Cardiorenal syndrome and iron supplementation-more benefits than risks: a narrative review.

Intravenous iron administration has emerged as a crucial intervention for managing patients with cardiorenal syndrome (CRS) and iron deficiency, with or without the presence of anemia. Multiple studies have demonstrated the benefits of intravenous iron supplementation in improving anemia, symptoms, and functional capacity in patients with HF and iron deficiency. Furthermore, iron supplementation has been associated with a reduction in hospitalizations for HF exacerbation and the improvement of patients' quality of life and clinical outcomes. In addition to its effects on HF management, emerging evidence suggests a potential positive impact on kidney function in patients with CRS. Studies have shown an increase in estimated glomerular filtration rate and improvements in renal function markers in patients receiving intravenous iron therapy, highlighting the potential of this intervention in patients with CRS. This paper reviews the existing literature on the impact of intravenous iron therapy in these patient populations and explores its effects on various clinical outcomes. Future research endeavors are eagerly awaited to further improve our understanding of its clinical implications and optimize patient outcomes.

Acute Coronary Syndromes in Women: A Narrative Review of Sex-Specific Characteristics.

Acute coronary syndromes (ACSs) encompass a spectrum of life-threatening cardiovascular conditions, including unstable angina (UA) and myocardial infarction. While significant progress has been made in the understanding and management of ACS over the years, it has become increasingly evident that sex-based differences play a pivotal role in the pathophysiology, presentation, and outcomes of these conditions. Despite this recognition, the majority of clinical research in the field has historically focused on male populations, leading to a significant knowledge gap in understanding the unique aspects of ACS in women. This review article aims to comprehensively explore and synthesize the current body of literature concerning the sex-specific characteristics of ACS, shedding light on the epidemiology, risk factors, clinical presentation, diagnostic challenges, treatment strategies, and prognosis in women. By elucidating the distinct aspects of ACS in women, this review intends to foster greater awareness and improved clinical management, ultimately contributing to enhanced cardiovascular care for female patients.

Novel therapeutic approaches in the management of chronic kidney disease: a narrative review.

Chronic kidney disease (CKD) remains a pathologic entity with constantly rising incidence and high rates of morbidity and mortality, which are associated with serious cardiovascular complications. Moreover, the incidence of end-stage renal disease tends to increase. The epidemiological trends of CKD warrant the development of novel therapeutic approaches aiming to prevent its development or retard its progression through the control of major risk factors: type 2 diabetes mellitus, arterial hypertension, and dyslipidemia. Contemporary therapeutics such as sodium-glucose cotransporter-2 inhibitors and second-generation mineralocorticoid receptor antagonists are utilized in this direction. Additionally, experimental and clinical studies present novel drug categories that could be employed in managing CKD, such as aldosterone synthesis inhibitors or activators guanylate cyclase, while the role of melatonin should be further tested in the clinical setting. Finally, in this patient population, the use of hypolipidemic agents may provide incremental benefits.

Epidemiology, Pathophysiology, and Clinical Perspectives of Intradialytic Hypertension.

BACKGROUND: Individuals with end-stage renal disease on chronic hemodialysis (HD) may encounter numerous HD-associated complications, including intradialytic hypertension (IDHYPER). Although blood pressure (BP) follows a predictable course in the post-HD period, BP levels during the session may vary across the individuals. Typically, a decline in BP is noted during HD, but a significant proportion of patients exhibit a paradoxical elevation. SUMMARY: Several studies have been conducted to understand the complexity of IDHYPER, but much remains to be elucidated in the future. This review article aimed to present the current evidence regarding the proposed definitions, the pathophysiologic background, the extent and clinical implications of IDHYPER, as well as the possible therapeutic options that have emerged from clinical studies. KEY MESSAGES: IDHYPER is noted in approximately 15% of individuals undergoing HD. Several definitions have been proposed, with a systolic BP rise >10 mm Hg from pre- to post-dialysis in the hypertensive range in at least four out of six consecutive HD treatments being suggested by the latest Kidney Disease: Improving Global Outcomes. Concerning its pathophysiology, extracellular fluid overload is a crucial determinant, with endothelial dysfunction, sympathetic nervous system overdrive, renin-angiotensin-aldosterone system activation, and electrolyte alterations being important contributors. Although its association with ambulatory BP in the interdialytic period is controversial, IDHYPER is associated with adverse cardiovascular events and mortality. Moving to its management, the antihypertensive drugs of choice should ideally be nondialyzable with proven cardiovascular and mortality benefits. Finally, rigorous clinical and objective assessment of extracellular fluid volume is essential. Volume-overloaded patients should be instructed about the importance of sodium restriction, while physicians ought to alter HD settings toward a greater dry weight reduction. The use of a low-sodium dialysate and isothermic HD could also be considered on a case-by-case basis since no randomized evidence is currently available.

Metabolic Dysfunction-Associated Fatty Liver Disease in Newly Diagnosed, Treatment-Naive Hypertensive Patients and Its Association with Cardiorenal Risk Markers.

INTRODUCTION: Patients with arterial hypertension frequently present with comorbidities that are associated with increased cardiorenal risk, such as metabolic dysfunction-associated fatty liver disease (MAFLD). AIMS: Our study aimed to assess the prevalence and the association of MAFLD with cardiorenal risk markers in newly diagnosed, treatment-naïve hypertensive patients. METHODS: We recruited 281 individuals with new-onset hypertension who were not prescribed any medication. Medical history, clinical examination findings, and laboratory test results were recorded. Liver steatosis was assessed through fatty liver index (FLI) calculation. Patients with FLI ≥ 60 together with one main metabolic abnormality (type 2 diabetes mellitus or overweight/obesity) or at least two metabolic risk abnormalities (increased waist circumference, blood pressure, plasma triglycerides, presence of prediabetes or insulin resistance, decreased plasma high-density lipoprotein) fulfilled the diagnostic criteria for MAFLD. RESULTS: The prevalence of MAFLD in our study population was 28.7%. Individuals with MAFLD were more frequently male and had increased body mass index. Systolic, diastolic, and pulse pressure values were significantly higher in this group of patients. Moreover, lipid, renal, glucose, and inflammatory markers were considerably deranged in patients with MAFLD. After multivariate regression analysis, uric acid, ferritin, and apoE emerged as independent predictors of MAFLD. Area under receiver operating characteristics curve revealed that uric acid had the greatest diagnostic accuracy, with the ideal cutoff being ≥ 5.2 mg/dl (sensitivity: 77.6%, specificity: 76.3%). CONCLUSION: MAFLD represents a common comorbidity in hypertensive patients and is associated with markers of cardiorenal risk. Uric acid may be indicative of MAFLD in particular.

Prognostic Significance of Risk Factors and Biomarkers in Patients Hospitalized for Cardiorenal Syndromes: A Pilot Study.

BACKGROUND: Cardiorenal syndromes (CRS), involving the heart-kidney cross-talk and the activation of neurohumoral and inflammatory pathways, are an entity characterized by high morbidity and mortality. OBJECTIVE: To evaluate the prognostic role of risk factors and biomarkers in patients hospitalized for CRS. METHODS: In this observational cohort study, 100 consecutive patients hospitalized for CRS were enrolled. Socio-demographic characteristics, personal medical history, and prior medication use were recorded upon admission, and echocardiography was performed. Moreover, an array of blood markers were measured. The endpoint of interest was a composite of death or dialysis dependence at discharge. RESULTS: Patients were classified into two groups; Group 1 (N= 52): discharged being dialysis-independent, Group 2 (N=48): death/dialysis dependence at discharge. No significant differences were detected in baseline characteristics between the two groups. Group 2 patients used renin-angiotensin-aldosterone system blockers (RAASb) less often and more frequently presented with oliguria/anuria. Group 2 patients had significantly lower hemoglobin, serum albumin, and 25-hydroxy-vitamin D (25(OH)D). At the same time, serum phosphate, potassium, and parathyroid hormone (PTH) were significantly higher in Group 2 patients. In a multivariate regression analysis, lack of prior RAASb and lower 25(OH)D levels were independently associated with an increased risk of death or dialysis dependence at discharge. 25(OH)D/PTH ratio was the most accurate predictor of the composite endpoint (Sensitivity: 79.4%, Specificity: 70.4%). CONCLUSION: Lack of prior RAASb use, high PTH, low 25(OH)D levels, and low 25(OH) D/PTH ratio are associated with a poor prognosis in patients hospitalized for CRS.

Trimethylamine N-Oxide Levels in Non-Alcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis.

Non-alcoholic fatty liver disease (NAFLD) represents an entity with an increasing prevalence which is characterized by significant hepatic and extrahepatic complications. Its pathophysiology is multifactorial, with gut dysbiosis being considered a major determinant. In this systematic review and meta-analysis, we tried to evaluate the association between the major gut microbial metabolite trimethylamine N-oxide (TMAO) and NAFLD. We performed a literature search for studies that determined circulating TMAO in patients with and without NAFLD. The database search identified 136 studies, and upon application of the exclusion criteria, 7 studies with 7583 individuals (NAFLD 2923, control 4660) were ultimately included in the meta-analysis. Compared to the control group, NAFLD patients had significantly higher circulating TMAO (SMD: 0.66, 95% CI -0.12 to 1.21, p = 0.02, I2: 94%). The results remained unaffected after the exclusion of one influential study. The subgroup analysis revealed significantly higher TMAO in individuals with histologically proven NAFLD and in studies measuring TMAO with high-performance liquid chromatography. No differences were observed according to the study design or study region. However, funnel plot asymmetry was observed, indicating publication bias. In conclusion, patients with NAFLD had increased levels of TMAO, a hazardous gut microbial metabolite, suggesting its important role in the gut-liver interaction.

Interplay between metabolic dysfunction-associated fatty liver disease and chronic kidney disease: Epidemiology, pathophysiologic mechanisms, and treatment considerations.

The recently proposed nomenclature change from non-alcoholic fatty liver disease to metabolic dysfunction-associated fatty liver disease (MAFLD) has resulted in the reappraisal of epidemiological trends and associations with other chronic diseases. In this context, MAFLD appears to be tightly linked to incident chronic kidney disease (CKD). This association may be attributed to multiple shared risk factors including type 2 diabetes mellitus, arterial hypertension, obesity, dyslipidemia, and insulin resistance. Moreover, similarities in their molecular pathophysiologic mechanisms can be detected, since inflammation, oxidative stress, fibrosis, and gut dysbiosis are highly prevalent in these pathologic states. At the same time, lines of evidence suggest a genetic predisposition to MAFLD due to gene polymorphisms, such as the PNPLA3 rs738409 G allele polymorphism, which may also propagate renal dysfunction. Concerning their management, available treatment considerations for obesity (bariatric surgery) and novel antidiabetic agents (glucagon-like peptide 1 receptor agonists, sodium-glucose co-transporter 2 inhibitors) appear beneficial in preclinical and clinical studies of MAFLD and CKD modeling. Moreover, alternative approaches such as melatonin supplementation, farnesoid X receptor agonists, and gut microbiota modulation may represent attractive options in the future. With a look to the future, additional adequately sized studies are required, focusing on preventing renal complications in patients with MAFLD and the appropriate management of individuals with concomitant MAFLD and CKD.

Metabolic Dysfunction-Associated Fatty Liver Disease in the National Health and Nutrition Examination Survey 2017-2020: Epidemiology, Clinical Correlates, and the Role of Diagnostic Scores.

The recent establishment of metabolic dysfunction-associated fatty liver disease (MAFLD) has led to a reevaluation of its epidemiology, diagnosis, and clinical implications. In this study, we aimed to evaluate MAFLD's epidemiology and its association with other pathologic states and biomarkers, as well as to assess the prevalence of the different fibrosis stages in the MAFLD population, together with the importance of diagnostic scores in the preliminary determination of significant fibrosis. After analyzing the National Health and Nutrition Examination Survey (NHANES) 2017-2020, we found a high prevalence of MAFLD, at 58.6% of the studied population. MAFLD was accompanied by numerous comorbidities, which were increasingly common in individuals with higher grades of liver fibrosis. Fatty liver index emerged as a reliable indicator of MAFLD, as well as significant fibrosis. The estimation of fatty liver index could be a reasonable addition to the evaluation of patients with metabolic risk factors and could lead a diagnosis in the absence of liver elastography or biopsy. Further studies are needed to enhance our knowledge regarding its prognosis, as well as the role of novel therapies in its prevention or regression.

Oxidative Stress Management in Cardiorenal Diseases: Focus on Novel Antidiabetic Agents, Finerenone, and Melatonin.

Oxidative stress is characterized by excessive production of reactive oxygen species together with exhausted antioxidant defenses. This constitutes a main pathophysiologic process that is implicated in cardiovascular and renal diseases. In particular, enhanced oxidative stress may lead to low-density lipoprotein accumulation and oxidation, endothelial cell activation, adhesion molecule overexpression, macrophage activation, and foam cell formation, promoting the development and progression of atherosclerosis. The deleterious kidney effects of oxidative stress are numerous, including podocytopathy, mesangial enlargement, renal hypertrophy, tubulointerstitial fibrosis, and glomerulosclerosis. The prominent role of oxidative mechanisms in cardiorenal diseases may be counteracted by recently developed pharmacotherapies such as novel antidiabetic agents and finerenone. These agents have demonstrated significant antioxidant activity in preclinical and clinical studies. Moreover, the use of melatonin as a treatment in this field has been experimentally investigated, with large-scale clinical studies being awaited. Finally, clinical implications and future directions in this field are presented.

The Role of Melatonin in Chronic Kidney Disease and Its Associated Risk Factors: A New Tool in Our Arsenal?

BACKGROUND: The increasing incidence of chronic kidney disease (CKD), as a consequence of the high prevalence of arterial hypertension and type 2 diabetes mellitus (T2DM), warrants the need for developing effective treatment approaches. In this regard, the pineal gland-derived hormone melatonin may represent an appealing treatment approach of CKD and its associated risk factors. SUMMARY: Targeting the adverse pathophysiology surrounding CKD and its associated risk factors has been the concept of pharmacologic treatment developed for its management. This review article aimed to present the role of melatonin in this direction, by providing an overview of melatonin's physiology followed by its effect as a therapeutic agent in arterial hypertension and T2DM. KEY MESSAGES: Melatonin, the primary darkness hormone, possesses pleiotropic mechanisms of action which may have important implications in various pathologic states since its receptors are situated across various organ systems. As a treatment tool in arterial hypertension, melatonin may be efficacious in reducing both daytime and nocturnal blood pressure by influencing endothelial function, oxidative stress, the autonomic nervous system, and the renin-angiotensin system. Melatonin may also increase insulin sensitivity and ß-cell function. However, late meal intake may be detrimental in glucose regulation, as consumption close to melatonin peak concentrations may induce hyperglycemia and insulin resistance. This finding may explain the inconsistent glycose regulation achieved with melatonin in clinical trials and meta-analyses. Additionally, the presence of genetic variants to melatonin receptor 2 may predispose to T2DM development. Finally, we present the available preclinical evidence supporting melatonin's efficacy in ameliorating CKD's pathophysiology since melatonin supplementation has not been adequately explored in patients with CKD. The combined use of stem cells with melatonin is an appealing therapeutic approach which ought to be assessed further.

Endothelial Dysfunction in Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis.

Individuals with nonalcoholic fatty liver disease (NAFLD) are characterized by increased cardiovascular risk. Endothelial dysfunction, a mechanism implicated in those processes, may constitute the missing link in this interaction. Therefore, this systematic review and meta-analysis aims to evaluate the association of endothelial dysfunction, assessed by flow-mediated dilation (FMD) of the brachial artery, with NAFLD. We conducted a systematic literature search for studies assessing the difference in FMD between patients with NAFLD and controls. Exclusion criteria consisted of preclinical studies, studies in children/adolescents, no FMD assessment, and the absence of an NAFLD/control group. The database search identified 96 studies. Following the application of the exclusion criteria, 22 studies were included in the meta-analysis (NAFLD: 2164 subjects; control: 3322 subjects). Compared with controls, patients with NAFLD had significantly lower FMD% values (SMD: −1.37, 95% CI −1.91 to −0.83, p < 0.001, I2: 98%). Results remained unaffected after exclusion of any single study. Subgroup analysis revealed significantly decreased FMD in NAFLD subjects diagnosed with liver ultrasound or liver biopsy compared with method combination or other methods, while no differences were observed according to the chosen cuff inflation threshold, the presence of a significant difference in obesity measures between the groups, or the type of the control group (age- and sex-matched vs. other). Funnel plot asymmetry was not observed. Finally, compared with patients with pure steatosis, individuals with nonalcoholic steatohepatitis had significantly lower FMD (SMD: −0.81, 95% CI −1.51 to −0.31, p = 0.003, I2: 81%). In conclusion, FMD of the brachial artery, indicative of endothelial dysfunction, was significantly reduced in subjects with nonalcoholic fatty liver disease. Patients with nonalcoholic steatohepatitis might be facing a more pronounced endothelial impairment.

Serum Uric Acid Levels and Cardiometabolic Profile in Middle-Aged, Treatment-Naïve Hypertensive Patients.

INTRODUCTION: Uric acid (UA) is a risk factor associated with cardiometabolic diseases. However, the appropriate threshold of UA remains a matter of controversy. AIM: To assess whether slightly increased UA levels have any significance in middle-aged, treatment-naïve persons with new-onset hypertension. METHODS: In this cross-sectional study we recruited middle-aged participants with new-onset hypertension who were treatment-naïve. Subjects below (Group 1) and above the median UA levels (Group 2) were compared regarding clinical and laboratory characteristics that are implicated in cardiovascular and renal risk. The study population consisted of 369 persons (mean age 48.4±10 years) with median UA of 4.8 mg/dl. Group 2 individuals were predominantly male and had higher levels of blood pressure, increased body mass index, waist circumference, and a greater degree of insulin resistance. Additionally, greater lipid profile abnormalities were detected. This group also exhibited a significantly decreased fractional excretion of UA. Multivariate analysis demonstrated that serum UA levels were correlated with male sex, waist circumference, estimated glomerular filtration rate (eGFR), serum calcium and insulin levels, as well as with fractional excretion of UA. A positive association between serum UA levels and the number diagnostic criteria of the metabolic syndrome (MtS) was also noticed. After reclassification of subjects according to UA quartiles, individuals with UA levels ≥ 3.8 mg/dl had significantly higher odds (2.5-fold to 9.8-fold) of having MtS after adjustment of age, sex, and eGFR. CONCLUSIONS: Uric acid levels in middle-aged, treatment-naïve hypertensive patients are correlated with risk factors for cardiovascular and renal disease.

COVID-19 and Kidney Disease: A Clinical Perspective.

Coronavirus disease-19 (COVID-19), caused by severe acute respiratory syndrome Coronavirus- 2 (SARS-CoV-2), has caused a global pandemic with high morbidity and mortality. The presence of several comorbidities has been associated with a worse prognosis, with chronic kidney disease being a critical risk factor. Regarding COVID-19 complications, other than classical pneumonia and thromboembolism, acute kidney injury (AKI) is highly prevalent and represents a poor prognostic indicator linked to increased disease severity and mortality. Its pathophysiology is multifactorial, revolving around inflammation, endothelial dysfunction, and activation of coagulation, while the direct viral insult of the kidney remains a matter of controversy. Indirectly, COVID-19 AKI may stem from sepsis, volume depletion, and administration of nephrotoxic agents, among others. Several markers have been proposed for the early detection of COVID-19 AKI, including blood and urinary inflammatory and kidney injury biomarkers, while urinary SARS-CoV-2 load may also be an early prognostic sign. Concerning renal replacement therapy (RRT), general principles apply to COVID-19 AKI, but sudden RRT surges may mandate adjustments in resources. Following an episode of COVID-19 AKI, there is a gradual recovery of kidney function, with pre-existing renal impairment and high serum creatinine at discharge being associated with kidney disease progression and long-term dialysis dependence. Finally, kidney transplant recipients represent a special patient category with increased susceptibility to COVID- 19 and subsequent high risk of severe disease progression. Rates of mortality, AKI, and graft rejection are significantly elevated in the presence of COVID-19, highlighting the need for prevention and careful management of the disease in this subgroup.

Overview of infections as an etiologic factor and complication in patients with vasculitides.

Vasculitides, a form of inflammatory autoimmune disease targeting the vessels, constitute an entity with significant morbidity and mortality. Infections have long been associated with vasculitides as a result of the incident immunosuppression following treatment induction and maintenance. Several microbial pathogens have been described as etiologic factors of infections in this patient population according to the type of vessels affected. Intense research has also been recently conducted in the interplay between vasculitides and certain viral infections, namely human immunodeficiency virus and severe acute respiratory syndrome coronavirus 2. Of note, a plethora of scientific evidence is available regarding the role of infections as triggering factors for vasculitides. Among the main mechanisms implicated in this direction are the activation of B and T cells, the direct endothelial insult, the immune complex-mediated vascular injury, and the cell-mediated, type IV hypersensitivity vessel damage. Therefore, this review aims to summarize all the available evidence concerning this bidirectional interplay between infections and vasculitides.

Chronic Pain and Its Association with Depressive Symptoms and Renal Function in Hypertensive Patients.

Chronic pain is a common concern and is considered to be one of the major problems in patients with chronic physical disorders. We studied the effect of pain in patients with hypertension with or without chronic kidney disease (CKD) and the association between pain and symptoms of depression. The study involved 158 hypertensive individuals (59.5% male, mean age 55 years), of whom 47 (29.8%) had CKD (estimated glomerular filtration rate < 60 mL/min/1.73 m2). Pain was assessed with the pain/discomfort domain of the EuroQol-5 D, while depressive symptoms were assessed with the depression module of the Patient health questionnaire (PHQ-9). The prevalence of chronic pain in our sample was 44.3%. Women exhibited chronic pain more often compared to men (57.1% vs. 42.9%, p < 0.001). The presence of CKD was not significantly associated with a higher prevalence of chronic pain among hypertensive patients. Depressive symptoms were significantly associated with the presence of chronic pain. These findings were confirmed in the logistic regression analysis. Chronic pain is common in hypertensive individuals and the association with depression warrants further investigation and may have practical implications in managing these patients.

A Narrative Review of Recent Studies on the Role of Vitamin D in the Prevention of Cardiac and Renal Risk and Additional Considerations for COVID-19 Vulnerability.

The role of vitamin D in maintaining a healthy cardiovascular (CV) and the renal system has received increasing attention. Low vitamin D levels are associated with the incidence of hypertension, cardiac remodeling, and chronic congestive heart failure. Low vitamin D levels also influence renal disease progression and albuminuria deterioration. Moreover, recent research indicates that vitamin D deficiency can be a potential risk factor for coronavirus disease-19 (COVID-19) infection and poorer outcomes. Data are inconclusive as to whether supplementation with vitamin D agents reduces CV disease risk or COVID-19 severity. Conversely, in patients with kidney disease, vitamin D supplementation is associated with an improvement in kidney function and albuminuria. This narrative review considers recent data on the effects of vitamin D on the CV and renal system, as well as its possible role regarding COVID-19 complications.

Metformin-associated lactic acidosis and acute kidney injury in the era of COVID-19.

COVID-19, provoked by SARS-CoV-2, constitutes a global health issue with high rates of mortality. The presence of diabetes mellitus is associated with severe coronavirus COVID-19 as it is related to increased death rates in patients admitted to the intensive care unit. Acute kidney injury is a frequent complication among patients hospitalized for COVID-19 and is met with high morbidity and mortality. Here, we present a case of a diabetic patient with acute kidney injury, metformin-associated lactic acidosis, and COVID-19. Lactic acidosis is a relatively rare but noteworthy complication of metformin use. However, the combination of those life-threatening situations could prove fatal for the patients despite optimal medical care.

Dyslipidemia in Chronic Kidney Disease: Contemporary Concepts and Future Therapeutic Perspectives.

BACKGROUND: Chronic kidney disease (CKD) is an increasingly prevalent disease state met with great morbidity and mortality primarily resulting from the high incidence of adverse cardiovascular outcomes. Therapeutic strategies in this patient population aim at controlling modifiable cardiovascular risk factors, including dyslipidemia. SUMMARY: In this review article, we first provide the latest pathophysiologic evidence regarding the altered dyslipidemia pattern in CKD, followed by its contemporary management according to the latest guidelines. Moreover, we present the current progress regarding the emerging therapeutic strategies. Key Messages: The presence of renal impairment leads to alterations in cholesterol structure, metabolism, and reverse transport paired with increased oxidative stress. Statins remain the cornerstone of dyslipidemia management in patients with kidney dysfunction who are at risk for cardiovascular events. However, their efficacy is debatable in end-stage renal disease under renal replacement therapy. Therefore, novel treatment approaches aiming at hypertriglyceridemia, proprotein convertase subtilisin/kexin type 9, and lipoprotein(a) are under rigorous investigation while the research of gut microbiome might provide additional mechanistic and therapeutic insight.