ORIGINAL RESEARCH

published: 13 June 2022

doi: 10.3389/fendo.2022.920340

Vitamin D Effects on Selected

Anti-Inflammatory and Pro-
Inflammatory Markers
of Obesity-Related
Chronic Inflammation
Maria Krajewska 1*, Ewelina Witkowska-Se˛ dek 1, Małgorzata Rumińska 1,
Anna Stelmaszczyk-Emmel 2, Maria Sobol 3, Anna Majcher 1 and Beata Pyrżak 1
1 Department of Paediatrics and Endocrinology, Medical University of Warsaw, Warsaw, Poland, 2 Department of Laboratory

Diagnostics and Clinical Immunology of Developmental Age, Warsaw, Medical University of Warsaw, Warsaw, Poland,
3 Department of Biophysics, Physiology and Pathophysiology, Medical University of Warsaw, Warsaw, Poland

Edited by:
Artur Mazur,
University of Rzeszow, Poland
Background: Obesity is related to changes in adipokine secretion, activity of adipose
Reviewed by:
tissue macrophages, helper T cells, and regulatory T cells. It has been confirmed that
Maria Giżewska, vitamin D has potent anti-inflammatory properties. It contributes to reduction in pro-
Pomeranian Medical University,
inflammatory mediators and an increase in anti-inflammatory cytokines. There is also
Poland
Serhiy Nyankovskyy, evidence that vitamin D could decrease C-reactive protein (CRP) and affect selected
Danylo Halytsky Lviv National Medical haematological indices.
University, Ukraine
Artemis Doulgeraki, Aim of the Study: We aimed to evaluate the effect of vitamin D on interleukin (IL)-10, IL-
Institute of Child Health, Greece
17, CRP, blood leukocyte profile, and platelet (PLT) count in overweight and obese
*Correspondence:
children before and after six months of vitamin D supplementation.
Maria Krajewska
maria.krajewska@wum.edu.pl Material and Methods: The study group consisted of 67 overweight and obese children
aged 9.08-17.5 years. The control group included 31 normal weight peers age- and sex-
Specialty section:
This article was submitted to
matched. None of the studied children had received vitamin D supplementation before the
Obesity, study. Data were analyzed at baseline and after vitamin D supplementation.
a section of the journal
Frontiers in Endocrinology Results: The study group had lower baseline 25(OH)D (p<0.001) and higher white blood
Received: 14 April 2022 cell (WBC) (p=0.014), granulocyte (p=0.015), monocyte (p=0.009) and CRP (p=0.002)
Accepted: 10 May 2022 compared to the control group. In the study group, vitamin D levels were related negatively
Published: 13 June 2022
to nutritional status. Leukocyte profile parameters, PLT, CRP, IL-10 or IL-17 were not
Citation:
Krajewska M, Witkowska-Se˛ dek E,
related to baseline 25(OH)D. Baseline IL-17 levels correlated with monocytes (R= 0.36,
Rumińska M, Stelmaszczyk-Emmel A, p=0.003) independently on 25(OH)D deficit. In children with vitamin D <15ng/ml, the
Sobol M, Majcher A and Pyrżak B
baseline 25(OH)D was related to CRP (R=-0.42, p=0.017). After six months of vitamin D
(2022) Vitamin D Effects on Selected
Anti-Inflammatory and Pro- supplementation, we noticed a decrease in CRP levels (p=0.0003). Serum 25(OH)D
Inflammatory Markers of Obesity- correlated with IL-10 in that period (R=0.27, p=0.028). Moreover, we noticed that IL-10
Related Chronic Inflammation.
Front. Endocrinol. 13:920340.
correlated with monocyte (R=-0.28, p=0.023). We did not find any significant associations
doi: 10.3389/fendo.2022.920340 between 25(OH)D and leukocyte profile parameters, PLT, or IL-17. The multivariable

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Krajewska et al. Vitamin D and Inflammatory Markers

stepwise regression analysis identified IL-10 as the parameter positively associated with
25(OH)D.
Conclusions: Our study confirmed beneficial effects of vitamin D supplementation in
overweight and obese paediatric populations. Vitamin D intake seems to exert its anti-
inflammatory effect mainly via decreasing the CRP level and protecting stabile values of IL-
10, rather than its impact on pro-inflammatory factors such as lL-17 and leukocyte profile
parameters.
Keywords: obesity, children, interleukin-10, interleukin-17, C-reactive protein, blood leukocyte profile, platelets,
vitamin D

INTRODUCTION inflammatory cytokines could affect systemic inflammation by

enhancing liver production of acute phase markers including
Vitamin D deficiency is commonly observed in overweight and fibrinogen and C-reactive protein (CRP) and by activating
obese children and adolescents (1, 2). The inverse associations granulocyte and monocyte progenitor cells (29–32). Higher
between 25-hydroxyvitamin D (25(OH)D) serum levels and both blood leukocyte, lymphocyte, granulocyte, eosinophil, and
fat volume and body mass index (BMI) have been confirmed (3, monocyte count is well documented in obese individuals
4). The main mechanisms involved in the obesity-related (33–36).
hypovitaminosis D include decreased bioavailability of vitamin Current studies show that vitamin D exerts multiple non-
D due to its fat solubility and sequestration in abdominal fat, calcaemic effects. Vitamin D receptors have been discovered in
reduced intestinal absorption, impaired metabolism, decreased many cells and types of tissues, including human subcutaneous
liver 25(OH)D synthesis as a result of hepatic steatosis, and the adipose tissue, visceral adipose tissue, pancreatic beta-cells, and
influence of leptin and interleukin-6 (IL-6) on hepatic vitamin D T cells (2, 37–42). Moreover, the presence of VDRs has been also
receptors (VDRs) (2, 3, 5–10). There is also some evidence that confirmed in the brain in arcuate and paraventricular nuclei of
inflammation could reduce 25(OH)D levels via oxidative stress the hypothalamus, which are responsible for regulation of body
resulting in the oxidative 25(OH)D catabolism (11, 12). weight (41, 42). Lumeng et al. (21) indicate that hypothalamic
Sedentary lifestyle and lower outdoor physical activity, leading inflammation impacts metabolism, mainly by reducing the
to insufficient sun exposure as well as inappropriate vitamin D release of insulin from beta cells, impairing insulin peripheral
dietary intake, also predispose obese individuals to vitamin D action and also by aggravating hypertension. The main
deficiency (8, 13). Taking into account the high prevalence of mechanisms of vitamin D action in obesity include the
overweight and obesity in people of all age groups, including influence on adipose tissue inflammatory process via effects on
children and young adults, the role of vitamin D in the adipokine secretion and on the immune system cells by
pathogenesis of obesity and prevention of obesity-related regulating their proliferation and metabolism leading to
metabolic disorders is extensively investigated (2, 11, 14–17). inhibition of T cell proliferation and induction of Treg
Adipose tissue cannot be considered only as an energy reservoir differentiation (17, 38, 43–46). It has been confirmed that the
that consists of adipocytes and their precursors. It also contains active form of vitamin D (1,25-dihydroxyvitamin D) has potent
mesenchymal progenitor/stem cells, endothelial cells, pericytes, anti-inflammatory properties resulting in a switch from Th1/
T cells, and M2 macrophages known as stromal vascular fraction, Th17 response, which is more inflammatory to Th2/Treg
which play an important role in the integration of endocrine, response, which has less inflammatory potential (11, 47–49).
metabolic, and inflammatory signals (2, 18). Excess body fat This results in decreased secretion of pro-inflammatory
mass is closely related to significant changes in adipokine mediators such as interferon gamma (IFN-g), TNF-a, IL-1b,
secretion, accumulation, and activity of adipose tissue IL-6, IL-8, IL-12, IL-17 and increased production of anti-
macrophages, helper T (Th) cells, and regulatory T (Treg) cells inflammatory cytokines such as IL-4 and IL-10 (11, 50–54).
(2, 19–24). Several studies have shown an increase in pro- There is also some evidence that vitamin D could decrease serum
inflammatory factors [IL-6, IL-8, IL-1b, IL-17, leptin, tumor CRP levels and the erythrocyte sedimentation rate (55–61). The
necrosis factor alpha (TNF-a)] and reduction in adiponectin and effect of hypovitaminosis D, as well as the influence of vitamin D
anti-inflammatory interleukins (IL-4, IL-10, IL-13) in obese supplementation on selected haematological indices has been
individuals (2, 25, 26). These mediators are involved in mutual also investigated but available data are limited (62–65). In
interactions between the immune and metabolic systems, addition to the fact that most authors reported the link
contributing to the development of insulin resistance, between vitamin D and red blood cell parameters (66–68),
hyperglycaemia, atherogenic dyslipidaemia, and hypertension there are also some studies describing the impact of vitamin D
which highly increase the risk of atherosclerotic cardiovascular on monocyte and platelet (PLT) count (64, 69, 70). Information
disease and diabetes mellitus type 2, even in the paediatric and about those associations in obese children and adolescents
young adult populations (25, 27, 28). Moreover, pro- is scarce.

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Krajewska et al. Vitamin D and Inflammatory Markers

In the present study we aimed to evaluate the effect of vitamin (OH)D < 15 ng/ml - a subgroup of overweight and obese
D on IL-10, IL-17, CRP, blood leukocyte profile, and PLT count children with “severe” baseline vitamin D deficiency and serum
in a group of overweight and obese children before and after six 25(OH)D ≥ 15 ng/ml - a subgroup of overweight and obese
months of vitamin D supplementation. children with “low” baseline vitamin D deficiency).

Biochemical Analyses
Blood samples were collected after overnight fasting and
MATERIAL AND METHODS analyzed by standard methods. White blood cells (WBC) and
This prospective study was conducted in the Department of PLT count were obtained by an automated blood cell counter
Paediatrics and Endocrinology of the Medical University of (XN-1000, Sysmex, Germany). The levels of CRP (mg/dl) were
Warsaw, Poland. Design of the study was approved by the measured using a fixed-point immune-rate method on the Vitros
Bioethics Committee at the Medical University of Warsaw, Poland 5600 analyzer (Ortho Clinical Diagnostic, New Jersey, USA).
(decision number KB/257/2013). The study group consisted of 67 Serum 25(OH)D levels (ng/ml) were determined by the
children (15 overweight and 52 obese) aged from 9.08 to 17.5 years immunoassay method using Architect Analyzer (Abbott
with mean body mass index (BMI) 30.9 ± 4.7. The control group Diagnostics, Lake Forest, USA). Serum levels of IL-10 (pg/ml)
included 31 normal weight peers with mean BMI 18.7 ± 2.7 age- and and IL-17 (pg/ml) were evaluated by ELISA (R&D Systems,
sex-matched. None of the studied children had received vitamin D Minneapolis, USA) using Asys UVM 340 analyzer.
supplementation within the last 12 months before being including in
the study. In both the study and the control groups, blood Statistical Analysis
morphology was evaluated to exclude iron deficiency anaemia due Statistical analysis was performed using Statistica 13.3. Data
to its possible effect on platelet count. Patients with iron deficiency distribution was checked using the Shapiro–Wilk test. Data were
features in blood morphology were not included in the study. At the presented as means with standard deviation or the median and
time of blood collection, children in both the study and the control interquartile ranges, as appropriate. Comparisons between
group were healthy, without any symptoms of infection and chronic baseline data of the study group and the control group were
diseases and were not taking any medication. During the study made using the T-test for parametric data or using the U Mann-
period the participants did not change their diet or the level of Whitney test for non-parametric data. Analysis of changes of the
physical activity. Vitamin D status, levels of IL-10, IL-17, CRP, blood same parameter at baseline and after six months of vitamin D
leukocyte profile, and PLT count were determined at baseline (in the supplementation were provided using the T-test or the Wilcoxon
study group and in the control group) and after six months of test, as appropriate. Correlation analysis was performed using
vitamin D supplementation (in the study group). the Spearman correlation coefficient. In further analysis, we used
The aim of vitamin D supplementation was to achieve the multivariable stepwise regression analysis to determine
reference serum 25(OH)D levels between 30 and 50 ng/ml after which inflammatory factors (model 1: IL-10, IL-17, CRP, WBC
six months of intervention (71). The doses of vitamin D ranged or model 2: IL-10, IL-17, CRP, monocytes) were associated with 25
from 2000 to 4000 units per day depending on the serum 25(OH) (OH)D levels (as dependent variable) at baseline and after six
D levels, which were assessed every month. Systematic evaluation months of vitamin D supplementation.
of serum 25(OH)D concentrations allowed us to control
compliance and to modify administered vitamin D doses to
achieve reference values after six months of the study. RESULTS
Anthropometric parameters (height, weight, waist and hip
circumference) were measured using standardized methods. Based Baseline anthropometric and biochemical characteristics of the
on these measurements, BMI, waist-to-hip ratio (WHR), and waist- study group and the control group are presented in Table 1. The
to-height ratio (WHtR) were calculated. The skinfold thickness study group characterized significantly lower baseline serum 25
(mm) was measured under the triceps brachii muscle and under the (OH)D levels compared to the control group (median 15.9 vs
inferior scapular angle. Body fat percentage was calculated in the 23.9 ng/ml, p < 0.001). We also found significant baseline
study group and in the control group using the Slaughter formula differences in leukocyte profile parameters and CRP levels
(72). Additionally, in the study group, the percentage of fat was between those groups, while baseline PLT count, IL-10, and
calculated using a bioimpedance analysis device (Maltron Body IL-17 levels did not differ significantly between the study group
FAT Analyzer BF-905). Height and weight were evaluated and the control group. Baseline WBC (p = 0.014), granulocyte (p
according to Polish 2010 growth references for school-aged = 0.015), monocyte (p = 0.009) count and CRP levels (p = 0.002)
children and adolescents (73). The degree of obesity expressed as were significantly higher in the group of overweight and obese
BMI standard deviation score (SDS) was calculated using the LMS children and adolescents.
method to normalize skewness of the distribution of BMI (73, 74). Severe baseline vitamin D deficiency was found in 54% (36
Obesity was defined as BMI SDS ≥ 2, and overweight as BMI SDS ≥ participants) of the study group. Taking into account baseline
1 and < 2 (75). vitamin D status of the study group we did not find any significant
Data of the study group were analyzed in the whole group and differences in anthropometric and biochemical parameters
in subgroups depending on baseline vitamin D status (serum 25 between subgroups with lower and severe vitamin D deficiency.

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Krajewska et al. Vitamin D and Inflammatory Markers

TABLE 1 | Baseline anthropometric measurements, haematological, and biochemical parameters in the study group and in the control group.

p value STUDY GROUP CONTROL GROUP

(n = 67) (n = 31)

Age (years) 13.3 ± 2.11 13.8 ± 2.45

ns
Height SDS 0.7 ± 1.26 -0.6 ± 1.37
< 0.001
Weight SDS 2.3 ± 0.66 -0.3 ± 1.09
< 0.001
WC (cm) 91.3 ± 10.17 62.3 ± 6.49
<0.001
HC (cm) 106.1 ± 10.48 78.7 ± 8.86
< 0.001
WHR 0.9 ± 0.06 0.8 ± 0.04
< 0.001
WHtR 0.9 ± 2.68 0.4 ± 0.03
< 0.001
% FAT (skinfolds) 36.9 ± 6.12 22.7 ± 6.06
< 0.001
BMI SDS 2.3 ± 0.46 -0.2 ± 0.83
< 0.001
25(OH)D (ng/ml) 15.9 (12.6 – 20.0) 23.9 (17.7 – 29.9)
< 0.001
WBC (cells × 103/ml) 6.7 (5.5 – 8.1) 5.7 (5.0 – 6.7)
0.014
Granulocytes (cells × 103/ml) 3.2 (2.4 – 4.5) 2.8 (1.9 – 3.7)
0.015
Monocytes (cells × 103/ml) 0.5 (0.5 – 0.7) 0.4 (0.4 – 0.6)
0.009
Lymphocytes (cells × 103/ml) 2.4 (2.1 – 2.9) 2.2 (1.9 – 2.9)
ns
PLT (cells × 103/ml) 270 (236 – 302) 260 (231 – 284)
ns
CRP (mg/dl) 0.5 (0.5 – 0.7) 0.5 (0.5 – 0.5)
0.003
IL-10 (pg/ml) 1.25 (0.03 – 1.74) 0.65 (0.19 – 1.15)
ns
IL-17 (pg/ml) 0.05 (0.0 – 0.13) 0.05 (0.0 – 0.12)
ns

Data are presented as means ± standard deviations score or as median with interquartile range, as appropriate. SDS, standard deviation score; WC, waist circumference; HC, hip
circumference; WHR, waist-to-hip ratio; WHtR, waist-to-height ratio; % FAT (skinfolds), percentage of body fat estimated from skinfolds; BMI, body mass index; 25(OH)D, 25-
hydroxyvitamin D; WBC, white blood cells; PLT, platelets; CRP, C-reactive protein; IL-10, interleukin-10; IL-17, interleukin-17; ns, not significant.

Baseline Associations Between Vitamin D related negatively to CRP levels (R= -0.42, p = 0.017). The
Status, Nutritional Status, and Biochemical distribution of serum 25(OH)D values in this subgroup is
Parameters in the Study Group and in the presented on two histograms (Figure 2. for participants with CRP
Control Group ≤ 0.5 mg/dl, Figure 3 for participants with CRP > 0.5 mg/dl).
At baseline, as expected, we found significant associations In further analysis, we also found that in this subgroup
between vitamin D status and nutritional status, especially in nutritional status parameters such as BMI SDS (R = 0.61, p =
children with excess body fat. In the study group, vitamin D 0.0003), waist circumference (R = 0.44, p = 0.014), WHR (R = 0.49,
levels were related negatively to body mass SDS (R = -0.27, p = p = 0.005), %FAT BIA (R = 0.43, p = 0.017), and WHtR (R = 0.70,
0.029), BMI SDS (R = -0.27, p = 0.025, Figure 1) and hip p = 0.00003) were significantly positively related to CRP levels.
circumference (R = -0.26, p = 0.039). In the control group those These relationships were not seen in the subgroup with low
associations were not seen, apart from the negative association baseline 25(OH)D deficiency and in the control group. In a
between vitamin D status and hip circumference (R = -0.52, p = subgroup with low 25(OH)D deficiency we found only positive
0.014). Leukocyte profile parameters, PLT count, CRP, IL-10, associations between hip circumference and WBC count (R = 0.47,
and IL-17 levels were not related to baseline vitamin D status in p = 0.006) and between hip circumference and granulocyte count
the study group nor in the control group. (R = 0.55, p = 0.001). We also observed that baseline IL-17 levels
Taking into account baseline vitamin D status of the study group correlated positively with baseline monocytes (R = 0.36, p = 0.003,
(serum 25(OH)D level ≥ 15 ng/ml or < 15 ng/ml), we noticed that in Figure 4) in the whole study group independently on baseline 25
children with severe vitamin D deficiency, 25(OH)D levels were (OH)D deficiency (R = 0.36, p = 0.032; R = 0.37, p = 0.038,

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Krajewska et al. Vitamin D and Inflammatory Markers

FIGURE 1 | Correlation between baseline 25(OH)D levels and baseline BMI FIGURE 3 | Distribution of vitamin D values in the subgroup with severe 25
SDS in the whole study group. (OH)D deficiency and CRP > 0.5.

respectively in subgroups with low and severe baseline vitamin find any significant association between 25(OH)D levels and
D deficiency). leukocyte profile parameters, PLT count, or IL-17 levels.
We also noticed that after six months of intervention, IL-10
Effects of Vitamin D Supplementation on levels correlated significantly negatively with monocyte count in
Leukocyte Profile Parameters, Platelet that period (R = -0.28, p = 0.023).
Count, CRP, IL-10, and IL-17 Levels in the In further investigation we used multivariable stepwise
Study Group regression analysis to determine which inflammatory factors
The characteristics of the study group at baseline and after six are associated with serum 25(OH)D levels (as dependent
months of vitamin D supplementation are shown in Table 2. After variable) at baseline and after six months of vitamin
six months of vitamin D supplementation its value increased by an D supplementation.
average of 11.3 ± 8.2 ng/ml. Simultaneously, we noticed a We did not find any significant relationships in multivariable
significant decrease in CRP levels (p = 0.0003) without any stepwise regression models including baseline 25(OH)D levels
changes in leukocyte profile parameters, PLT count, or IL-10, and chosen baseline inflammatory parameters as independent
and IL-17 levels. Serum 25(OH)D levels correlated significantly variables (model 1: IL-10, IL-17, CRP, WBC; model 2: IL-10, IL-
with IL-10 levels in that period (R = 0.27, p = 0.028). We did not 17, CRP, monocytes).

FIGURE 2 | Distribution of vitamin D values in the subgroup with severe 25 FIGURE 4 | Correlation between baseline IL-17 levels and baseline
(OH)D deficiency and CRP <= 0.5. monocyte count in the whole study group.

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Krajewska et al. Vitamin D and Inflammatory Markers

TABLE 2 | Comparison between anthropometric measurements, haematological, and biochemical parameters in the study group at baseline and after six months of
vitamin D supplementation.

p value BASELINE SIX MONTHS

Height SDS 0.7 ± 1.26 0.6 ± 1.25

ns
Weight SDS 2.3 ± 0.66 2.2 ± 0.75
0.047
WC (cm) 91.3 ± 10.17 90.6 ± 11.06
ns
HC (cm) 106.1 ± 10.48 106.4 ± 11.71
ns
WHR 0.9 ± 0.06 0.9 ± 0.05
ns
WHtR 0.9 ± 2.68 0.5 ± 0.06
< 0.001
% FAT (skinfolds) 36.9 ± 6.12 34.2 ± 6.34
< 0.001
% FAT BIA 40.6 ± 7.59 38.3 ± 8.93
ns
BMI SDS 2.3 ± 0.46 2.2 ± 0.55
ns
25(OH)D (ng/ml) 15.9 (12.6 – 20.0) 27.1 (22.9 – 32.6)
< 0.001
WBC (cells × 103/ml) 6.7 (5.5 – 8.1) 6.2 (5.6 – 7.8)
ns
Granulocytes (cells × 103/ml) 3.2 (2.4 – 4.5) 3.3 (2.4 – 4.0)
ns
Monocytes (cells × 103/ml) 0.5 (0.5 – 0.7) 0.5 (0.4 – 0.6)
ns
Lymphocytes (cells × 103/ml) 2.4 (2.1 – 2.9) 2.3 (2.0 – 2.8)
ns
PLT (cells × 103/ml) 270 (236 – 302) 261 (232 – 311)
ns
CRP (mg/dl) 0.5 (0.5 – 0.7) 0.5 (0.5 – 0.6)
0.001
IL-10 (pg/ml) 1.25 (0.03 – 1.74) 0.78 (0.34 – 1.58)
ns
IL-17 (pg/ml) 0.05 (0.0 – 0.13) 0.04 (0.01 – 0.10)
ns

Data are presented as means ± standard deviations score or as median with interquartile range, as appropriate. SDS, standard deviation score; WC, waist circumference; HC, hip
circumference; WHR, waist-to-hip ratio; WHtR, waist-to-height ratio; %FAT (skinfolds), percentage of body fat estimated from skinfolds; %FAT BIA, percentage of body fat estimated using
bioelectrical impedance analysis method; BMI, body mass index; 25(OH)D, 25-hydroxyvitamin D; WBC, white blood cells; PLT, platelets; CRP, C-reactive protein; IL-10, interleukin-10; IL-
17, interleukin-17; ns, not significant.

After six months of vitamin D supplementation, the profile parameters and PLT count, as well as IL-17 levels, seemed
multivariable stepwise regression analysis, that included 25 not to be vitamin D-dependent. As expected, we confirmed
(OH)D levels (as dependent variable) and IL-10, IL-17, CRP, significant negative relationships between 25(OH)D levels and
WBC (model 1) or IL-10, IL-17, CRP, monocytes (model 2) as nutritional status parameters. Overweight and obese children
independent variables, identified IL-10 as the parameter from the study group had significantly lower serum baseline 25
significantly positively associated with 25(OH)D levels. Both (OH)D levels compared to age- and sex-matched healthy peers,
models were significant with cumulative R2 = 0.12, p = 0.004 despite the lack of vitamin D supplementation in both groups before
and the received correlations coefficients were respectively equal the initiation of the study. Obesity-dependent hypovitaminosis D
b = 0.344 ± 0.116. has been previously confirmed in many studies in paediatric and
adult population (3, 19, 76). Low-grade chronic inflammation
characteristics for obese individuals seem to be involved with
vitamin D deficiency in this group (11, 12). Analyzing baseline
DISCUSSION values of selected inflammatory markers in both groups, we noticed
that WBC, granulocyte, and monocyte count, as well as CRP levels,
In our study we focused on the relationships between vitamin D were significantly higher in the study group than in the control
status, both baseline and after six months of vitamin D group. Similar results were presented in our previously published
supplementation and selected anti-inflammatory and pro- study which considered almost 100 overweight and obese children.
inflammatory markers. We found significant associations between Our previous research indicated that WBC and granulocyte count
serum 25(OH)D levels and levels of CRP and IL-10, while leukocyte were related to BMI SDS, while monocyte count was related to waist

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Krajewska et al. Vitamin D and Inflammatory Markers

circumference, which could suggest that visceral adipose tissue has vitamin D deficiency and could confirm mutual associations
much greater pro-inflammatory potential than subcutaneous tissue, between pro-inflammatory interleukins and monocytes
as a source of pro-inflammatory adipokines and cytokines (36). enhancing their inflammatory potential.
The main findings of our present study regarded the In our study we also analyzed the impact of vitamin D
interactions between vitamin D and serum levels of IL-10 and supplementation on selected markers of inflammation. Our
CRP and could support hypothesis of anti-inflammatory vitamin study revealed that six months of vitamin D supplementation
D properties. Despite this, we did not find any baseline led to a significant decrease in CRP levels, influenced IL-10 levels,
associations between vitamin D status and leukocyte profile but did not affect leukocyte profile, PLT count, and IL-17 levels.
parameters, PLT count, CRP, IL-10, and IL-17 levels in the Interestingly, those effects were observed despite the lack of
whole study group, and we noticed that in participants with significant changes in body fat mass and BMI in our study
severe baseline vitamin D deficiency (serum 25(OH)D values group. Data from animal and human studies regarding the
below 15 ng/ml) 25(OH)D levels were inversely related to CRP impact of vitamin D supplementation on obesity-related
values. Moreover, in this subgroup, CRP levels correlated inflammation are contradictory. The rat study by Gomma et al.
positively with nutritional status parameters. Similar (80) showed that vitamin D administration in rats that received
associations were reported by Rodriguez et al. (77) who high fat diet (HFD) led to significant decrease in body weight
examined more than one hundred Spanish overweight and gain, decrease in serum CRP levels, and significant increase in
obese children from 9 to 12 years of age and reported that low serum IL-10 levels in comparison with HFD-rats that did not
serum 25(OH)D levels were significantly associated with receive vitamin D supplementation. Mirzavandi et al. (81) who
increased high sensitive CRP (hs-CRP). In the study by Bellia investigated the effect of vitamin D intramuscular megadose
et al. (61), based on a cohort of 147 severely obese patients with injections (200 000 IUs at baseline and next at week 4 of
mean BMI 43.6 ± 4.3 kg/m2 who were prepared to bariatric intervention) reported significant decrease in CRP levels in
surgery, a multivariate regression analysis showed that serum 25 vitamin D deficient adults with diabetes mellitus type 2.
(OH)D was inversely related to hs-CRP levels, even after Similar results, also in patients with diabetes mellitus type 2,
accounting for age, gender, season of recruitment, BMI, total were shown by Mousa et al. (55), who provided a systematic
body fat, and truncal fat mass. The cross-sectional analysis by de review and meta-analysis including twenty trials with a total of
Oliveira et al. (78) based on data of 5,870 adult participants from 1,270 individuals. The authors reported that vitamin D
the English Longitudinal Study of Ageing (ELSA) showed an supplemented patients had lower CRP and TNF-a levels, lower
inverse relationship not only between serum levels of 25(OH)D erythrocyte sedimentation rate, and higher leptin levels
and CRP values but also between 25(OH)D and WBC count. In compared to the control groups. Conversely, a systematic
our analysis WBC count did not depend on vitamin D status but review with meta-analysis by Jamka et al. (82), who assessed
the protocols of our study and the study by de Oliveira et al. (78) changes in 25(OH)D and CRP levels in 1,955 obese and
were not exactly consistent. The main differences between our overweight subjects, showed that vitamin D supplementation
study and ELSA included the age of studied groups (children and did not affect CRP levels. Systematic review and meta-analysis of
adolescents in our study vs adult patients 50 years of age and randomized control trials (RCTs) by Mazidi et al. (83) also
over), the duration of obesity and associated inflammation indicated that vitamin D supplementation had no impact on
(possibly much longer in de Oliveira group), differences in the serum CRP, IL-10, and TNF-a levels but the authors recommend
number of participants (67 in our study vs almost 6,000 in RCTs with longer period of follow-up time (12 months) for
ELSA). The study by Palaniswamy et al. (19) based on a cohort of future studies to provide explicit results.
3,586 individuals with mean BMI 24.8 kg/m2 and mean 25(OH) Based on our data we noticed that serum 25(OH)D values,
D levels 50.3 nmol/L also confirmed negative associations achieved after six months of vitamin D supplementation,
between 25(OH)D and hs-CRP leve ls, which were correlated significantly positively with IL-10 levels in that
simultaneously positively associated with BMI. Those period. Those relationships found firstly, using the Spearman
findings are strictly in-line with our observations. Conversely, correlation, was also confirmed in a multivariable stepwise
Palaniswamy et al. (19) concluded that their large observational regression analysis taking 25(OH)D levels as dependent
and Mendelian randomization study, which analyzed the variables and IL-10, IL-17, CRP, WBC (model 1), IL-10, IL-17,
associations between 25(OH)D, BMI, and 16 inflammatory CRP, and monocytes (model 2) as independent variables. In both
biomarkers (including IL-17, IL-1a, IL-1b, IL-4, IL-6, IL-8, models we identified IL-10 levels measured at six months of
TNF-a and hs-CRP), considered together with data from intervention as the parameter significantly positively associated
review of randomized controlled trials, did not confirm the with 25(OH)D levels. Moreover, we found that IL-10 levels were
beneficial role of vitamin D supplementation in obesity-related inversely related to monocyte count also evaluated at six months
inflammation. Similar observations were previously reported by of vitamin D intake. After six months of vitamin D
Shea et al. (79) based on data from the Framingham Offspring supplementation, we did not find any relationships between
Study. The lack of association between vitamin D and IL-17 vitamin D status and leukocyte profile parameters, PLT count,
levels is in-line with our findings. Interestingly, we observed or IL-17 levels. The mechanisms of association between vitamin
baseline positive correlation between IL-17 levels and monocyte D status and both interleukins and leukocyte profile parameters
count, which was independent from the severity of baseline are not clearly explained and literature data in this field are

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Krajewska et al. Vitamin D and Inflammatory Markers

insufficient. Hashemi et al. (84), reported that based on a group ETHICS STATEMENT
of multiple sclerosis patients, vitamin D supplementation up-
regulates IL-27 and TGF-b1 levels, which in consequence, The studies involving human participants were reviewed and
increases the secretion of anti-inflammatory IL-10 and inhibits approved by Bioethics Committee of Medical University of
pro-inflammatory IL-17 production. The anti-inflammatory role Warsaw. Written informed consent to participate in this study
of IL-27 was also reported by other authors (85, 86). However, was provided by the participants’ legal guardian/next of kin.
the precise mechanism of vitamin D-dependent regulation of
immune cells function is much more complicated and includes
activation of various signalling cascades (2, 17). Most of the AUTHOR CONTRIBUTIONS
presented studies concern the adult population or animals, while
the number of studies in the paediatric population is very limited. MK, EW-S and MR contributed to conception and design of the
In conclusion, our study confirmed beneficial effects of vitamin study. MK and MR organized the database. MK and EW-S
D supplementation in overweight and obese paediatric population. prepared the tables. AM performed anthropometric
Vitamin D intake seems to exert its anti-inflammatory effect mainly measurements. MK and AS-E took measurements of serum IL-
via decreasing of CRP level and protecting stabile values of IL-10, 10 and IL-17 levels. MK, MR, EW-S and MS performed statistical
rather than its impact on pro-inflammatory factors such as lL-17 analysis. MK and EW-S wrote the manuscript. BP supervised the
and leukocyte profile parameters. work. All authors contributed to manuscript revision, read, and
approved the submitted version.

DATA AVAILABILITY STATEMENT

ACKNOWLEDGMENTS
The original contributions presented in the study are included in
the article/supplementary material. Further inquiries can be The authors would like to thank the nurse Małgorzata Przybylska
directed to the corresponding author. for her contribution in blood sample collection.

11. Cannell JJ, Grant WB, Holick MF. Vitamin D and Inflammation.
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Frontiers in Endocrinology | www.frontiersin.org 10 June 2022 | Volume 13 | Article 920340