect to CTV algorithms, the most common algorithms for calculating ventilation metrics were evaluation of lung volume changes using CT intensity or Hounsfield Unit values (CTV-HU) and deformation vectors , although variants and other methods were also reported in the literature. Overall, there was no clear evidence that one method was superior to another.3He) or xenon-129 (129Xe) can help circumvent the relative lack of proton signal in the airspace, better capturing images of the lung tissue  to enhance their MR signaling properties  is a functional lung imaging technology that provides non-invasive quantification of regional ventilation during the respiratory cycle. XV technology is based on the principle of Particle Image Velocimetry (PIV), which allows to study the motion of particles within a medium. In practical terms, XV involves acquisition of fluoroscopic images over one complete and continuous tidal breath, which is captured at five angles, while the same center of rotation is maintained. The limited angles required for image acquisition allow for a significantly lower radiation dose to the patient compared to standard CT protocols .The analysis of the acquired images involves measuring tissue expansion over the duration of a tidal breath. Tissue expansion is then used to calculate regional ventilation at every location within the lung with several derived parameters. The information additionally enables spatial detection of regional ventilation defects and correlation to underlying lung structure .Early and accurate detection of respiratory disease remains an important goal in risk reduction and early treatment to prevent disease progression. Diagnosis and monitoring of lung disease relies primarily on functional measurements such as spirometry to assess the extent of functional impairment , 9, and Few studies incorporating Xenon CT in animal models have been conducted. A murine study was able to successfully use continuous CT acquisition with Xe contrast to measure regional ventilation . A canin4DCT has been applied to evaluate ventilatory and perfusion defects in swine models with lung injury either from radiation for lung cancer or mechanical stress from mechanical ventilation. Wuschner et al. developed a specific swine model and correlated with human subjects to determine optimal biomarkers to monitor ventilatory changes after radiation therapy . Swine mMany pre-clinical studies have used hyperpolarized gas MRI to help elucidate the dynamic process by which gas diffusion and transport occurs and further understand the pathophysiology of pulmonary diseases . Mouse mOne limitation of prior models using hyperpolarized gas MR imaging is the necessity for well-controlled tidal volumes and timing of breaths. Although this is an approximate simulation for mechanically ventilated patients, these requirements limit the potential scope of use for hyperpolarized gas MR in free-breathing animal models. Recent studies have documented potential methods for obtaining functional lung imaging in free-breathing animal models. Loza et al. utilized a free-breathing murine model to assess imaging techniques that capture gas-phase images, measuring regional fractional ventilation, and dissolved-phase images, measuring gas uptake and distribution . These mCF) disease  has been used to visualize and quantify significant differences in ventilation between COPD and asthma-COPD overlap syndrome . AnotherOther studies have shown that Xe CT may be useful in diagnosing ventilation changes in other clinical contexts. One study identified additional ventilatory diagnostic information with Xe CT among mechanically ventilated patients, like discriminating bullae from pneumothorax, airway-to-pneumothorax fistula, and airway-to-mediastinum fistula . AnotherSimilarly to pre-clinical trials, there are limited, but ongoing, clinical trials that are focused on using 4D CT to preserve functional regions of lung ventilation for patients treated with radiation therapy for lung cancer. One ongoing phase 2 trial demonstrates 4D CT-guided ventilation as a useful clinical application in functional avoidance in patients with at least grade 2 radiation pneumonitis . SimilarHyperpolarized gas MRI is utilized in a variety of pulmonary pathologies, offers a more dynamic evaluation of pulmonary function, and lacks ionizing radiation . Roos et129Xe about diffusion and gas exchange would provide more useful information about pulmonary function than what is obtained with current pulmonary function testing, like spirometry. As an example of a possible clinical application, Lin et al. found that parameters measured with 129Xe hyperpolarized gas MR in pediatric asthmatics correlated with asthma severity and corticosteroid use (The ability to obtain functional information with a gaseous agent like roid use . Similarroid use . As hyperoid use , 66. Thiroid use , 67.To date, no clinical studies related to XV have been published, though as the ventilation heterogeneity may occur over multiple breaths the application in clinical models could allow for breath-by-breath analysis.Although functional lung imaging has the potential to better characterize ventilatory disease and heterogeneity in ventilation within the lung, most of the imaging modalities have been applied within experimental settings and only recently have been included in clinical studies. Imaging modalities, such as Xe CT, 4DCT, and hyperpolarized gas MRI, are often cost-prohibitive for large clinical studies, requiring expensive isotopes and specialized equipment. Additionally, these studies represent different amounts of ionizing radiation exposure, limiting longitudinal assessments in some modalities . More reOngoing clinical trials, including multi-center studies, continue to evaluate healthy patients and patients with various lung diseases. This information will help generate reference ranges for regional ventilation that can be used to support clinical decision making. Future directions to assess the additive clinical benefit of functional lung imaging will require inclusion of cohort studies that further elucidate natural histories of disease and monitor therapeutic response to treatment.Innovations in imaging techniques, including functional lung imaging, show promise and the potential to improve our current assessment of lung function in preclinical and clinical models, as well as for clinical applications. To achieve robustness and precision, it is likely that future pulmonary function testing will incorporate these modalities to detect specific regional deficiencies in addition to characterizing global lung function. Such an approach will generate clinical information that will ultimately trigger a new era of pulmonary disease classification, patient monitoring and improved personalized care. Research is now ongoing to determine the utility of functional lung imaging in characterizing lung function in the clinical setting, as well as predicting morbidity in different kinds of pulmonary diseases.DK, MS, JP, JK, and TS performed initial writing of manuscript. SB, VT, KY, EP, NE, TO, AK, ML, and AF provided revisions to initial draft. All authors approved the final manuscript.NE, TO, AF, and JK, are employed by 4D Medical.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Clinical and cognitive progression in alpha-synucleinopathies is highly heterogeneous. While some patients remain stable over long periods of time, other suffer early dementia or fast motor deterioration. Sleep disturbances and nocturnal blood pressure abnormalities have been identified as independent risk factors for clinical progression but a mechanistic explanation linking both aspects is lacking. We hypothesize that impaired glymphatic system might play a key role on clinical progression. Glymphatic system clears brain waste during specific sleep stages, being blood pressure the motive force that propels the interstitial fluid through brain tissue to remove protein waste. Thus, the combination of severe sleep alterations, such as REM sleep behavioral disorder, and lack of the physiological nocturnal decrease of blood pressure due to severe dysautonomia may constitute the perfect storm for glymphatic failure, causing increased abnormal protein aggregation and spreading. In Lewy body disorders (Parkinson’s disease and dementia with Lewy bodies) the increment of intraneuronal alpha-synuclein and extracellular amyloid-β would lead to cognitive deterioration, while in multisystemic atrophy, increased pathology in oligodendroglia would relate to the faster and malignant motor progression. We present a research model that may help in developing studies aiming to elucidate the role of glymphatic function and associated factors mainly in alpha-synucleinopathies, but that could be relevant also for other protein accumulation-related neurodegenerative diseases. If the model is proven to be useful could open new lines for treatments targeting glymphatic function  with the objective to ameliorate cognitive and motor progression in alpha-synucleinopathies. Aggregation of misfolded alpha-synuclein (α-syn) is the neuropathological hallmark of Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). While in PD and DLB α-syn aggregates are intraneuronal , MSA is characterized by oligodendroglial cytoplasmic inclusions. Hence, albeit LBD and MSA share underlying synucleinopathy, their clinical presentation largely differs, and they disclose this different cellular-type involvement .Within LBD, PD and DLB can be conceptualized as extremes of the same disease spectrum, in which the Lewy pathology is initially restricted to brainstem and midbrain in PD  and has Although PD has traditionally been conceived as a motor disease mainly related to alterations in the basal ganglia, up to 80% of PD patients develop dementia during the progression of the disease . Other pThe progressive extension of Lewy-like pathology to cortical and limbic areas has been related to cognitive impairment and dementia in PD . A meta-AQP4 moderates the association between sleep and amyloid-β burden  transport system that exports the excess of interstitial fluid and proteins . The CSFβ burden , and, ingression . Arteriagression , whereasgression . The glygression , when thgression . It has gression , may potgression , and evegression . In the gression . In lineRBD is a clinical disorder characterized by loss of the normal muscle atonia during the REM phase of sleep, which results in impaired suppression of movement generators and complex dream enactment behaviors . ClinicaArterial pulsatility is the major mechanism for clearance of brain proteins by the glymphatic system . Thus, aSome studies have partially addressed the relationship between blood pressure alterations in PD and cognitive impairment. In a cross-sectional study, Further than global BP abnormalities, aberrant nocturnal blood pressure profiles , have been associated with the incidence of mild cognitive impairment in elderly population . The abnThe other major condition in the category of synucleinopathies is MSA. It clinically presents as either levodopa-unresponsive parkinsonism or cerebellar syndrome, but autonomic failure is mandatory for the diagnosis . Unlike Sleep disturbances and nocturnal BP abnormalities have been clearly identified as risk factors for cognitive deterioration in alpha-synuclein related disorders. However, to date, no research group has clearly linked both as acting through glymphatic system failure. On the one hand, In our view, the clinical features of patients with alpha-synucleinopathies that develop dementia conform the perfect storm for glymphatic failure. Since the glymphatic system is mainly active during deep sleep stages, it is not surprising that presence of RBD, which seems to also affect NREM sleep features, is ubiquitous in patients with rapid cognitive decline. Further, vascular pulsatility provides the motion force that propels the interstitial fluid through brain tissue to remove protein waste. Accordingly, any deviation from the physiological fall of BP that occur during the night, such as the abnormal pattern of nocturnal BP (non-dipping/riser) that is tightly related to dysautonomia, could impair the removal of waste solutes. Within this model, the paradigm of earlier and more severe glymphatic failure would be DLB, in which RBD, severe dysautonomia and early dementia is associated to widespread cortical pathology. In the other extreme of this continuum would be PD patients that during all the course of disease do not clearly deteriorate, with main symptoms restricted to the motor domain.brain-first vs gut-first hypothesis  pattern, in which the initial pathological α-syn aggregates appear in the dorsal motor nucleus of the vagus and propagate via retrograde axonal transport (brain-first). Interestingly, the proposed gut-first pattern is tightly related to presence of RBD, and it has been reported that patients with idiopathic RBD display neuronal dysfunction in the peripheral nervous system and locus coeruleus equivalent to PD patients, but normal nigrostriatal dopaminergic innervation  have more severe dysautonomic symptoms and RBD than patients with idiopathic PD and more frequent cognitive impairment , PD patiA possible criticism to the presented model to explain cognitive decline may relate to MSA pathology. In MSA, patients’ cognition is not typically compromised in the context of a prominent autonomic failure provoking severe BP abnormalities that may include non-dipping and rising nocturnal profiles accompanied by RBD. However, in MSA the clinical expression of severe glymphatic dysfunction via dysautonomia and sleep disturbance would be an aggressive and fast motor progression, rather than cognitive decline, owing to predominant subcortical tropism due to different strains and/or kinetics of α-syn aggregation, which might relate to pathological and clinical differences, and also to differences in seeding assays results .primum movens of alpha-synucleinopathy and only focuses on the interplay between factors involved in clinical progression. It aims to foster research studies in the spectrum of alpha-synucleinopathies by incorporating nocturnal BP alterations and sleep abnormalities causing glymphatic failure as a mechanistic driver of abnormal cortical aggregation of proteins and subsequent deterioration. Adding glymphatic functioning measures, such as MRI-ALPS, circadian BP monitoring, or relevant polymorphisms, such as AQP4, and epigenetic biomarkers in research studies may lead to personalized risk models for dementia and the development of strategies to prevent it.The presented model is agnostic regarding the In summary, we argue that in alpha-synucleinopathies there may be a pathophysiological link between abnormal nocturnal tension profile, associated to dysautonomia and sleep disorder, and clinical progression. Such association would be mediated by the glymphatic system functioning. Altered sleep architecture and blunted arterial pulsatility would lead to severe glymphatic failure, which in turn produces impaired waste clearance and increased abnormal protein accumulation . While iThe original contributions presented in this study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.MB and YC conceptualized the manuscript. MB and GS-B wrote the first draft. YC, CM, MF, NC, LM, AS, and JK critically revised the manuscript and made relevant changes. All authors approved the final version of the manuscript.


Vitamin K and vitamin K-dependent proteins have been reported to be associated with a large spectrum of age-related diseases. While most of these associations have been deduced from observational studies, solid evidence for the direct impact of vitamin K on cellular senescence remains to be proven. As vitamin K status reflects the complexity of interactions between dietary intake, gut microbiome activity and health, we will demonstrate the pivotal role of the diet-microbiome-health axis in human ageing and exemplify how vitamin K is implicated therein. We propose that food quality  should be highlighted beyond the quantity of total vitamin K intake. Instead of focusing on a single nutrient, exploring a healthy diet containing vitamin K may be more strategic. As such, healthy eating patterns can be used to make dietary recommendations for the public. Emerging evidence suggests that dietary vitamin K is a modulator of the diet-microbiome-health axis, and this needs to be incorporated into the investigation of the impact of vitamin K on gut microbial composition and metabolic activities, along with host health outcomes. In addition, we highlight several critical caveats that need to be acknowledged regarding the interplay between diet, vitamin K, gut microbiome and host health that is pivotal for elucidating the role of vitamin K in ageing and responding to the urgent call of healthy eating concerning public health. According to WHO (2021), healthy ageing is “The process of developing and maintaining the functional ability that enables well-being in older age” [There has been an unprecedented increase in the number and proportion of people aged >60 years old worldwide. This will accelerate in the coming decades, particularly in developing countries. In 2020, for the first time in history, people aged >60 years outnumbered children < 5 years. By 2050, this global aged population will have more than doubled to 2.1 billion, outnumbering adolescents and young people aged 15–24 years [Consequently, the global ageing population is becoming overwhelmed by age-related diseases and multi-morbidities, such as chronic kidney disease (CKD), cardiovascular disease (CVD), type 2 diabetes, obesity, cancer and neurodegenerative disorders . FurtherMany age-related chronic diseases and physiological dysfunctions related to the burden of lifestyle can be prevented and even reversed by implementing healthy lifestyle interventions ,6. It isAn unhealthy diet, characterized by a suboptimal intake of fruit, vegetables, and whole grains and high consumption of processed food products high in saturated fat, with added sugar and salt, constitutes a significant risk factor for poor health . The shiNatural forms of vitamin K comprise different naphthoquinone derivatives with various long aliphatic side chains. There are two significant forms comprising vitamin K1 (phylloquinone) and vitamin K2 species  . There iWhile more investigations are needed to fill the knowledge gap between vitamin K synthesis and bioavailability, current evidence  suggestsVKDPs are involved in various pathophysiologic pathways . ProthroGiven the data indicating that an unhealthy diet contributes to the burden of lifestyle diseases in modern society, it is conceivable that a healthy diet is fundamental to maintaining a longer health span . The sigkB) activity, it may decrease inflammatory burden [Vitamin K has recently been attributed to antioxidant and anti-inflammatory properties ,49. As sy burden . This may burden .Notably, while multiple existing data support the association between vitamin K deficiency and adverse health outcomes derived from observational studies, solid evidence for the salutogenic impact of vitamin K on human health remains to be fully justified. For instance, despite the established role of MGP in inhibiting vascular calcification, it remains to be elucidated whether vitamin K deficiency is directly accountable for CVD morbidity, as several randomized clinical trials (RCTs) have failed to support its cardiovascular benefits ,58,59, pInconsistent results from observational studies and RCTs investigating the role of vitamin K in age-related diseases have proven frustrating. We propose that the link between diet and health could provide insights to resolve these otherwise equivocal findings. For example, portion size estimation might help resolve differing data from epidemiological studies evaluating vitamin K nutrient intake through dietary recall. Moreover, a fundamental question remains regarding the dietary source and bioavailability of phylloquinone and menaquinones. For instance, green vegetables are known to be the predominant source of dietary vitamin K. It has been reported that mixed dishes  , while in Japan, it comes from food such as natto. Intriguingly, fermented food intake has been recently highlighted as an effective strategy to promote healthy eating in the current industrialized era, as modern diets are typically depleted in fermented foods . It is wThese considerations suggest that health outcomes based upon an intake of vitamin K calculated using phylloquinone intake are largely biased. This may be redressed by including other food sources in such determinations, namely processed food and red meat, despite their otherwise detrimental effects on health. Recent data from a prospective follow-up study investigating the association of meat intake with the incidence of diseases found that higher consumption of separate or combined unprocessed red and processed meat was associated with an increased risk of ischemic heart disease, pneumonia, diverticular disease, colon polyps and diabetes . MoreoveThe benefit of dietary vitamin K intake  has been demonstrated in large population-based studies, where both the Rotterdam Study and Prospect-EPIC cohort study have shown a high intake of dietary menaquinones was related to a reduction in cardiovascular events ,71. HoweMoreover, results from the systemic analysis do not support the beneficial effect of nutritional supplementation for the primary prevention of CVD or cancer ,75. SuchAs VKDPs  play an important role in skeletal and vascular health , it is iThough not fully deciphered, emerging evidence indicates that the human gut microbiome has evolved from an ancient paleo-microbiome and becoming profoundly altered in the current industrialized era . Aside fCompared to macronutrients , less is known about the impact of micronutrients on gut microbiome composition and metabolic profiles. Nevertheless, there is evidence that micronutrients, including vitamins  and minerals , can influence gut microbiota composition and metabolism . SpecifiRecent work from Eills et al.  has showSimilarly, vitamin K2 intake from fermented food, including yoghurt, cheese, and natto, constitutes a healthy food pattern. In contrast, processed and fresh meat products are other rich dietary menaquinones yet to be included in dietary vitamin K determinations. The total vitamin K intake may remain unchanged with a reduced healthy food intake and compensated by an elevated unhealthy food source. As such, food pattern is crucial in evaluating vitamin K intake and its impact on human health.As vitamin K inadequacy is usually triggered by depletion of dietary vitamin K intake, the majority of vitamin K requirement in humans comes from the diet. While the full picture of dietary vitamin K and its influence on VKDPs and human health remains to be elucidated, it is plausible that bacterial synthesis of menaquinones contributes indirectly to human health through modulation of the composition of the gut microbiota, supporting the notion of nutrient-microbiota interactions. Similarly, Karl et al.  have repDespite the emerging clues of vitamin K and gut microbiome interactions, more is needed about the direct impact of such interaction on measures of human health. A large body of research has demonstrated the role of vitamin K and VKDPs in ageing and age-related diseases ,49,50, bInvestigations into vitamin K and its role in human ageing and age-related dysfunctions are expanding and progressing exponentially. However, several critical caveats need to be acknowledged to avoid equivocal findings. Firstly, comprehensive identification of various dietary sources of vitamin K and their bioavailability requires description, among which specific food patterns need to be addressed as possible confounders in estimating total vitamin K intake. As the Westernized diet has shifted from fresh vegetables, fruits, and whole grain intake into an urbanized diet , the total vitamin K intake may remain unchanged, with a reduced vegetable intake compensated by an elevated meat/processed food source  Figure . This ca


Ceramides are a group of sphingolipids located in the external plasma membrane layer and act as messengers in cellular pathways such as inflammatory processes and apoptosis. Plasma ceramides are biomarkers of cardiovascular disease, type 2 diabetes mellitus, Alzheimer’s disease, various autoimmune conditions and cancer. During pregnancy, ceramides play an important role as stress mediators, especially during implantation, delivery and lactation. Based on the current literature, plasma ceramides could be potential biomarkers of obstetrical adverse outcomes, although their role in metabolic pathways under such conditions remains unclear. This review aims to present current studies that examine the role of ceramides during pregnancy and obstetrical adverse outcomes, such as pre-eclampsia, gestational diabetes mellitus and other complications. Ceramides are a diverse family of sphingolipids in mammalian cell membranes synthesized by at least six ceramide synthases . From a Three ceramide biosynthesis pathways have been identified: an anabolic (de novo), a mixed recycling  and a catabolic (sphingomyelinase) pathway  7]. The. The7]. Ceramides play a multi-faceted role in the cell. They constitute an essential cell membrane component, provide structural integrity, and are biologically active . On the As mediators of stress signals and pro-inflammatory responses, ceramides play important roles in gestation, an inflammatory process with distinct phases at blastocyst implantation and delivery. In this context, Signorelli et al.  proposedLongitudinal studies are needed to understand the role of ceramides in pregnancy, but these are scarce. One study in cows followed lipid accumulation in the transition from gestation to lactation and showed that ceramides and glycosylated ceramides accumulate during the transition, while plasma sphingomyelin, a potential source of ceramides, reaches a nadir at labor. This and other findings were interpreted as ceramides being an intrinsic mediator of adaptive metabolism that accompanies the onset of lactation and facilitates milk synthesis . In humaFrom the above, it is apparent that sphingolipid metabolism is finely regulated during gestation and is tissue-specific. This effect has been shown in mice at the maternal-embryonic interface . It has There are no studies concerning the correlation of diet during pregnancy with ceramide concentrations. Nevertheless, a correlation between obesity and ceramide concentrations in non-pregnant populations has been reported . More stPre-eclampsia (PE) is a multi-system pregnancy disorder affecting up to 8% of pregnant women and is associated with a high risk of preterm births ,42. It iCeramides emerge as a promising diagnostic marker and therapeutic target of PE. Increasing attention is given to lipid imbalances. The roles of lipid metabolism in the pathophysiology of adverse outcome pregnancies have been suspected for a long time, but not studied in large cohorts . LipidomThe search for ceramides suitable for early diagnosis relies on a comprehensive understanding of their regulation during PE and gestation, which remains controversial. Lipidomic studies are heterogeneous regarding PE characteristics , tissues , and gestational stage . SamplinWith improvements in lipidomics continuously unlocking the potential of these technologies for comprehensive tissue profiling, additional aspects of ceramide roles in PE are expected to be discovered. The studies are limited in sample size and inclusivity. Notably, the average size rarely exceeds 20, which does not allow for robust conclusions, especially in a comparative context. Moreover, although ethnicity has been identified as a confounding factor for PE , cohortsDefined as a decreased response of the peripheral tissues to insulin action, insulin resistance (IR) is a multi-faceted disorder triggered by obesity and consumption of a high-fat diet. Numerous studies in humans, rodents, and cell cultures have established participation of ceramides in the development of IR. Ceramides antagonize insulin signaling by interfering with glucose uptake and impairing the storage of nutrients, while they inhibit oxidation, stimulate fatty acid uptake, and enhance cell death. Ceramide accumulation in skeletal and adipose tissue exerts the above effects by inhibiting signal transmission and activating pro-inflammatory cytokines and other regulatory molecules . AccumulBesides its association with pathologies, such as obesity and type-2 diabetes mellitus (T2DM), IR has been observed as a metabolic adaptation in the transition from late pregnancy to early lactation. Female adipose tissue metabolism changes from lipogenic to lipolytic at this stage to ensure adequate nutrition, development and milk synthesis for the growing fetus. The role of ceramides in this transition has been poorly investigated. In pregnant women, long- and very long-chain ceramides  commonly associated with the development of T2DM were positively correlated with the triglyceride index, a proxy of insulin resistance that reaches its highest values during pregnancy . AccumulBeyond the inherent IR associated with pregnancy, gestational diabetes mellitus (GDM) is a common complication characterized by glucose intolerance and hyperglycemia . As its GDM is conventionally treated with insulin. Nevertheless, a study demonstrated disrupted trophoblast function in insulin-treated individuals. Through immunohistochemistry, the study established a link between ceramide accumulation and hyperosmolar stress in the placenta and showed that insulin and ceramide may elicit adverse mitochondrial anomalies .Besides PE and GDM, ceramides have been associated with pregnancy complications. An example is the identification of glucoside ceramides as sensitive and specific indices of chorioamnionitis. The latter is often associated with preterm labor. Accumulation of the ceramide was found in granulocytes, fetal membranes neutrophils, and corresponding amniotic fluids, but was acknowledged only to reflect the activity of inflammatory cells . Later, Studies highlighting changes in ceramide concentrations in preterm labor indicate that different types might be involved in its pathogenesis at distinct gestation stages. At 20 gestational weeks, reduced expression of ceramides CerP(44:1) and galactosyl-Cer(42:2) was observed in association with spontaneous preterm birth . At the The mechanism by which ceramides and, in general, sphingolipids exert their effects in preterm labor is unclear, but the most plausible hypothesis is that they activate pro-inflammatory transcription factors involved in uterine contractions and cervical ripening. Ceramides may further contribute to preterm birth by affecting liver functions, as indicated in two lipidomic studies focusing on intrahepatic cholestasis of pregnancy (ICP), a liver dysfunction that increases the risk for preterm birth. In one study, ceramides 18:1/22:0 and 18:1/24:0 were downregulated in mid and high-severity ICP compared with uncomplicated pregnancies . In contThe increased risk of adverse pregnancy outcomes, including miscarriage and low birth weight, indirectly relates to sphingolipid metabolism, through polycystic ovary syndrome (PCOS). Two types of ceramides, hexosylceramide HexCer (d18:2/24:0) and dihydroceramide Cer (d18:0/24:1), were reported among the best indicators of low birth rate (up to 10% lower) in newborns of women with PCOS compared with their matching controls . MoreoveStudies highlighting ceramides’ roles in other pregnancy complications have made a case for extending clinical trials on substances targeting sphingolipids. Initially part of anti-inflammatory strategies, there is growing interest in using them as therapeutic targets of preterm labor and ICP .Ceramides play an important role throughout gestation and labor. A higher concetration is observed during natural birth compared to caesarian section due to the inflammatory process. In addition, ceramides may stimulate labor. There are few data about ceramide concentrations during pregnancy and the impact of diet on their concentrations.Most research on pregnancy and adverse obstetrical outcomes has been conducted for preeclampsia. Biomarkers of preeclampsia are related to hypoxia and endothelial damage. Although the exact metabolic pathway is unknown, abnormal placental angiogenesis during preeclampsia seems to have an impact on ceramide production. The elevation of ceramide concentration in preeclampsia is caused not only from placental abnormalities, but also from liver injury and platelet activation. Data from current research, regarding the correlation of ceramides alterations with preeclampsia, are conflicting. Long chain ceramides are the most affected.Ceramides have also been studied in gestational diabetes mellitus. It is known that ceramides are altered in individuals with obesity, insulin resistance and type 2 diabetes mellitus. Long chain ceramides, especially Cer 18 and Cer 24, were found to be related to gestational diabetes mellitus.Other obstetrical adverse outcomes, such as preterm labor, were related to alterations of ceramide concentrations in a few studies. Chorioamnionitis, an inflammation of the membranes and chorion of the placenta, is a major cause of preterm labor and ceramides are elevated due to the inflammatory process. Another explanation of ceramide alterations in preterm labor are pre-inflammatory agents deriving from uterine contractions and cervical ripening. Few data exist on intrahepatic cholestasis of pregnancy and ceramides.Ceramides have been studied in various health conditions due to their role in signaling pathways and their potential use as biomarkers. Pregnancy and obstetrical adverse effects are complex situations in which ceramides may be involved. Ceramides are mediators of stress and seem to play a role, especially during implantation, labor and lactation. The current literature about obstetrical adverse effects includes pre-eclampsia, gestational diabetes mellitus, preterm birth, chorioamnionitis, intrahepatic cholestasis of pregnancy and fetal chromosomal abnormalities. Only a deeper comprehension of their role in uncomplicated pregnancy and during pregnancy adverse outcomes will allow possible use of ceramides in clinical practice.Lipids seem to play a crucial role throughout pregnancy and obstetrical adverse outcomes. First trimester biomarkers could improve prognosis and therapeutic strategies. Ceramides are potential and promising biomarkers of such complications as preeclampsia and gestational diabetes mellitus. The current literature on alteration of ceramides is limited and results are conflicting. More research in large cohorts is needed to define their role in metabolic pathways and clinical use as pregnancy biomarkers.


Cirrhosis is a complex diffuse process whereby the architecture of the liver is replaced by abnormal nodules because of the presence of fibrosis. Several pediatric diseases such as extrahepatic portal vein obstruction, biliary atresia, alpha-1-antitrypsin deficit and autoimmune hepatitis can lead to cirrhosis and portal hypertension in children. In this article the authors describe interventional radiology procedures that can facilitate the diagnosis and treatment of diseases associated with liver cirrhosis and portal hypertension in the pediatric population. These procedures include image-guided liver biopsy, mesenteric–intrahepatic left portal vein shunts, balloon-occluded retrograde transvenous obliteration, transjugular intrahepatic portosystemic shunts and splenic embolization. Liver biopsy is a fundamental tool in the wide field of pediatric liver cirrhosis and can be considered the gold standard procedure to obtain a liver sample for histopathological examination, supporting diagnosis, management and prognosis of many pediatric acute and chronic liver diseases. Liver biopsy can be performed in either native or transplanted liver for diagnostic and prognostic purposes, for assessing the severity of known disease and for monitoring disease progression or response to therapy . Liver b3) and ensure that the child is not on anti-aggregant or anticoagulant therapy at the time of the procedure. An abnormal coagulation status is an absolute contraindication to performing percutaneous liver biopsy.The first step in liver biopsy is to perform an abdominopelvic US examination to look for the presence of free intraperitoneal fluid , colonic interposition or marked dilatation of the biliary tree and to determine the best site of access to liver parenchyma, which may be subcostal or intercostal. The next step is to determine the international normalized ratio (INR)  and platelet count  needle  with a 13-mm to 23-mm range and usually one needle pass; more needle passes may be performed when examining a single nodular lesion.Abdominopelvic US evaluation is done immediately after the biopsy to detect any potential complication, because perihepatic fluid collections and any intra-abdominal free fluid that was absent in the pre-procedural US examination are considered bleeding complications .The child is monitored for at least 6 h after the procedure, with blood evaluation repeated 2 h after the end of the biopsy to look for any hemodynamic changes and, in cases of pain or other symptoms, to carry out a control US examination.The European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) defines minor complications of liver biopsy as the presence of pain, subcapsular bleeding that does not require transfusion or prolonged hospitalization, infection, minor bile leak or hemobilia and arteriovenous fistula . ESPGHAN3, INR > 1.5, presence of abundant intraperitoneal fluid and anti-aggregant or anticoagulant therapy that cannot be discontinued. Some authors consider other indications for this procedure, even if coagulation abnormalities or ascites are not detected, including previous unsuccessful percutaneous biopsy, morbid obesity, atrophic liver, suspected amyloidosis, cardiac liver, hemodialysis and chronic renal insufficiency, peliosis hepatis and hereditary hemorrhagic telangiectasia, which all increase bleeding risk [Performing a biopsy via the venous system reduces the risk of bleeding because the Glisson capsule is not perforated , 13 and,ing risk , 15.A contraindication to transjugular liver biopsy is the presence of thrombosis in the right internal jugular vein. Contralateral or external jugular, or femoral vein approaches are riskier than the right internal vein approach, and therefore are used as a last resort. Other contraindications to this biopsy approach are thrombosis of hepatic veins, hydatid cysts and cholangitis .The first step in the transjugular liver biopsy procedure is to perform an 18-G  US-guided right internal jugular vein puncture using a superficial high-frequency linear probe, introducing a 0.035-in. guidewire  and then to insert a 4- to 6-French (Fr) introducer sheath (Terumo Europe) according to the Seldinger technique. The right hepatic vein is then catheterized with a 4- to 7-Fr end-hole catheter (Terumo Europe) and, if necessary, a J-tipped 0.035-in. flexible hydrophilic guidewire (Terumo Europe). An angiography is performed to check that the catheter is in the right position.Once the interventionist is assured of correct positioning, biopsy is performed under both US and fluoroscopic guidance, using a biopsy needle set (14–18 G/7 Fr) with Colapinto needle . Cholongitas et al.  found thInterventional radiology management of portal hypertension in children usually differs from that in adults . Portal In pediatric patients, pre-hepatic portal vein thrombosis is the most common cause of both portal hypertension (∼70% of cases) and upper gastrointestinal bleeding and is usually the result of iatrogenic injury by neonatal catheterization of the umbilical vein or infection , intra-abdominal abscess, sepsis, severe dehydration, abdominal trauma or unknown causes in up to 50% of cases  , 20, 21.Surgical management of portal hypertension has not been well standardized by pediatric liver centers worldwide . While lSurgical non-selective portosystemic shunts  help to reduce portal hypertension but are associated with higher rates of clinical complications such as hepatopulmonary syndrome, encephalopathy or hyperammonemia, which are undesirable in children . OtherwiPreoperative imaging is pivotal in the setting of surgical planning. While CT and magnetic resonance (MR) angiography are essential to confirm the pre-hepatic portal vein thrombosis diagnosis and evaluate both the extension of portal cavernoma and size of the extra- and intrahepatic portal system, particularly of the superior mesenteric vein, wedged hepatic venous portography is the mainstay imaging examination for assessing the surgical feasibility of the meso-Rex bypass , 20. WedSpecifically, Bertocchini et al.  categoriMeso-Rex bypass is the recommended option for children with pre-hepatic portal vein thrombosis but requires normal liver architecture to ensure long-term patency . MoreoveBleeding from ruptured esophagogastric varices is one of the most serious complications in children with liver cirrhosis and is a major cause of death in these children . Balloonantegrade transvenous obliteration is recommended instead. Therefore balloon-occluded retrograde transvenous obliteration can be useful in multiple ways and in combination with other techniques [The two main clinical indications for this procedure are active or impending esophagogastric variceal bleeding and esophagogastric varices with hepatic encephalopathy refractory to medical management. On the other hand, the contraindications to balloon-occluded retrograde transvenous obliteration are considerable and include severe uncontrollable coagulopathy associated with liver failure, splenic vein thrombosis, portal vein thrombosis and uncontrolled bleeding from esophagogastric varices. While uncontrolled esophageal variceal bleeding can be considered a contraindication to balloon-occluded retrograde transvenous obliteration therapy alone, TIPS combined with balloon-occluded retrograde transvenous obliteration or balloon-occluded chniques .In conducting balloon-occluded retrograde transvenous obliteration, preprocedural CT imaging is important to document the presence of a portosystemic shunt and assess eventual contraindications such as venous thrombosis. The balloon-occluded retrograde transvenous obliteration procedure in the pediatric population is performed under general anesthesia or deep sedation by interventional radiologists. It consists of endovascular closure of the portosystemic shunt outflow, using an occlusion balloon  followed by injection of a sclerosing agent directly into the gastro-variceal complex. The role of balloon occlusion can be diagnostic or therapeutic. It is useful to perform retrograde venography to visualize the gastric–variceal complex, to modulate flow and to cause stagnation of the sclerosing agent within the gastric–variceal system without reflux of the sclerosant into either the portal or systemic vasculature once occlusion of the shunt has been accomplished. Flow stagnation is helpful to maximize the effect of the sclerosing agent on the gastrovariceal system endothelial lining, leading to thrombosis and subsequent scarring of the system .The use of a sclerosing agent can be selective or superselective and the agents frequently used are ethanolamine-oleate-iopamidol, sodium-tetradecyl-sulfate, polidocanol as foam and N-butyl-2-cyanoacrylate. Microcatheters and embolization coils are adjunctive tools used to administer the sclerosant in high concentration within the varix, minimizing loss of sclerosant into nontarget vascular beds .Possible adverse effects of balloon-occluded retrograde transvenous obliteration include transient ascites, pleural effusion and worsening of esophageal varices. These adverse effects can be caused by elevation of portal pressure in response to occlusion of the portosystemic shunt . BleedinRecent reviews of balloon-occluded retrograde transvenous obliteration reported high rates (> 90%) of complete eradication of gastric varices and low rates (< 10%) of gastric variceal recurrence during long-term follow-up compared to endoscopic variceal ligation . BalloonSplenomegaly is a common condition resulting from cirrhosis. Portal hypertension causes splenomegaly and formation of esophageal varices and a collateral venous circulation , 36. In Hypersplenism may worsen the course of the disease in children with cirrhosis, because of the increased risk of infection and bleeding, and it may also adversely affect the administration of drugs that could induce leukocytopenia or thrombocytopenia , 39. As Surgical splenectomy has been traditionally performed in hypersplenism accompanying chronic liver disease , 38. ButHowever, in the last few decades partial splenic embolization has emerged as an excellent alternative to these treatments in the setting of portal hypertension , 38, 44.Since then, the partial splenic embolization approach has been widely used and approved worldwide, resulting in good outcomes and reduction in the number of reports of major complications , 47, 49.The unique anatomical arterial characteristics of the spleen make it an ideal organ for partial embolization , 53. SmaIn the pediatric population, partial splenic embolization is performed under general anesthesia or deep sedation by an interventional radiologist. Usually, the percutaneous approach is through the femoral artery using the Seldinger technique under sterile conditions.Embolization is carried out according to guidelines based on Spigos et al.’s  recommenPartial splenic embolization can be performed using two methods: selective catheterization and embolization, or non-selective embolization , 54. In In partial splenic embolization the most used embolic agents are gelatin sponge pledgets, polyvinyl alcohol particles and trisacryl gelatin microspheres. These agents can be injected in a suspension containing a contrast agent and antibiotics , 54.According to the literature, in cirrhotic patients the ideal splenic volume target for partial splenic embolization should be 50–70%; a higher incidence of complications is described when embolization involves more than 70% of the total splenic volume , 54, 58.Data show that partial splenic embolization has, over time, become a safe procedure for pediatric patients if certain criteria are met. These criteria include: procedure performed by an experienced interventional radiologist, maximum of 70% spleen infarction, respect of aseptic conditions and use of antibiotics and highly effective analgesia to prevent pulmonary complications , 50, 58.Following partial splenic embolization, a so-called post-embolization syndrome is observed in most patients, at a frequency of 73.4%; this condition is considered a minor complication and consists mainly of fever, nausea, left upper quadrant pain and perisplenic fluid collection, and these symptoms are usually controlled with antibiotic prophylaxis, narcotics and antiemetics –37, 54. In summary, recent data indicate that partial splenic embolization is a safe and effective alternative procedure to splenectomy in the pediatric population with splenomegaly and hypersplenism secondary to portal hypertension. Partial splenic embolization can be used to improve liver function and hematological status, to prevent variceal hemorrhage and to treat hepatic encephalopathy , 53, 59.In adults with cirrhosis, complications of portal hypertension have traditionally been managed with endoscopic variceal ligation . HoweverTransjugular intrahepatic portosystemic shunt placement is considered difficult in children. The technique can be challenging in situations of distorted hepatic vascularization, modified liver anatomy or segmental liver grafts, where advanced skills are required. Children with < 10 kg of body weight might not tolerate TIPS because of the size of the device (manufactured for adults) and the hemodynamic changes that follow the placement of a large shunt, which can cause a remarkable increase in the systemic venous return to the right heart. Perhaps for these reasons, few children have been proposed and undergone this procedure –72.However, the procedure is not impossible in children, as reported by Izaaryene et al. , who desAll procedures are performed under general anesthesia. A 9-Fr or 10-Fr sheath (Terumo Europe) is inserted into the right internal jugular vein. A 5-Fr Cobra catheter (Terumo Europe) is then wedged centrally in the liver in the right or middle hepatic vein and a wedged hepatic vein phlebography is performed to identify the portal vein. A 16-G Colapinto needle  is used to puncture the portal vein under continuous US monitoring. After entering the portal vein, a 0.035-in. wire is advanced followed by a 5-Fr catheter (Terumo Europe) into the portal vein. A portal venogram (Fig. Ghannam et al.  reportedMinor and major complications are common after TIPS placement and include extracapsular puncture, shunt occlusion and dysfunction, recurrence of ascites or variceal hemorrhage, intraperitoneal hemorrhage and hepatic encephalopathy. In Ghannam et al.’s  report, Hepatic encephalopathy and stent malfunction are two of the most common post-procedural complications of TIPS placement ; as compThe major complications rate reported by Bertino et al.  was 8.2%To summarize, TIPS creation in children and adolescents is a technically feasible and efficacious procedure with a low complication rate for the treatment and prevention of uncontrolled variceal hemorrhage and refractory ascites and should not only be considered as a bridge to transplantation, but also as an effective and less invasive alternative to surgical vascular shunts.


Nutrition and metabolism modify epigenetic signatures like histone acetylation and DNA methylation. Histone acetylation and DNA methylation in the central nervous system (CNS) can be altered by bioactive nutrients and gut microbiome via the gut–brain axis, which in turn modulate neuronal activity and behavior. Notably, the gut microbiome, with more than 1000 bacterial species, collectively contains almost three million functional genes whose products interact with millions of human epigenetic marks and 30,000 genes in a dynamic manner. However, genetic makeup shapes gut microbiome composition, food/nutrient metabolism, and epigenetic landscape, as well. Here, we first discuss the effect of changes in the microbial structure and composition in shaping specific epigenetic alterations in the brain and their role in the onset and progression of major mental disorders. Afterward, potential interactions among maternal diet/environmental factors, nutrition, and gastrointestinal microbiome, and their roles in accelerating or delaying the onset of severe mental illnesses via epigenetic changes will be discussed. We also provide an overview of the association between the gut microbiome, oxidative stress, and inflammation through epigenetic mechanisms. Finally, we present some underlying mechanisms involved in mediating the influence of the gut microbiome and probiotics on mental health via epigenetic modifications. Mental disorders are known as global and serious problems which influence one in four people during their lives, and both genetic and environmental factors play an important role in their disease pathogenesis ,2. AlthoEpigenetics refers to modifications to DNA or RNA capable of influencing gene expression levels without alerting the underlying DNA sequence . During As more than 1000 bacterial elements (predominantly nonpathogenic bacteria) as well as viruses, archaea, protozoa, and fungi live in a healthy intestinal ecosystem, they display powerful roles in metabolic functions, immunomodulation, and modulating gene expression via epigenetic mechanisms . MicrobiThe intestinal microbiome is involved in numerous physiological processes including host defense , homeostAn imbalance of the gut microbiome occurs when people are subjected to aggressive factors including an unhealthy diet ,27, streEpigenetic alterations play significant roles in the pathogenesis of severe mental disorders like schizophrenia, autism, bipolar disorder, and depression ,37,38. EEpigenetic mechanisms have been found to be flexible which can be changed by a variety of stimuli like stress and environmental conditions ,47. EmerOther studies have shown that DNA methylation and its physiological effects on the host can be regulated by commensal bacteria in colonic epithelial cells (CoECs) , one of Besides DNA methylation, diverse types of histone modifications  are among other important epigenetic mechanisms for gene expression regulation affected in mental diseases. Histone acetyltransferases (HATs) mediate acetylation of specific lysine residues on the N-terminal tail of core histones which in turn give rise to DNA uncoiling and increasing accessibility to transcription factor binding. Conversely, histone deacetylases mediate chromatin remodeling that is involved in suppressing gene transcription . TherefoThe interplay between the intestinal microbiome and the brain through the gut–brain axis, results in extra-intestinal effects . The gutMicrobiome-derived SCFAs also act as histone deacetylase inhibitors and play important roles in numerous physiological processes such as promoting the differentiation of T cells, producing neurotransmitters, regulating immune homeostasis, inhibiting intestinal pro-inflammatory macrophage function, regulating gut and blood–brain barrier (BBB) permeability, and neuroprotection ,75,76,77Escherichia coli can produce methionine through specific enzymatic pathways [Regarding methylation reactions, although the availability of methyl groups for DNA or histone methylation in the CNS and consequently neurobehavioral functions can be affected by nutritional status, it is also regulated by the host’s microbiome. For example, as choline (found in vegetables like spinach) is the main source of methyl groups, some bacteria compete with the host and consume this nutrient intensifying metabolic diseases associated with global DNA methylation alterations in mice under high-fat diet and in their offspring . Methionpathways . Productpathways .phylum Bacteroidetes and an increased abundance of the Actinobacteria and Firmicutes have been found in bipolar disorder with current major depressive episodes [Actinobacteria phylum [A variety of serious diseases especially mental disorders are linked to differences in gut microbiome composition and function ,89. For episodes . Howevera phylum .There is a microbial connection between mother and offspring from the early moments of life . The chaFor example, acetate production from the breakdown of alcohol gives rise to dynamic acetylation of histones in the brain tissue. In a pregnant mouse, the incorporation of labeled acetyl groups into gestating fetal brains occurred following exposure to labeled alcohol. Extracellular acetate could mediate transcriptional programs relevant to learning and memory, highlighting the importance of gut microbial metabolites in epigenetic regulating learning and memory . AdditioGene regulation and expression can be tuned by gut microbial products because gut bacterial-derived metabolites act as epigenetic agents. It has also been reported that host molecular signaling can be influenced by gut bacterial-derived metabolites. Physiological effects of SCFAs are mediated via at least two mechanisms: (i) they are capable of inhibiting histone deacetylases through acetylation of lysine residues which in turn confers promoting the binding of transcription factors to genes promoter regions for regulating gene expression ; (ii) thBifidobacterium and Erysipelatoclostridium and increasing the abundance of six genera such as Candidatus Saccharimonas, Lachnoclostridium, and Romboutsia, compared to the Western diet [The preservation of intercellular junctions, epithelial cell architecture, and the integrity of the epithelial barrier heavily depend on the gut microbiome. The leaky gut is defined as the lack of integrity of the epithelial barrier and increasing the permeability of the intestinal mucosa, which in turn can result in the development of many systemic, intestinal, and even brain dysfunctions. The leaky gut provides the opportunity for bacteria, bacterial toxins, toxic digestive metabolites, and small molecules to translocate systemically, and even cross the BBB and induce neuroinflammation . For insern diet . Experimern diet . For exaern diet . In anotern diet .On the other hand, a high-fat diet (HFD) can lead to increased induction of DNA damage, higher inflammatory activities, and altered gene expression and DNA methylation of DNA methyltransferases1 (DNMT1) and MutL homolog 1 (MLH1) genes, which are involved in DNA methylation and mismatch repair, respectively, but (-)-epigallocatechin gallate (EGCG), a component of tea can attenuate these alterations . Kim et Pseudomonas putida, Morganella morganii, and Pseudomonas aeruginosa [In humans, the lower levels of paraoxonase 1 enzyme (PON1) activity in schizophrenia, leading to impaired function of the innate immune system and increased oxidative stress, has been linked to increased IgA responses to ruginosa . With thruginosa . In thisruginosa .Although the gut microbiota composition has been found to be a critical factor in modulating the bioavailability of phenolic acids  associated with memory promotion , it has Furthermore, the resident gut bacteria have demonstrated abilities for the fermentation of dietary fiber and consequently for producing SCFAs which are mediators of improving mood and cognition, and reducing the risk of psychiatric diseases like depression in humans . The gutKO) [KO mice. Their results revealed that supplementation with the microbial metabolite acetate could hamper social deficits in microbiome-depleted mice by altering transcriptional regulation in the prefrontal cortex. Olaniyi and coworkers also showed that acetate could rescue polycystic ovary syndrome (PCOS) associated depression by inhibiting DNA methyltransferase in prefrontal and hippocampal regions of the brain in adult female Wistar rats [Acetate, another microbial metabolite is known to be an important epigenetic regulator since it can inhibit histone deacetylase activity and change gene expression and behavioral responses in mice brains ,171. TheKO) . In additar rats .Butyrate is another SCFA and a secondary metabolite of the gut microbiome which acts as an endogenous inhibitor of class I HDACs, a well-known class of epigenetic modulatory genes ,175. NeuA preclinical study revealed that sodium butyrate could ameliorate social behavior deficits by modifying the transcription of inhibitory/excitatory genes in the frontal cortex of the BTBR autism mouse model . MoreoveIndole 3-propionic acid, an enteric microbiome-derived deamination product of tryptophan also contributes to intermittent fasting-dependent axonal regeneration by modulating the function of neutrophils and interferon-gamma ,185. In The potential health benefits of a ketogenic diet and its underlying molecular mechanisms can be mediated through epigenetic mechanisms such as elevating histone acetylation ,187,188.Akkermansia and Blautia) [Some previous reports have shown that a ketogenic diet can be considered to be an effective remedy to rescue social interaction deficits in a Shank3 mouse model of autism because β-hydroxybutyrate, a secondary metabolite of gut microbiome and an endogenous inhibitor of class I HDACs can be produced by this diet. In an interesting study, Yan et al. reported reduced levels of the HDACs downstream target genes encoding the N-methyl-D-aspartate (NMDA) receptor subunits, glutamate ionotropic receptor NMDA type subunit 2A (GRIN2A) and glutamate ionotropic receptor NMDA type subunit 2 B (GRIN2 B) in the prefrontal cortex of an autism mouse model with a deficient Shank3 gene . It was Blautia) .Turicibacter abundance and lower butyric acid levels were reported in a valproic acid (VPA)-induced autism mouse model, and the treatment with Lactobacillus could alleviate autistic-like behaviors by reducing Turicibacter abundance and elevating butyric acid levels [L. reuteri PBS072 and B. breve BB077 are excellent probiotic candidates for improving cognitive functions and stress resilience via suppressing the epigenetic enzyme LSD1, increasing gamma-aminobutyric acid (GABA), and serotonin [Roseburia hominis (R. hominis) and its possible molecular mechanisms in germ-free rats [R. hominis-treated group could exhibit increased serum levels of propionate and butyrate (as histone deacetylase inhibitors), reduced levels of monocyte chemoattractant protein-1 (MCP-1), interferon-gamma (IFN-γ), and interleukin-1 alpha (IL-1α), and reducing microglial activation compared to germ-free rats. Therefore, gut microbiome-derived metabolites, ketogenic diet, and probiotic therapy can be considered promising remedies to alleviate memory dysfunction and social cognitive deficits in mental disorders by targeting epigenetic events connecting the microbiota-gut-brain axis.As fecal transplantation from patients with autism, schizophrenia, and MDD to germ-free mice induces corresponding disease-like phenotypes associated with related neurochemical and metabolic alterations in the recipient mice, probiotics were shown to be useful in reversing social and cognition deficits by targeting the gut–brain axis ,195. Thed levels . Probiotd levels . In anoterotonin . Additioree rats . In theiBifidobacterium treatment could restore the fecal Clostridium spp. balance and rescue social interaction impairment and hippocampal BDNF expression [Fecal microbiota transplantation is considered a promising strategy for improving human mental health via modulation of the gut–brain axis. Fecal microbiota transplantation is defined as the transfer of intestinal microbiota from one individual to another and typically is carried out through colonoscopy . Fecal mpression .Clostridioides difficile infections four weeks after fecal transplantation [Prevotella ASVs is associated with DNA methylation alterations of actin filament-associated protein 1 (AFAP1) which affect mitochondrial functions and insulin sensitivity [Some current studies utilized this experimental procedure to induce mental diseases or improve mental health and prevent gut dysbiosis and anxiety-like behaviors . For exaantation . It has sitivity . In anotsitivity . More stThe pathogenesis of many major mental disorders is associated with epigenetic aberrations. Currently, several lines of evidence suggest that disease pathogenesis can be linked to changes in the microbiome structure and composition via the microbiome–gut–brain axis. The complex interplay among environmental factors  and gastrointestinal microbiome consisting of more than three million functional genes, which interact with millions of human epigenetic marks and 30,000 human genes, and their role in accelerating or delaying the onset of mental disorders is a fundamental issue that has garnered much attention from the scientific community in recent years. Improved DNA/RNA sequencing technologies have paved the way for researchers to determine the exact strains of the affected bacteria and their interaction with genetic and epigenetic landscapes in disease pathogenesis. Describing microbial activity at the strain level will increase the chance of establishing a causal relationship among certain bacteria, epigenetic mechanisms, and specific mental disorders. More research on the modifications of the maternal microbiome during pregnancy by environmental factors and diet is still required to completely unravel the mechanisms of their roles in accelerating or delaying the onset of mental disorders via epigenetic changes. In particular, further research is still required to obtain greater insights on abnormally transmitted microbiomes on infant health, to mitigate the development of diseases such as ASD at early ages. Furthermore, comprehensive human studies with much larger sample sizes and well-balanced cohorts are necessary to confirm the potential benefits of probiotics, gut microbiome-derived metabolites, and different types of diets for epigenetic modulations alleviating major mental disorders.