Dermatology: Practical and Conceptual Original Article | Dermatol Pract Concept. 2023;13(2):e2023116 1 The Relationship of Serum Trimethylamine N-Oxide Levels with Carotid Intima-Media Thickness and Disease Activity in Psoriasis Patients Emre Zekey1, Fatma Tunçez Akyürek2, Abdullah Tunçez3, Fikret Akyürek4, Merve Ezgi Doğan5 1 Department of Dermatology, Sivas Numune Hospital, Sivas, Turkey 2 Department of Dermatology, Selcuk University Medical Faculty, Konya, Turkey 3 Department of Cardiology, Selcuk University Medical Faculty, Konya, Turkey 4 Department of Biochemistry, Selcuk University Medical Faculty, Konya, Turkey 5 Department of Public Health, Selcuk University Medical Faculty, Konya, Turkey Key words: Psoriasis, trimethylamine n-oxide , gut microbiota, atherosclerosis, carotid intima-media thickness Citation: Zekey E, Tunçez Akyürek F, Tunçez A, Akyürek F, Doğan ME. The Relationship Of Serum Trimethylamine N-Oxide Levels With Carotid Intima-Media Thickness And Disease Activity In Psoriasis Patients. Dermatol Pract Concept. 2023;13(2):e2023116. DOI: https://doi.org/10.5826/dpc.1302a116 Accepted: November 16, 2022; Published: April 2023 Copyright: ©2023 Zekey et al. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. Funding: None. Competing Interests: None. Authorship: All authors have contributed significantly to this publication. Corresponding Author: Emre Zekey, Department of Dermatology, Sivas Numune Hospital, Sivas, Turkey. E-mail: emre.zekey@gmail.com Introduction: Psoriasis is an inflammatory disease that can cause cardiovascular comorbidities. Some recent studies have indicated that impaired gut microbiota and metabolites may be associated with inflammatory diseases. Objectives: In this study, the relationship between serum trimethylamine n-oxide (TMAO, a gut bac- terial metabolite) level and carotid intima-media thickness (CIMT) and disease severity in psoriasis patients was investigated. Methods: Age- and gender-matched 73 patients and 72 healthy controls were included in the study. In both groups serum trimethylamine n-oxide(TMAO), oxidized low- density lipoprotein (ox-LDL), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycer- ide, total cholesterol, high-sensitivity C-reactive protein (hs-CRP), creatinine, aspartate aminotrans- ferase (AST) and alanine aminotransferase(ALT) levels were recorded and the carotid intima-media thickness (CIMT) was measured by B-mode ultrasonography by a cardiologist. Results: TMAO, hs-CRP, oxidized-LDL, triglyceride and CIMT levels were statistically higher in the patient group. HDL levels were statistically higher in the control group. There was no significant ABSTRACT 2 Original Article | Dermatol Pract Concept. 2023;13(2):e2023116 Introduction Psoriasis is a chronic inflammatory disease managed by the immune system. Systemic inflammation that psoriasis causes can affect many organs and systems [1]. Effector T lympho- cytes such as TH1 and TH17 are involved in the pathogenesis of psoriasis and atherosclerosis. Although the mechanisms underlying the relationship between these two diseases are still poorly understood, the inflammatory cytokine profile that plays a fundamental role in both diseases seems to provide a common pathogenic basis [2]. TMAO (oxidized product of trimethylamine) is an in- testinal microbial metabolite. Most of the trimethylamine produced from the metabolism of choline and L-carnitine by intestinal bacteria is absorbed into the blood- stream and oxidized to TMAO by the flavin-containing monooxygenase-3 (FMO-3) enzyme in the liver [3]. Increased serum TMAO concentration is associated with intestinal dysbiosis [4]. Remarkably, a dysbiotic microbi- ome similar to the dysbiosis detected in individuals with elevated serum TMAO levels has also been demonstrated in psoriasis patients [5,6]. Cross-sectional and prospective studies show a positive association between elevated plasma TMAO levels and in- creased risk for major cardiovascular events. These studies demonstrated a positive correlation between circulating TMAO levels and carotid intima-media thickness after con- trolling for strong predictors of cardiovascular disease in- cluding age, sex and visceral fat mass [7,8]. Due to similar laminar flow properties, imaging of the carotid arterial system can provide information about coronary atherosclerosis. Carotid intima-media thickness (CIMT) measured by B-mode ultrasonography can reliably demonstrate changes in the arterial wall [9,10]. Objectives In this study, we aimed to compare serum TMAO levels in psoriasis patients and healthy participants and to determine the relationship between TMAO levels and CIMT and other atherosclerotic risk factors in atherosclerotic disease risk prediction. Methods Patients and Controls Seventy-three patients diagnosed with plaque psoriasis (clin- ically and histopathologically) and 72 healthy participants as the control group were included in the study. An informed consent form was obtained from all participants and they were informed about the study. The study was conducted between 01.06.2020 and 01.06.2021. The exclusion criteria were determined as follows: Special dietary practices, continuous use of prebiotics and probiotics Consumption of >2 eggs per day, meat and fish >3 times per week Use of any medication that may adversely affect the mi- crobiota in the last 1 month Those diagnosed with diseases that may affect the micro- biome such as inflammatory bowel diseases, irritable bowel disease Those diagnosed with diabetes mellitus, hypertension, hypercholesterolemia and/or taking antidiabetic drugs, antihypertensive drugs, antihyperlipidemic drugs Thyroid disease, cardiovascular and cerebrovascular dis- eases, peripheral vascular disease and systemic vascu- litis, chronic kidney/liver disease, systemic infectious disease, collagen tissue disease and/or antiaggregant/ anticoagulant drug users Use of methotrexate, cyclosporine, biologic agents, systemic steroid and hormonal therapy in the last 3 months Malignancy, pregnancy, breastfeeding Patients under 18 years of age Obesity, smokers, drinkers difference between the two groups in terms of total cholesterol and LDL-C levels. In partial correlation analyzes in the patient group, positive correlations were observed between TMAO and CIMT, LDL-C and total cholesterol levels. Linear regression analysis showed that TMAO levels positively predicted CIMT levels. Conclusions: This study confirmed that psoriasis is a risk factor for the development of cardiovascular disease and that elevated serum TMAO levels in these patients indicate the presence of intestinal dysbi- osis. Furthermore, TMAO levels were found to be a predictor of the risk of developing cardiovascular disease in psoriasis patients. Original Article | Dermatol Pract Concept. 2023;13(2):e2023116 3 Demographic information of all participants was re- corded and systolic/diastolic blood pressure was measured from the brachial artery after 5 minutes of rest. Body-mass index (BMI) of all participants and psoriasis area severity in- dex (PASI) of patients were calculated and recorded. TMAO, oxidized-LDL, hs-CRP, cholesterol panel, ALT-AST, creati- nine, ALT-AST, creatinine levels were determined in serum samples obtained after 12 hours of fasting. Right and left ca- rotid intima-media thicknesses were measured and recorded in all participants. Measurement of Biochemical Markers Blood samples were collected from the antecubital re- gions of the participants into gel propylene tubes using a vacutainer. Blood samples were allowed to clot for 20  minutes, centrifuged at 3000 rpm for 10 minutes and stored at -80°C until the study day. Frozen serum samples were kept at room temperature on the study day and the samples were thawed. MyBioSource brand Oxidized LDL (catalog No: MBS265658) commercial kit for oxidized-LDL analysis and MyBioSource brand TMAO (catalog No: MBS7254766) commercial kits for TMAO analysis were used. Analyzes were performed using Rayto RT-2600Microplate Washer and BMG LABTECH Enzyme-Linked ImmunoSorbent As- say (ELISA) reader. The quantitation limits for the oxidized LDL kit are 31.2-2000 pg/mL, and the quantitation limits for TMAO are 0-100 ng/mL. Samples were diluted 1/10 before the study. ALT, AST, creatinine, total cholesterol, triglycer- ide, HDL-cholesterol, total cholesterol, triglyceride, HDL-cholesterol levels were analyzed by spectrophotometric method on Beckman Coulter AU5800 Series using Beckman Coulter commercial kits. Hs-CRP levels were analyzed by immunoturbidimetric method using Beckman Coulter brand commercial kits in Beckman Coulter AU5800 Series device. Measurement of Carotid Intima-Media Thickness Carotid artery ultrasound to measure carotid intima-media thickness was performed by a cardiologist using a commer- cially available ultrasound system (Vivid E9, GE Vingmed) and a linear transducer probe (11L-D, 5-12 MHz). Participants were examined in the supine position after resting for at least 5 minutes. Imaging of both arteria carotids communis was per- formed with the participants' head in a slightly extended and slightly retracted position with the carotid bifurcation as the reference point. Two-dimensional, real-time, grayscale images in the lon- gitudinal plane were acquired at frame rates of 20-50 fps with focus and gain settings adjusted to maximize visibility of the near and far wall of the artery. Statistical Method All data were analyzed in computer environment using SPSS 22.0 package program. Categorical data were evaluated with the Chi-Square Exact test. The Kolmogorow-Smirnow test was performed to determine whether the continuous data showed a normal distribution. Continuous data that did not show normal distribution were tested for their con- formity to the normal distribution by data transformation. In the comparison of continuous data of two independent groups, Student-t test was used when parametric test con- ditions were met, Mann Whitney U test was used when parametric test conditions were not met. In order to deter- mine the relationship between continuous variables, Pear- son correlation test was used when normality conditions were met and Spearman correlation test was used when normality conditions were not met. In order to determine the true relationship between the data, the partial cor- relation test was used by controlling the related variables. Simple and multiple linear regression analysis was applied to determine the risk of cardiovascular disease. Regression analysis data were reported as R square, adjusted R square, standardized coefficiency β coefficients. In the analysis of all hypothesis tests, the level of significance (P value) was accepted as 0.05. Results The patient and control groups were similar in terms of gender. There was no significant difference between the patient and control groups in terms of mean age, BMI, systolic/ diastolic blood pressure(P > 0.05). TMAO (323.34 ± 240.36 ng/ml versus 220.96 ± 85.36 ng/ml), hs-CRP (2.318 ± 2.00 mg/L versus 1.306 ± 0.74 mg/L), oxidized-LDL(82.50 ± 42.03 pg/ml versus 61.34 ± 31.34 pg/ml) and triglyceride (150.87 ± 87.85 mg/dl versus 119.83 ± 70.02 mg/dl) levels were higher in the patient group compared to the control group (Figure 1). There was no significant difference in total choles- terol and LDL-cholesterol levels in the patient and control groups(P > 0.05). HDL-cholesterol levels were higher in the control group compared to the patient group (47.75 ± 10.12 mg/dl versus 39.09 ± 9.38 mg/dl). Left-anterior (0.598 ± 0.129 nm versus 0.534 ± 0.068 nm), left-posterior (0.602 ± 0.172 nm versus 0.528 ± 0.093 nm) and right-anterior (0.623 ± 0.177 nm versus 0.537 ± 0.086 nm), right-posterior (0.605 ± 0.164 nm versus 0.520 ± 0.075 nm) 4 Original Article | Dermatol Pract Concept. 2023;13(2):e2023116 carotid intima-media wall thicknesses were significantly higher in the patient group compared to the control group (Figures 2 and 3). The clinical and laboratory data of the patient and control groups are given in Table 1. In the partial correlation analysis performed after con- trolling for age, disease duration and BMI parameters, pos- itive correlations were observed at various levels between TMAO levels and total cholesterol, LDL cholesterol, left an- terior and right posterior CIMT (Table 2). When parameters that may affect CIMT (age, BMI, dis- ease duration, PASI score, blood cholesterol, hs-CRP and oxidized-LDL) were controlled, positive correlations were found between TMAO levels and left anterior and right pos- terior CIMT at various levels (Table 3). Simple linear regression analysis was performed to pre- dict the left CIMT variable by using TMAO levels. A signif- icant regression model was found in which 10% (R square adjusted = .10) of the variance in the left CIMT was explained by the independent variable (F [1, 71]:8.084, P = 0.006). Accordingly, TMAO predicted left CIMT positively and sig- nificantly, ß= .32, t(71) = 2.843, P = :0.006 (Table.4). Multivariate linear regression analysis was performed to predict the left CIMT variable by using TMAO, PASI, dis- ease duration, age, ox-LDL, total cholesterole, triglyceride, BMI variables. A significant regression model was found in which 41% (R square adjusted= .41) of the variance in the left CIMT was explained by the independent variables (F [9, 63]:6,644, P < 0.001). Accordingly, TMAO predicted left CIMT positively and significantly (ß= .371, t(63)=3.801, CONTROL PATIENT 0 50 100 150 200 250 300 350 TMAO (ng/ml) Figure 1. Trimethylamine n-oxide levels in patient and control groups. P < 0.001). In addition, age predicted left CIMT posi- tively and significantly (ß= .618, t(63)=5.428, P < 0.001). Oxidized-LDL, hs-crp, triglyceride, total cholesterol, PASI, disease duration and BMI did not significantly predict left CIMT in this model (P > 0.05). The regression model con- firmed that TMAO was a positive predictor for left anterior CIMT and may be a predictor for cardiovascular disease sec- ondary to these outcomes (Table 5). Conclusions Psoriasis is not only a skin and joint disease, but also a sys- temic inflammatory disease that can be associated with var- ious comorbidities. It is associated with an increased risk of developing serious vascular events, particularly myocardial infarction and stroke. Psoriasis and atherosclerotic cardio- vascular disease share common genetic and pathophysio- logical pathways, including genetic factors, inflammatory pathways, secretion of adipokines, insulin resistance, lipo- protein composition and function, angiogenesis, oxidative stress and hypercoagulation [11]. The development of atherosclerosis is a major pathologi- cal process that can lead to myocardial infarction and stroke. In the literature, there are studies showing that arterial wall thickness is increased in patients with psoriasis compared to healthy controls and this increase is correlated with disease severity. Positron emission tomography/computed tomog- raphy studies have found that aortic wall inflammation is higher in patients with psoriasis than in the healthy popula- tion and that there is a positive correlation between disease Original Article | Dermatol Pract Concept. 2023;13(2):e2023116 5 LEFT POSTERIOR CIMT LEFT ANTERIOR CIMT 0.48 0.5 0.52 0.54 0.56 0.58 0.6 0.62 Control(mm) Patient(mm) Figure 2. Left carotid intima-media thickness levels in patient and control groups. RIGHT POSTERIOR CIMT RIGHT ANTERIOR CIMT 0.46 0.48 0.5 0.52 0.54 0.56 0.58 0.6 0.62 0.64 Control(mm) Patient(mm) Figure 3. Right carotid intima-media thickness levels in patient and control groups. severity and inflammation severity. Furthermore, aortic in- flammation decreases with healing of skin lesions [12,13]. The finding of higher CIMT levels in psoriasis patients compared to healthy controls in carotid artery ultrasonogra- phy studies clearly demonstrates an increased risk of cardio- vascular disease in psoriasis patients [14-16]. Our study showed that CIMT levels were significantly higher in psoriasis patients compared to the control group. There were also positive correlations between CIMT values and patient age, disease duration, TMAO, hs-CRP, triglycer- ide, total cholesterol, body mass index and blood pressures. In the light of these data, CIMT measurement can be used 6 Original Article | Dermatol Pract Concept. 2023;13(2):e2023116 to detect the risk of early atherosclerotic disease in patients with psoriasis, which is consistent with previous studies. Microbiota related immunomodulation has shown that the gut microbiome plays a role in influencing distant organs, mucosal and hematopoietic immune function. Disruption in the composition and function of the intestinal microbiota is associated with a variety of chronic diseases, from gas- trointestinal inflammatory and metabolic diseases to neuro- logical, cardiovascular and respiratory system diseases. The changes observed in the composition of the gut microbiome in studies with psoriasis patients have prompted researchers to investigate the molecular mechanisms associated with the microbiome and its possible impact on the disease [17-19]. In recent years, the TMAO molecule formed by the oxidation in the liver of TMA produced from choline and L-carnitine by the gut microbiome is thought to be associ- ated with increased cardiovascular risk and atherosclerosis, but there are also conflicting results. The dysbiotic gut microbiome observed in psoriasis pa- tients is similar to the composition of the dysbiotic microbi- ome, which is involved in TMAO production [5,6,17]. TMAO Table 1. Data for patients and healthy controls. Patient (N = 73) Mean ± SD Control (N = 72) Mean ± SD Pa Disease type Type-1(%86.30) Type-2(%13.70) Age (year) 41.57 ± 12.98 41.22 ± 9.25 0.851 BMI (kg/m2) 26.14 ± 4.20 25.63 ± 3.35 0.420 Systolic blood pressure (mmHg) 121.34 ± 10.05 122,06 ± 10.50 0.676 Diastolic blood pressure (mmHg) 79.74 ± 7.27 81.26 ± 7.62 0.187 TMAO (ng/ml) 323.34 ± 240.36 220.96 ± 85.36 0.028 HsCRP (mg/L) 2.318 ± 2.00 1.306 ± 0.74 0.013 Oxidized-LDL (pg/ml) 82.50 ± 42.03 61.34 ± 31.34 0.010 Total cholesterol (mg/dl) 189.77 ± 41.12 194.29 ± 34.71 0.475 HDL cholesterol (mg/dl) 39.09 ± 9.38 47.75 ± 10.12 0.001 LDL cholesterol (mg/dl) 120.74 ± 36.71 121.99 ± 29.68 0.323 Triglyceride (mg/dl) 150.87 ± 87.85 119.83 ± 70.02 0.025 AST (IU/L) 20.50 ± 5.53 20.93 ± 4.27 0.291 ALT (IU/L) 17.13 ± 8.18 17.82 ± 7.95 0.523 Creatinine (mg/dL) 0.75 ± 0.14 0.75 ± 0.20 0.948 Left anterior CIMT (mm) 0.598 ± 0.129 0.534 ± 0.068 0.010 Left posterior CIMT (mm) 0.602 ± 0.172 0.528 ± 0.093 0.030 Right anterior CIMT (mm) 0.623 ± 0.177 0.537 ± 0.086 <0.001 Right posterior CIMT (mm) 0.605 ± 0.164 0.520 ± 0.075 0.020 ALT = alanine aminotransferase; AST = aspartate aminotransferase; BMI = body mass index; CIMT = carotid intima-media thickness; HsCRP = high sensitivity C-reactive protein; HDL = high density lipoprotein; LDL = low density lipoprotein; SD = standard deviation; TMAO = trimethylamine n-oxide. aThe level of significance (P value) was accepted as 0.05. plays an important role in oxidized-LDL accumulation and foam cell formation within macrophages by increasing the expression of CD36 and macrophage scavenger receptors (SR-A1). It enhances macrophage chemotaxis, expression of inflammatory cytokines including TNF-alpha and IL-6, and may exacerbate inflammation via MAPK and NF-κB. It also decreases the expression of the anti-inflammatory cytokine IL-10 [20-23]. Studies investigating serum TMAO levels and their re- lationship with comorbidities in patients with psoriasis are still very limited. Sikora et al. found that TMAO levels were significantly higher in psoriasis patients than in controls and this elevation was in parallel with the increased cardiovas- cular risk [24]. In this study, we found that serum TMAO levels were significantly higher in psoriasis patients compared to the control group. In the patient group, there were positive cor- relations between serum TMAO concentrations and CIMT values when other cardiovascular risk markers were con- trolled. The results support the presence of gut dysbiosis in psoriasis patients, and these data support the idea that Original Article | Dermatol Pract Concept. 2023;13(2):e2023116 7 Ta b le 2 . C o rr el at io n s w h en c o n tr o ll in g fo r ag e, B M I, a n d d is ea se d u ra ti o n i n t h e p at ie n t gr o u p . T M A O O x id iz e d -L D L H s- C R P Tr ig ly ce ri d e To ta l- C H D L- C LD L- C PA S I Le ft a n t C IM T Le ft p o st C IM T R ig h t a n t C IM T R ig h t p o st C IM T T M A O P 1 .0 0 0 r 0 .0 0 0 O x id iz ed -L D L P 0 .6 6 7 1 .0 0 0 r 0 .0 5 2 0 .0 0 0 H sC R P P 0 .5 1 0 0 .8 4 7 1 .0 0 0 r -0 .0 8 0 0 .0 2 3 0 .0 0 0 T ri gl yc er id e P 0 .8 2 1 0 .0 2 2 0 .2 6 5 1 .0 0 0 r -0 .0 2 7 0 .2 7 4 0 .1 3 5 0 .0 0 0 T o ta l- C P 0 .0 0 6 0 .4 6 5 0 .7 4 8 0 .0 0 3 1 .0 0 0 r 0 .3 2 5 0 .0 8 9 -0 .0 3 9 0 .3 4 5 0 .0 0 0 H D L -C P 0 .6 5 5 0 .5 7 3 0 .0 1 4 0 .0 0 1 0 .9 0 3 1 .0 0 0 r 0 .0 5 4 -0 .0 6 9 -0 .2 9 3 -0 .3 8 7 0 .0 1 5 0 .0 0 0 L D L -C P 0 .0 0 3 0 .9 6 0 0 .8 0 4 0 .8 3 7 < 0 .0 0 1 0 .5 5 9 1 .0 0 0 r 0 .3 4 9 -0 .0 0 6 -0 .0 3 0 0 .0 2 5 0 .9 1 8 -0 .0 7 1 0 .0 0 0 PA SI P 0 .5 8 0 0 .2 8 8 0 .6 1 3 0 .3 8 0 0 .1 1 4 0 .5 1 1 0 .1 2 9 1 .0 0 0 r -0 .0 6 7 -0 .1 2 9 0 .0 6 2 -0 .1 0 6 -0 .1 9 1 0 .0 8 0 -0 .1 8 3 0 .0 0 0 L ef t an t C IM T P < 0 .0 0 1 0 .3 4 0 0 .5 4 7 0 .4 7 1 0 .1 4 1 0 .0 7 0 0 .1 0 0 0 .2 1 0 1 .0 0 0 r 0 .4 5 3 0 .1 1 6 -0 .0 7 3 0 .0 8 8 0 .1 7 8 -0 .2 1 8 0 .1 9 8 -0 .1 5 2 0 .0 0 0 L ef t p o st C IM T P 0 .7 7 3 0 .3 6 2 0 .2 3 8 0 .1 8 9 0 .6 6 1 0 .0 9 5 0 .7 5 8 0 .5 8 3 0 .0 1 9 1 .0 0 0 r 0 .0 3 5 0 .1 1 1 0 .0 4 7 0 .1 5 9 0 .0 5 3 -0 .2 0 1 0 .0 3 8 -0 .0 6 7 0 .2 8 1 0 .0 0 0 R ig h t an t C IM T P 0 .9 4 3 0 .0 6 8 0 .4 8 2 0 .6 1 9 0 .7 4 0 0 .0 8 6 0 .4 6 2 0 .4 2 3 0 .0 0 6 0 .0 3 2 1 .0 0 0 r 0 .0 0 9 0 .2 1 9 0 .0 8 5 0 .0 6 1 0 .0 4 0 -0 .2 0 7 0 .0 8 9 -0 .0 9 7 0 .3 2 7 0 .2 5 6 0 .0 0 0 R ig h t p o st C IM T P 0 .0 3 4 0 .1 5 0 0 .0 8 4 0 .2 0 8 0 .2 2 6 0 .0 9 4 0 .2 7 2 0 .9 5 1 < 0 .0 0 1 0 .0 0 4 0 .6 1 3 1 .0 0 0 r 0 .2 5 3 0 .1 7 4 0 .2 0 8 0 .1 5 2 0 .1 4 7 -0 .2 0 2 0 .1 3 3 -0 .0 0 8 0 .4 6 1 0 .3 4 3 0 .0 6 1 0 .0 0 0 A LT = a la n in e am in o tr an sf er as e; A ST = a sp ar ta te a m in o tr an sf er as e; B M I = b o d y m as s in d ex ; C IM T = c ar o ti d i n ti m a- m ed ia t h ic k n es s; H sC R P = h ig h s en si ti vi ty C -r ea ct iv e p ro te in ; H D L = h ig h d en si ty l ip o p ro te in ; L D L = l o w d en si ty l ip o p ro te in ; PA SI = P so ri as is A re a an d S ev er it y In d ex ; SD = s ta n d ar d d ev ia ti o n ; T M A O = t ri m et h yl am in e  n -o x id e. 8 Original Article | Dermatol Pract Concept. 2023;13(2):e2023116 Table 5. Multiple linear regression model adjusted for trimethylamine n-oxide, Psoriasis Area and Severity Index, disease duration, age, ox- low density lipoprotein, total cholesterol, triglyceride, body mass index (dependent variable: left anterior carotid intima-media thickness). Standardized coefficients beta t P Variance inflation factor (VIF) TMAO 0.371 3,801 <0.001 1.169 Age 0.618 5.428 <0.001 1.590 Oxidized-LDL 0.047 0.499 0.620 1.108 HsCRP -0.040 -0.399 0.691 1.248 Triglyceride 0.078 0.705 0.483 1.503 Total cholesterol -0.023 -0.209 0.835 1.543 PASI -0.088 -0.943 0.350 1.068 Disease duration -0.005 -0.047 0.963 1.420 BMI -0.079 -0.794 0.430 1.201 BMI = body mass index; HsCRP = high sensitivity C-reactive protein; LDL = low density lipoprotein; PASI = Psoriasis Area and Severity Index Table 3. Correlations between trimethylamine n-oxide and carotid intima-media thickness levels when age, body mass index, disease duration, Psoriasis Area and Severity Index score, blood cholesterol, high sensitivity C-reactive protein and oxidized- low density lipoprotein were controlled. TMAO Left ant CIMT Left post CIMT Right ant CIMT Right post CIMT TMAO P 1.000 r 0.000 Left ant CIMT P <0.001 1.000 r 0.447 0.000 Left post CIMT P 0.711 0.028 1.000 r 0.048 0.277 0.000 Right ant CIMT P 0.905 0.004 0.077 1.000 r -0.015 0.358 0.225 0.000 Right post CIMT P 0.047 <0.001 0.025 0.870 1.000 r 0.251 0.439 0.282 0.021 0.000 CIMT = carotid intima-media thickness; TMAO = trimethylamine n-oxide. Table 4. Simple linear regression model, predictor: trimethylamine n-oxide, dependent: left anterior and right posterior carotid intima-media thickness. R2 Standardized coefficients beta t P f Predictor: TMAO Dependent: Left Ant CIMT 0.102 0.320 2.843 0.006 8.084 Predictor: TMAO Dependent: Right Post CIMT 0.020 0.141 1.199 0.235 1.199 CIMT = carotid intima-media thickness; TMAO = trimethylamine n-oxide. TMAO is a metabolite originating from the gut microbiota that increases the risk of cardiometabolic disease. In regres- sion models, TMAO levels were found to be a positive pre- dictor of cardiovascular disease risk (Figure 4). CRP is a circulating acute phase reactant that reflects ac- tive systemic inflammation. Increased hs-CRP levels are as- sociated with a higher risk of cardiovascular disease, even in individuals without clinical manifestations of atherosclerotic disease [25]. In psoriasis patients, hs-CRP levels are higher than in the healthy population and correlated with the risk of atherosclerotic disease [26,27]. In this study, hs-CRP levels were found to be higher in the patient group compared to healthy controls. 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Relationship of serum trimethylamine N-oxide (TMAO) levels with early ath- erosclerosis in humans. Sci Rep. 2016;6:26745. DOI: 10.1038 /srep26745. PMID: 27228955. PMCID: PMC4882652. 9. Jadhav UM, Kadam NN. Carotid intima-media thickness as an independent predictor of coronary artery disease. Indian Heart J. 2001;53(4):458-462. PMID: 11759935. and BMI, negative correlation between hs-CRP and HDL-C in psoriasis patients shows that obesity and metabolic syn- drome actually cause systemic inflammatory response. Cytokine profile observed in psoriasis patients contrib- utes to the formation of dyslipidemia and atherosclerosis through mechanisms such as irregularities in membrane protein synthesis of lipoproteins in the liver, impaired re- verse cholesterol transport via HDL-C, the effect of chylo- micron residues on atherosclerosis and paradoxical LDL-C increase [28]. In this study, oxidized-LDL and triglyceride levels were higher and HDL-C levels were lower in the patient group compared to healthy controls. There was no statistically dif- ference between the two groups in terms of total cholesterol and LDL-C. Limitations of the study: this was a cross-sectional study and was conducted in a limited population. Psoriasis is a chronic systemic inflammatory disease and has been associated with an increased risk of cardio- vascular mortality and morbidity in many studies. The data obtained in this study also showed that psoriasis is a risk factor for cardiovascular disease. Although TMAO has been recognized in recent years as an intestinal microbiota and diet-related molecule that triggers atherosclerosis in the ves- sel wall, there are conflicting results in studies. In this study, serum TMAO levels were significantly higher in psoriasis patients, indicating intestinal dysbiosis, in addition TMAO level is an independent positive predictor for cardiovascular disease risk status. Further studies are needed to determine the diversity of gut bacterial colonization in psoriasis pa- tients, genetic factors, molecular mechanisms controlling gut wall permeability, and the role of probiotics, prebiotics, and perhaps antibiotics to reduce cardiovascular disease risk. 1.20 1.00 0.80 0.60 0.40 0.20 0.00 0.00 200.00 400.00 600.00 800.00 1000.00 1200.00 1400.00 TMAO (ng/ml) Le ft A n te ri o r C IM T (m m ) Figure 4. Relationship between trimethylamine n-oxide and left anterior carotid intima-media thickness. 10 Original Article | Dermatol Pract Concept. 2023;13(2):e2023116 20. Geng J, Yang C, Wang B, et al. Trimethylamine N-oxide pro- motes atherosclerosis via CD36-dependent MAPK/JNK path- way. Biomed Pharmacother. 2018;97:941-947. 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Trimethylamine N-Oxide, a Gut Microbiota-Derived Metabolite, Is Associated with Cardiovascular Risk in Psoriasis: A Cross-Sectional Pilot Study. Dermatol Ther (Heidelb). 2021;11(4):1277-1289. DOI: 10.1007/s13555-021-00547-3. PMID: 33983475.PMCID: PMC8322249. 25. Yu H, Rifai N. High-Sensitivity C-Reactive Protein and Atherosclerosis: From Theory to Therapy. Clin Biochem. 2000;33(8):601-610. DOI: 10.1016/s0009-9120(00)00186-7. PMID: 11166006. 26. Niknezhad N, Haghighatkhah HR, Zargari O, et al. High-sensitivity C-reactive protein as a biomarker in detecting subclinical ath- erosclerosis in psoriasis. Dermatol Ther. 2020;33(4):e13628. DOI: 10.1111/dth.13628. PMID: 32431027. 27. Yiu K-H, Yeung C-K, Chan H-T, et al. Increased arterial stiff- ness in patients with psoriasis is associated with active sys- temic inflammation. Br J Dermatol. 2011;164(3):514-520. DOI: 10.1111/j.1365-2133.2010.10107.x. PMID: 21039409. 28. Armstrong EJ, Krueger JG. 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