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Effect of Very-Low-Calorie Ketogenic Diet on Psoriasis Patients: A Nuclear Magnetic Resonance-Based Metabolomic Study


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Psoriasis is an inflammatory disease of the epidermis based on an immunological mechanism involving Langerhans cells and T lymphocytes that produce pro-inflammatory cytokines. Genetic factors, environmental factors, and improper nutrition are considered triggers of the disease. Numerous studies have reported that in a high number of patients, psoriasis is associated with obesity. Excess adipose tissue, typical of obesity, causes a systemic inflammatory status coming from the inflammatory active adipose tissue; therefore, weight reduction is a strategy to fight this pro-inflammatory state. This study aimed to evaluate how a nutritional regimen based on a ketogenic diet influenced the clinical parameters, metabolic profile, and inflammatory state of psoriasis patients. To this end, 30 psoriasis patients were subjected to a ketogenic nutritional regimen and monitored for 4 weeks by evaluating the clinical data, biochemical and clinical parameters, NMR metabolomic profile, and IL-2, IL-1β, TNF-α, IFN-γ, and IL-4 concentrations before and after the nutritional regimen. Our data show that a low-calorie ketogenic diet can be considered a successful strategy and therapeutic option to gain an improvement in psoriasis-related dysmetabolism, with significant correction of the full metabolic and inflammatory status.
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Eect of Very-Low-Calorie Ketogenic Diet on Psoriasis Patients: A
Nuclear Magnetic Resonance-Based Metabolomic Study
Giuseppe Castaldo, Imma Pagano, Manuela Grimaldi, Carmen Marino, Paola Molettieri, Angelo Santoro,
Ilaria Stillitano, Rocco Romano, Paola Montoro, Anna Maria DUrsi,*and Luca Rastrelli*
Cite This: J. Proteome Res. 2021, 20, 15091521
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sıSupporting Information
ABSTRACT: Psoriasis is an inammatory disease of the epidermis based on an
immunological mechanism involving Langerhans cells and T lymphocytes that
produce pro-inammatory cytokines. Genetic factors, environmental factors,
and improper nutrition are considered triggers of the disease. Numerous studies
have reported that in a high number of patients, psoriasis is associated with
obesity. Excess adipose tissue, typical of obesity, causes a systemic inammatory
status coming from the inammatory active adipose tissue; therefore, weight
reduction is a strategy to ght this pro-inammatory state. This study aimed to
evaluate how a nutritional regimen based on a ketogenic diet inuenced the
clinical parameters, metabolic prole, and inammatory state of psoriasis
patients. To this end, 30 psoriasis patients were subjected to a ketogenic
nutritional regimen and monitored for 4 weeks by evaluating the clinical data,
biochemical and clinical parameters, NMR metabolomic prole, and IL-2, IL-
1β, TNF-α, IFN-γ, and IL-4 concentrations before and after the nutritional
regimen. Our data show that a low-calorie ketogenic diet can be considered a successful strategy and therapeutic option to gain an
improvement in psoriasis-related dysmetabolism, with signicant correction of the full metabolic and inammatory status.
KEYWORDS: psoriasis, obesity, 1H NMR metabolomics, very-low-calorie ketogenic diet, biomarkers
Psoriasis is a chronic inammatory and multifaceted disease.
This condition aects approximately 23% of the worlds
and is less common in children than in adults.
Psoriasis is associated with morbidity and mortality.
Generally, signicant dierences among individuals from
various ethnic groups and geographical location have been
recorded, with an increased incidence in individuals living at
high latitudes.
From a sex viewpoint, some studies reported
dierences between males and females.
Patients with
psoriasis have a decreased quality of life,
with anxiety and
depression. Psoriasis is a disorder of multifactorial etiology
with both genetic and trigging factors. Numerous studies have
reported the identication of genetic loci, in particular, 10 loci
as susceptibility regions. The factors identied as triggers for
the development of psoriasis are trauma, obesity, infections,
medications, sunlight, stress, alcohol, smoking, and endocrine
Histologically, this disease is characterized by hyper-
proliferative keratinocytes and the inltration of prominent T
cells, dendritic cells, and neutrophils in the dermis. The
diagnosis is usually clinical, including an examination of the
primary lesion and aected areas. General presentations
include plaque, inverse, guttate, erythrodermic, and pustular
forms, with cutaneous manifestations and nail, scalp, and joint
abnormalities. The psoriasis area and severity index (PASI),
body surface area (BSA), and dermatology life quality index
(DLQI) are tools that are commonly used for the classication
of plaque psoriasis.
A systematic review and meta-analysis summarize the
epidemiological association between psoriasis and obesity,
indicating a higher prevalence and incidence of obesity in
psoriasis patients, compared with the general population.
Moreover, numerous studies have reported evidence of a
causal relationship between obesity and psoriasis, investigating
the connection between body mass index (BMI) and
A few studies of weight-loss interventions have been shown
to improve psoriasis and to increase the response to
especially adherence to a low-calorie dietary
Fatty tissue is an active endocrine tissue and
causes a pro-inammatory state in obese patients.
clinical eect of weight loss is the reduction of adipose tissue as
Received: August 20, 2020
Published: November 9, 2020
© 2020 American Chemical Society 1509
J. Proteome Res. 2021, 20, 15091521
a source of pro-inammatory cytokines. From this perspective,
a very-low-calorie diet with adequate protein content is
responsible for weight loss and the reduction of visceral fat
The ketogenic diet is a nutritional regimen characterized by
a reduction in carbohydrates and a relative increase in protein
and fat.
At a biochemical level, the ketogenic diet induces a
switch to ketone metabolism, causing a reduction in blood
glucose and an increase in blood ketones and mitochondrial
Recent scientic studies have shown the
therapeutic potential of ketogenic diets in many diseases,
such as diabetes, polycystic ovary syndrome, acne, neurological
diseases, cancer, and the amelioration of respiratory and
cardiovascular disease risk factors.
Moreover, the
ketogenic diet has been identied as an eective remedy for
obesity and psoriasis, with a signicant reduction in
inammatory components that are possibly localized in visceral
adipose tissue.
In recent years, metabolomic studies have played a
signicant role in revealing biomarkers, identifying the
biochemical pathways involved in many diseases, and in
providing information related to pathway perturbations.
Nuclear magnetic resonance (NMR) spectroscopy represents
a robust and suitable technique for metabolomic approaches:
low-molecular-mass compounds can be concurrently qualita-
tively and quantitatively detected in biological samples.
this novel study, we performed an NMR-based metabolomic
analysis of the sera of psoriasis patients subjected to a
ketogenic nutritional regimen for 4 weeks. Metabolomic data
analyzed with the aid of univariate and multivariate statistical
methods were correlated with the biochemical and clinical
parameters, including IL-2 and IL-1βcytokines. Metabolomic
proles of psoriasis patients compared to those of healthy
controls before and after a 4 week ketogenic diet provide
preliminary indications to identify candidate biomarkers useful
in the theranostic control of psoriasis. Results of the metabolic
pathway analysis reveal the therapeutic potential of a dietary
regimen and provide new insights into the etiopathogenesis of
The study was conducted at the NutriKeto_LAB, Azienda
Ospedaliera San Giuseppe Moscati, Avellino, Italy, between
October 1, 2018, and March 1, 2019. Consecutive participants
were recruited from hospital wards. Demographics and clinical
information are reported in Table 1.
Inclusion and Exclusion Criteria
Participants eligible for inclusion criteria in the psoriasis group
were overweight patients, aged 1865 years old, with plaque
psoriasis: 35 patients were screened, and 30 patients were
recruited and completed the intervention study. The exclusion
criteria were pregnancy; breastfeeding; insulin treatment;
heart, kidney, or liver disease; obesity due to hypothyroidism;
neoplastic disease; intentional or unintentional weight loss of
more than 5 kg up to 3 months before the study; active
treatment or treatment in the past 2 weeks with topical drugs
or retinoic acid, ultraviolet light therapy or systemic therapy
(in the recent 4 weeks), or biological preparations in the past
12 weeks; and recent history of drug addiction or alcohol
Study Design
Blood serum samples were collected from 30 healthy subjects
used as controls and 30 subjects diagnosed with psoriasis
according to the mentioned psoriasis diagnostic criteria. The
institutional ethical committee of Azienda Ospedaliera San
Giuseppe Moscati, Avellino, Italy, approved the study
protocol, which followed the 1964 Declaration of Helsinki
and its later amendments, and all subjects gave written
informed consent.
Clinical Assessments
The diagnosis of plaque psoriasis was made by dermatologists
based on clinical characteristics. PASI, BSA, the DLQI, and the
VAS for itch ratings were employed to measure psoriasis
severity. All the participants had height and body weight
measured by calibrated at scales equipped with a telescopic
vertical steel stadiometer (SECA 711, Hamburg, Germany).
BMI was calculated as the weight (kg) divided by the height
squared (m2) kg/m2.Aexible plastic tape was used to assess
waist and hip circumferences. Blood samples were analyzed in
the clinical laboratory using automated analyzers and available
commercial kits. Quantitative evaluation of the following
clinical parameters was performed: hemoglobin, total lympho-
cyte count, creatinine, uric acid, glucose, insulin, C-peptide,
glycated hemoglobin, growth hormone (GH), total cholesterol,
high-density lipoprotein (HDL) cholesterol, low-density lip-
oprotein (LDL) cholesterol, triglycerides, apolipoproteins A1
and B (Apo A1 and Apo B, respectively), albumin,
cholinesterase, serum aspartate aminotransferase (AST),
alanine aminotransferase, gamma glutamyl transferase (γGT),
lactate dehydrogenase, sodium, potassium, magnesium,
calcium, phosphorus, the homeostasis model assessment
insulin resistance (HOMA-IR), bilirubin, hematocrit, pro-
thrombin activity, cortisol, vitamin B12, folic acid, azotemia,
insulin, and homocysteine. For the assessment of visceral
adipose tissue (VAT), ultrasound measurement of the
aortomesenteric fat thickness (AMFT) was performed
according to a previous procedure.
Dietary Intervention and Assessment
The recommendations for daily nutrient intake were met
during the entire study time. The participants met a study
dietician every week to verify food intake and adherence to
administered dietary intervention. During group meetings, the
diet regimen was given to subjects with encouragement and
Table 1. This Table Describes the Demographics and
Clinical Information of the Participants
parameter psoriasis group
(N= 30) control group
(N= 30) P
sex (male/female) 11/19 10/20
age (mean ±SD, years) 42.8 ±14.04 50.0 ±9.90 0.003
BMI (kg/m2) 30.82 ±5.96 28.4 ±1.61 0.044
disease duration (mean ±
SD, years) 5.09 ±1.80 NA
BSA (mean ±SD) 16.02 ±3.39 NA 0.069
PASI (mean ±SD) 8.69 ±1.80 NA 0.007
PsO/PsO + PsA 25/5 NA
smokers 60% 50%
Pvalue obtained by the MannWhitney Utest between the psoriasis
group and control group. BMI, body mass index; NA, not applicable;
BSA, body surface area; PASI, psoriasis area and severity index; PsO,
psoriasis; PsA, psoriatic arthritis.
Pvalue obtained by the
MannWhitney Utest of psoriasis group between T0 and T1.
Journal of Proteome Research Article
J. Proteome Res. 2021, 20, 15091521
instructions for the use of dietary supplements. Treatment
ecacy was assessed at baseline (T0) and after 4 weeks (T1).
The control group (healthy controls) adopted a conventional
diet and was instructed to eat ordinary food according to the
national guidelines for a healthy diet.
Diet recommendations for psoriasis patients included the
consumption of a very-low-calorie (<500 kcal/day) protein-
based diet providing 1020 g of carbohydrates (from
vegetables, 400500 g/day), 2030 g of lipids, and 1.4 g
per kg of ideal body weight (calculated using Lorentzs
equation) of protein per day. Half of this protein dosage is
sucient to supply 12 g of 90% whey protein, with the
addition of L-arginine, α-ketoglutarate, L-ornithine, L-carnitine,
L-glutamine, taurine, L-citrulline, L-cysteine, and vitamin B6.
Other dietary supplements were alkalizing substances (calcium
carbonate, magnesium citrate, potassium bicarbonate, potas-
sium citrate, and sodium bicarbonate) and herbal remedies
(with diuretic, anti-inammatory, hepatoprotective, and
antioxidant activities), such as garcinia (Garcinia cambogia),
hawthorn (Crataegus oxyacantha), java tea (Orthosiphon
stamineus), dandelion (Taraxacum ocinale), thistle fruit
extract (Silybum marianum), a multivitamin (C, D, K, and
A)/multimineral supplement, and 10 g of hydrolyzed collagen
powder. Ashwagandha (Withania somnifera) and bacopa (
Bacopa monnieri) were also administered for psychophysical
balance, and Triphala (Phyllanthus emblica,Terminalia chebula,
and Terminalia bellirica) was administered to implement the
correct intestinal function. Patients were advised to drink at
least 2 L of bicarbonate-rich alkaline water per day (not tea or
coee) and to not use table salt but to salt their food with
potassium chloride. All treatments with hypoglycemic agents
and diuretics were interrupted.
Outcomes (Primary and Secondary)
The primary outcome was PASI, an index of psoriasis severity:
the PASI was measured at baseline (T0) and at 4 weeks (T1),
along with BSA assessment. The secondary outcome was
DLQI to determine the quality of life, the reduction in BSA,
the improvement in itch severity, and weight loss.
Sample Pretreatment for NMR Analysis
NMR sample preparation and NMR spectra acquisition were
performed as previously reported.
To obtain the blood
serum, the whole blood was collected into tubes not containing
anticoagulant and allowed to clot at room temperature for 30
to 120 min. After centrifugation at 12,000 g, the blood serum
was aliquoted and stored at 80 °C in Greiner cryogenic vials
before NMR spectroscopy measurements. Before being
transferred to a 5 mm heavy-walled NMR tube, samples
were thawed at room temperature. NMR samples were
prepared by mixing 300 μL of blood sera with 200 μLof
phosphate buer, including 0.075 M Na2HPO4·7H2O, 4%
2O. Trimethylsilyl propionic-2,2,3,3-d4acid,
sodium salt (0.1% TSP in D2O) was used as an internal
reference for the alignment and quantication of NMR signals;
the mixture, homogenized by vortexing for 30 s, was
transferred to a 5 mm NMR tube (Bruker NMR tubes) before
analysis started.
NMR Data Acquisition
NMR experiments were carried out on a Bruker DRX600 MHz
spectrometer (Bruker, Karlsruhe, Germany) equipped with a 5
mm triple-resonance z-gradient CryoProbe. TOPSPIN, version
3.0, was used for spectrometer control and data processing
(Bruker Biospin, Fällanden, Switzerland). For nonltered
biouids, low-mass metabolites coexist with high-mass
biomolecules, such as lipids, proteins, and lipoproteins;
therefore, to selectively observe small-molecule components
in solutions, CarrPurcellMeiboomGill (CPMG) experi-
ments were performed. 1D 1H pulse-sequence CPMG
experiments comprised a spectral width of 7 kHz, 32,000
data points, water presaturation applied over 3.5 s of relaxation
delay, and a spin-echo delay of 80 ms.
The pulse sequence
used included an excitation sculpting routine for the
suppression of the water signal.
Due to the eect of
excitation sculpting on the signal height of resonances in the
region close to the water resonance,
the metabolites that
have resonances close to this region (ascorbate, glucose,
mannose, and pyroglutamate) were quantied using reso-
nances from those metabolites in other spectral regions. A
weighted Fourier transform was applied to the time domain
data with a 0.5 Hz line-broadening followed by a manual phase
and baseline correction in preparation for targeted proling
NMR Data Processing
NMR spectra were manually phased and baseline-corrected.
The quantication of serum metabolites was achieved using
Chenomx NMR-Suite v8.0 (Chenomx Inc., Edmonton,
Briey, the Chenomx proler is linked to the
Human Metabolome Database (HMDB), containing more
than 250 metabolite NMR spectral signatures encoded at
dierent 1H spectrometer frequencies, including 600 MHz
( A comparison of the spectral data
obtained for each serum sample with the Chenomx metabolite
library results in a list of compounds together with their
respective concentrations based on the known concentration of
the added internal reference compound TSP-d4(5.8 mM).
Statistical Analysis
Multivariate statistical analysis, principal component analysis
(PCA), and partial least-squares discriminant analysis (PLS-
DA) were conducted with normalized metabolomics data
using MetaboAnalyst 4.0 (
The performance of the PCA and PLS-DA model was
evaluated using the coecient Q2(using the 7-fold internal
cross-validation method) and coecient R,
dening the
variance predicted and explained by the model, respectively.
The loading plot was used to identify signicant metabolites
responsible for maximum separation in the PLS-DA score plot,
and these metabolites were ranked according to their variable
inuence on projection (VIP) scores. VIP scores are weighted
sums of squares of the PLS-DA weights, which indicate the
importance of the variable.
Quantitative Analysis
The data relative to the metabolite concentrations were
analyzed using the PRincipal COmponent Normalization
Algorithm (PRICONA),
and the normalization strategy
was applied.
Accordingly, the proportional variations of
1H NMR signals were described by normalization factors, and
the normalization constant was calculated as the score relative
to the normalization setting.
Cytokine Analysis: ELISA
Serum concentrations of the cytokines IL-2, IL-1β, TNF-α,
IFN-γ, and IL-4 were determined by enzyme-linked
immunosorbent assay (ELISA) commercial kits (Diaclone
SAS (Besançon Cedex, France)) according to the manufac-
Journal of Proteome Research Article
J. Proteome Res. 2021, 20, 15091521
turers instructions. All tests were performed in duplicate. The
ranges of the sensitivity standard curve of the ELISA kits were
31.21000 pg/mL for IL-2, 15.6500 pg/mL for IL-1β,25
800 pg/mL for TNF-α, 12.5400 pg/mL for IFN-γ, and 1.1
35 pg/mL for IL-4.
Standard diluents, the capture antibody, and the detection
antibody were obtained as a complete kit for each cytokine.
Standard diluentserum samples were used to obtain a Cedex
standard curve. The samples in the multiwell plate were mixed
by repeated aspirations and ejections, taking care not to scratch
the inner surfaces. Freeze-dried control vials were also
reconstituted with the most appropriate standard diluent to
the sample to gain a solution at the concentration stated on the
vial. Biotinylated anticytokines, biotinylated secondary anti-
body, and streptavidin-HRP were also prepared according to
the manufacturers protocol. The absorbance value of each well
was read on a Thermo Scientic Multiskan GO spectropho-
tometer using 450 nm as the primary wavelength and 620 nm
as the reference wavelength (610 to 650 nm is acceptable).
Clinical Analysis
Clinical data for 30 patients with psoriasis before and after the
ketogenic diet were statistically analyzed using the Mann
Whitney Utest to assess their signicance and Pvalue. The
VIP score was calculated using the R package to identify the
variables that discriminated between the two groups. The
variables with VIP scores >1 were considered signicant for the
analysis. The VIP score values for selected variables concerning
psoriasis patients before and after the ketogenic diet are given
in Table 2.
Table 2 shows clinical and biochemical clinical parameters
for psoriasis patients. An analysis of the data indicated that all
parameters related to psoriasis improved after the ketogenic
diet. In particular, the DLQI, visual analogue scale (VAS)
pruritus, VAS pain, and PASI improved, indicating that the
ketogenic diet reduced psoriasis symptoms.
Clinical data
identied by the VIP score also included several biochemical
and clinical parameters derived from blood analysis. In
particular, the concentrations of folic acid, vitamin B12, AST,
cortisol, calcium, and direct bilirubin were higher in patients at
T1 than at T0. LDL cholesterol, total cholesterol, and HOMA-
IR levels were lower in patients at T1 than at T0 (see Table 2).
Quantitative Analysis
To quantitatively evaluate the 1H NMR spectra of the serum of
participants at T0 in comparison to the NMR spectra of the
serum of the same participants at T1, the PRincipal
COmponent Normalization Algorithm (PRICONA) and
normalization strategy were applied. The PRICONA and
normalization strategy are based on the assumption that, since
concentration dierences result in proportional variations of
spectral intensities, nonproportional changes most likely can be
attributed to the eects of the disease. The proportional
variations are described by the normalization factor R, which
must be calculated to compare the intensities of the T0 and T1
signals. When the rst principal component (PC) explains the
major part of the variance of a spectral data set, it represents
the function shape of the sum of a group of proportional peaks
(normalization set), and its scores represent the proportion-
ality constants (normalization constants). Once the spectra are
normalized, peak intensities can be directly compared.
According to the normalization procedure described above,
signals that showed signicant variations were quantied. At
the same time, an opportune strategy based on the PRICONA
is performed to achieve a reliable NMR metabolomic analysis.
The normalization algorithm is based on PCA with some
advantages: it allows simultaneous normalization of data sets of
spectra by identifying signals aected by the agent (in this case,
after the diet regimen) and quantitative measurement of
variations. In this way, the dierences in peak intensities are
excluded, and the real dierences do not depend on dierences
in sample concentration. All extraneous sample-to-sample
variations and those within each metabolite are removed. After
spectral normalization, all dierences related to metabolites
can be used to identify potential candidate biomarkers. Figure
1shows the most signicant dierences observed in the signals
of the spectra at T1 compared to those at T0: the variations in
concentration are indicated as log2(fold change); the
dierences characterized by P< 0.05 are considered signicant.
An analysis of the data indicated a signicant increase in L-
serine, dimethyl sulfone, and hydroxybutyric acid and a
decrease in malonate, choline, and pyruvic acid.
Multivariate Data Analysis
Matrices, including metabolites and their concentrations as
derived from 1H NMR data collected in 1D-1H-CPMG,
analyzed according to multivariate statistical analysis using
MetaboAnalyst 4.0.
Multivariate analysis (MVA) was
performed to identify the metabolic prole of psoriasis
patients. The original matrix included the sera from 30
subjects with psoriasis and the sera from 30 healthy controls.
The data matrix, after normalization by sum, log trans-
formation, and Pareto scaling, was analyzed by PLS-DA
(Figure 2). To minimize false discoveries and to obtain robust
statistical models, t-tests and fold-change tests were applied
according to good standardized practice (see Tables S1 and S2,
Supporting Information).
In Figure 2, PLS-DA shows that
the data sets relative to psoriasis sera are well separated from
control sera. The rst component explains 21.9% of the
variance, while the second explains 9.6%.
The creation of separate clusters indicates a dierent
metabolome characterizing patients with psoriasis and healthy
controls. This evidence is conrmed by applying VIP score
analysis (Figure 3). Accordingly, the metabolites characterized
Table 2. VIP Score and PValue Relative to Clinical Features
Calculated by the R Package
parameter VIP score T0 T1 P
DLQI 2.2108 + 1.3 ×1005
folic acid 1.9214 + 4.3 ×1005
VAS pain 1.7323 + 3.3 ×1003
VAS pruritus 1.7504 + 2.5 ×1003
vitamin B12 1.7297 + 6.3 ×1004
AST 1.7140 + 3.4 ×1002
LDL 1.6913 + 8.7 ×1006
cortisol 1.6028 + 1.3 ×1002
PASI 1.4916 + 7.0 ×1003
calcium 1.3501 + 5.3 ×1003
total cholesterol 1.2921 + 4.3 ×1006
direct bilirubin 1.2533 + 1.9 ×1002
HOMA-IR 1.2406 + 2.8 ×1003
Pvalue calculated by the MannWhitney Utest.
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J. Proteome Res. 2021, 20, 15091521
by a VIP score higher than 1 are considered good classiers
between psoriasis patients and healthy controls. The
metabolites considered as discriminative of the metabolomes
of controls and those of subjects with psoriasis are represented
in the VIP score graph in Figure 3. In particular, we observed
an amino acid dysmetabolism correlated to a lower
concentration of L-tryptophan, L-tyrosine, L-lysine, L-histidine,
L-methionine, L-arginine, L-ornithine, and L-glutamine in
psoriasis patients.
The multivariate analysis was repeated, taking into account
patients before ketogenic diet (T0) and after the 4 week
ketogenic diet (T1). Original matrices were normalized
according to the concentration ranges of HMDB.
The data
matrix, after normalizationbysamplemedianandlog
transformation, was analyzed by PCA (see Figures S1 and
S2,Supporting Information) and PLS-DA (see Figure S3,
Supporting Information). To obtain robust statistical models
and to calculate the Pvalue, the MannWhitney Utest was
Figure 1. Histogram summarizing the fold change as log2(T1/T0) in the various metabolites quantied after the normalization procedure. Fold
changes are obtained by comparing the means of the metabolite signals of 30 psoriasis patients at T0 to those at T1. Positive dierences are relative
to overexpressed metabolites at T1 with respect to T0. The dierences were considered signicant (P< 0.05). Metabolites with a signicant
dierence are marked with asterisks.
Figure 2. PLS-DA score scatter plot (A) and PLS-DA loading scatter plot (B) for the 1H NMR data collected in 1D-1H-CPMG spectra acquired at
600 MHz. Data represent the sera from 30 controls and 30 psoriasis patients before the ketogenic diet.
Journal of Proteome Research Article
J. Proteome Res. 2021, 20, 15091521
For each sample, 38 metabolites were identied and
An inspection of the PLS-DA score scatter plot (Figure 4A)
and loading scatter plot (Figure 4B) points to 3-hydrox-
ybutyrate, L-leucine, pyruvic acid, and choline as metabolites
that signicantly discriminate patients at baseline from those
after 4 weeks of the diet. This evidence is conrmed through
the application of VIP score analysis (Figure 5) (for details, see
Table S3,Supporting Information). In particular, the graph
reported in Figure 5 shows that, before the diet, psoriasis
patient sera contain a higher concentration of L-leucine,
pyruvic acid, choline, L-alanine, and acetoacetate and a lower
concentration of 3-hydroxybutyrate and acetone than after the
The results shown in Figure 5 are in agreement with those of
the quantitative analysis regarding the signicant metabolite
identication, except for L-leucine. Furthermore, regarding the
Figure 3. Metabolites discriminating healthy controls from psoriasis
patients before the ketogenic diet according to VIP score values.
Figure 4. PLS-DA score scatter plot (A) and PLS-DA loading scatter plot (B) for the 1H NMR data collected in the 1D-1H-CPMG spectra
acquired at 600 MHz. Data are relative to sera of 30 psoriasis patients at T0 (before ketogenic diet) and those of 30 psoriasis patients at T1 (after 4
weeks of the diet).
Figure 5. Metabolites discriminating psoriasis patients at baseline
(T0) from psoriasis patients after 4 weeks of the diet (T1) according
to VIP score values. Only metabolites with VIP score > 1 are
discriminant between patients before diet (T0) and psoriasis patients
after 4 weeks of the diet (T1).
Journal of Proteome Research Article
J. Proteome Res. 2021, 20, 15091521
trends of the concentrations of signicant metabolites before
and after the diet, there are concordances with the PRICONA
analysis, such as the increase in hydroxybutyric acid and the
decrease in choline and pyruvic acid at T1 (see Figure 1).
To gain meaningful insight from these data, we applied
metabolic pathway analysis using MetaboAnalyst 4.0.
to the MVA, we carried out pathway analysis on two clusters:
(i) controls against psoriasis patients before the ketogenic diet
and (ii) psoriasis patients before the ketogenic diet (T0)
against psoriasis patients after 4 weeks from the ketogenic diet
(T1). Table 3 shows that the results of the pathway analysis
come from the comparison between patients at T0 (before the
ketogenic diet) and controls and the comparison between
psoriasis patients at T0 and psoriasis patients at T1 (after 4
weeks of diet). The Pvalue and false discovery rate (FDR)
are reported to conrm the signicance of the pathways. We
also reported the most discriminating metabolite (P< 0.05)
belonging to the pathway and detected through the KEGG
The comparison between controls and patient at T0
identied an amino acid dysmetabolism related to dierent
pathways, in particular, arginine and proline metabolism;
histidine metabolism; arginine biosynthesis; cysteine and
methionine metabolism; alanine, aspartate, and glutamate
metabolism; glycine, serine, and threonine metabolism; and
phenylalanine, tyrosine, and tryptophan biosynthesis. In
addition, the comparison between psoriasis patients at T0
and psoriasis patients at T1 highlighted the involvement of
pathways related to ketogenic diet, in particular, synthesis and
degradation of ketone bodies and butanoate metabolism,
which are not disregulated in comparison with previous
clusters. Also, in the comparison between psoriasis patients at
dysmetabolism related to glycine, serine, and threonine
metabolism; arginine and proline metabolism; alanine,
Table 3. Metabolic Pathway Analysis Related to the Comparison between Control and Psoriasis Patients at T0 and the
Comparison between Psoriasis Patients at T0 and Psoriasis Patients at T1 (after 4 Weeks of Diet)
pathway (control vs psoriasis patients before ketogenic diet) raw PFDR discriminant metabolites C P
arginine and proline metabolism 2.59 ×1025 9.58 ×1025 arginine (P=3.34 ×1008)+
ornithine (P= 6.85 ×1006)+
proline (P= 0.0020) +
aminoacyl-tRNA biosynthesis 3.86 ×1019 7.14 ×1018 histidine (P= 2.14 ×1010)+
lysine (P= 6.08 ×1011)+
tryptophan (P= 1.18 ×1011)+
tyrosine (P= 1.56 ×1011)+
glyoxylate and dicarboxylate metabolism 3.69 ×1011 4.55 ×1010 formate (P= 4.45 ×1018)+
L-glutamine (P= 8.81 ×1005)+
L-serine (P= 3.42 ×1007)+
histidine metabolism 3.79 ×1008 3.51 ×1007 histidine (P= 2.14 ×1010)+
arginine biosynthesis 9.39 ×1008 6.38 ×1007 arginine (P= 3.34 ×1008)+
cysteine and methionine metabolism 1.21 ×1007 6.38 ×1007 methionine (P= 3.36 ×1010)+
β-alanine metabolism 5.18 ×1007 2.05 ×1006 histidine (P= 2.14 ×1010)+
alanine, aspartate, and glutamate metabolism 5.94 ×1004 1.83 ×1003 L-glutamine (P= 8.81 ×1005)+
succinate (P= 6.71 ×1005)+
glycine, serine, and threonine metabolism 1.14 ×1003 3.24 ×1003 choline (P= 2.36 ×1006)+
phenylalanine, tyrosine, and tryptophan biosynthesis 1.73 ×1003 4.27 ×1003 tyrosine (P= 1.56 ×1011)+
pathway (psoriasis patients before ketogenic diet vs psoriasis patients after
ketogenic diet) raw PFDR discriminant metabolites PT0 PT1
synthesis and degradation of ketone bodies 2.27 ×1013 4.33 ×1012 3-hydroxybutanoate (P= 1.96 ×
butanoate metabolism 2.28 ×1013 4.33 ×1012 3-hydroxybutanoate (P= 1.96 ×
L-glutamate (P= 0.008) +
glycine, serine, and threonine metabolism 7.95 ×1003 7.55 ×1002 choline (P= 2.11 ×1007)+
pyruvate (P= 4.21 ×1005)+
arginine and proline metabolism 4.19 ×1006 3.11 ×1005 proline (P= 0.007) +
pyruvate (P= 4.21 ×1005)+
alanine, aspartate, and glutamate metabolism 3.94 ×1006 3.11 ×1005 L-alanine (P= 0.0019) +
pyruvate (P= 4.21 ×1005)+
L-glutamate (P= 0.008) +
aminoacyl-tRNA biosynthesis 8.84 ×1006 4.20 ×1005 L-alanine (P= 0.0019) +
leucine (P= 1.96 ×1011)+
L-glutamate (P= 0.008) +
proline (P= 0.007) +
valine, leucine, and isoleucine degradation 7.95 ×1006 4.20 ×1005 leucine (P= 1.96 ×1011)+
valine, leucine, and isoleucine biosynthesis 1.16 ×1005 4.87 ×1005 leucine (P= 1.96 ×1011)+
pyruvate metabolism 1.59 ×1005 4.87 ×1005 pyruvate (P= 4.21 ×1005)+
The Pvalue, FDR value, and the most signicant metabolites with the concentration variation related to the clusters taken in examination are
reported for each pathway.
Journal of Proteome Research Article
J. Proteome Res. 2021, 20, 15091521
aspartate, and glutamate metabolism; and valine, leucine, and
isoleucine degradation and biosynthesis.
In enrichment analysis, by increasing the number of
reference metabolites and evaluating concentrations of
metabolites present in our matrix, it is possible to identify a
change in the metabolome of psoriasis patients before and after
the diet regimen. All dysmetabolism identied in the pathway
analysis was conrmed by the enrichment analysis (see Table
S4,Supporting Information). The graph in Figure 6 shows the
pathways that best discriminate between the two classes (T0
and T1). In particular, in the pathway of fatty acids, there is a
physiological variation of the ketone bodies related to the
ketogenic diet, with an increase of 3-hydroxybutyrate and
acetic acid in the serum of patients after 4 weeks. Choline
pathways (phospholipid biosynthesis and phosphatidylcholine
biosynthesis) indicated a reduction in serum choline levels of
patients with post-diet psoriasis.
Amino acid dysmetabolism
was conrmed by a change in L-leucine, L-isoleucine, and L-
valine levels, which decreased after the diet,
and by the
dysfunction of the urea cycle.
Enrichment analysis was repeated using the parameter
location-based metabolite setto understand which tissue was
the most involved in the previously described dysmetabolism.
The graph in Figure 7 represents the output of the enrichment
analysis that showed a dysmetabolism related to the epidermis,
muscular tissue, and skeletal muscle tissue, which is already
known to be involved in the physiopathogenesis of psoriasis.
A more accurate analysis of the metabolic pathways involved
in psoriasis was carried out by Reactome analysis
(see Table
S5,Supporting Information). Pathway analysis by Reactome
conrmed all dysmetabolism individuated to pathway analysis
by MetaboAnalyst 4.0 and has shown a possible link to
SLC6A14 gene variations that may be associated with obesity.
Several studies have conrmed the correlation between obesity
and psoriasis.
To assess the benets of ketogenic diet for patients with
psoriasis, the average of the concentrations of metabolites with
VIP score > 1 was calculated in the following groups: (i)
healthy controls, (ii) patients with psoriasis at T0 (before the
ketogenic diet), and (iii) patients with psoriasis at T1 (after 4
weeks of diet). Table 4 shows the average metabolite values for
each cluster and the dierence between the metabolites mean
concentration of healthy controls and patients before and after
the diet. Analysis of the data shown in Table 4 indicates that
the mean concentration dierence of the metabolites in the
patients vs controls at T1 is lower than the mean concentration
dierence in the patients vs controls at T0. The metabolites
formate, L-histidine, methionine, L-arginine, choline, L-
ornithine, pyruvic acid, and L-alanine are the most discrim-
ELISA Results
ELISAs performed on serum samples to evaluate the levels of
IL-2, IL-1β, TNF-α, IFN-γ, and IL-4 showed that there were
signicant dierences in the levels of the cytokines IL-2 (P=
0.04) and IL-1βin patients between T0 and T1 (P= 0.006)
(Figure 8). The signicance of the data was assessed by the
Wilcoxon statistical analysis test.
The graph in Figure 8
represents the signicant dierence in mean cytokine
Figure 6. Pathway enrichment analysis: the pathways related to a Pvalue that excludes randomness and is correlated with psoriasis.
Journal of Proteome Research Article
J. Proteome Res. 2021, 20, 15091521
concentrations for the patient group before the ketogenic diet
(T0) and after 4 weeks of the diet (T1). No signicant changes
in concentrations were detected for TNF-α(P= 0.47), IFN-γ
(P= 0.17), and IL-4 (P= 0.65).
In the present study, we evaluated the eect of a ketogenic diet
on psoriasis disease progression. Thirty psoriasis patients were
subjected to a ketogenic nutritional regimen and monitored by
evaluating (i) the clinical symptoms, (ii) the blood biochemical
parameters, including IL-2, IL-1β, TNF-α, IFN-γ, and IL-4,
and (iii) the metabolomic prole, as derived from 1H NMR
analysis. As a preliminary step, we identied the psoriatic
patientsmetabolomic prole and the healthy controls
metabolomic prole.
Based on preliminary data previously
obtained in our laboratory and for reasons related to the
restrictions imposed from the nutritional regimen, the patients
were subjected to 4 week treatment. As the parallel evaluation
of ketogenic diet eects in psoriatic and healthy subjects was
not possible, we considered the healthy controlsmetabolomic
prole as our experimental control. By following the
indications of the Italian Society of Endocrinology (ISE),
the enrollment of healthy subjects for the low-calorie ketogenic
nutritional regimen is not recommended as the low-calorie
ketogenic diet causes alteration of the metabolic prole in
healthy subjects, with potentially harmful implications in blood
pH equilibrium, calcium homeostasis, and lean mass balance.
Therefore, we considered the therapeutic eect of ketogenic
diets by comparing the metabolomic prole of psoriatic
patients at T1 with healthy subjectsmetabolomic prole at
Data resulting from the clinical evaluation showed caloric
restriction-induced psoriasis disease regression after 4 weeks
with a signicant reduction in the DLQI, PASI, VAS pain, and
VAS pruritus clinical scores (P< 0.05). In particular, the PASI
showed a reduction of approximately 50%.
Biochemical and clinical parameters indicated a general
improvement in the metabolitesconcentration known to be
related to the condition of psoriasis:
folic acid, vitamin B12,
calcium, bilirubin, cortisol, LDL, and total cholesterol. High
levels of folic acid and vitamin B12 are known to improve the
pathological condition related to psoriasis.
As reported in
Figure 7. Metabolite set enrichment overview: the tissue related to a
Pvalue that excludes randomness and correlates with psoriasis.
Table 4. Mean Discriminant Metabolites (VIP Score > 1) Concentration and Dierence Mean Concentration Relative to
Controls, Psoriasis Patients before Diet (T0), and Psoriasis Patients after 4 Weeks of Diet (T1)
metabolites (VIP > 1) M[]ctrl (μM) M[]p(T0) μM M[]p(T1) (μM) M[]ctrl M[]p(T0) M[]ctrl M[]p(T1)
formate 143.34 206.62 162.48 65.76 19.14
tryptophan 107.41 203.79 214.17 96.38 106.76
tyrosine 43.79 103.03 83.41 59.24 39.62
L-lysine 129.48 116.48 186.24 13 56.76
L-histidine 303.27 348.10 300.10 44.83 3.17
methionine 74.72 118.45 50.18 43.71 24.56
L-arginine 17.83 53.31 14.00 35.48 3.83
L-lactic acid 1235.86 13,490.45 10,661.03 12,254.59 9425.17
choline 39.83 116.86 39.41 77.03 0.42
isoleucine 171.72 2507.27 1912.76 2335.55 1741.04
L-ornithine 70.17 136.96 91.41 66.79 21.24
succinate 12.69 401.03 509.34 388.34 496.65
L-glutamine 743.69 2087.62 2079.38 1343.93 1335.69
3-hydroxybutiric acid 69.34 385.90 4526.07 316.56 4456.73
L-leucine 21.48 101.48 19.62 80 1.86
pyruvic acid 52.48 410.93 123.62 358.45 71.14
L-alanine 182.48 662.55 410.14 480.07 227.66
acetone 147.96 1336.14 2800.55 1188.17 2652.59
M[]ctrl, mean concentration in control group; M[]p(T0), mean concentration in psoriasis patients at T0; M[]p(T0), mean concentration in
psoriasis patients at T1.
Journal of Proteome Research Article
J. Proteome Res. 2021, 20, 15091521
Table 2, our data indicated low levels of folic acid and vitamin
B12 at T0, whereas an increase in the concentration was
registered at T1. Hypocalcemia was observed as a risk factor in
Our data show an increase in calcium levels in
subjects after the ketogenic diet. Bilirubin, an essential
antioxidant metabolite, was present in low concentrations in
subjects with psoriasis;
after our diet regimen, bilirubin
concentration increased. Signicant variation was observed in
the concentrations of cortisol, LDL, and total cholesterol.
Recent scientic studies assert that low cortisol levels are
related to high stress levels in subjects with psoriasis.
According to the DLQI, investigating the quality of life in
subjects with psoriasis, cortisol levels following a low-calorie
ketogenic diet increased.
The ketogenic diet resulted in weight loss at T1,
corresponding to 10% of the initial body weight. Other
signicant modications of anthropometric measurements
were waist circumference and hip circumference (see Table
S6,Supporting Information). The weight loss was associated
with a signicant increase in ketone bodies at T1, as shown in
the NMR-based metabolomic analysis. This eect was the
main physiological eect of the ketogenic diet. The basic
principle of the low-calorie ketogenic diet is to limit the
availability of carbohydrates, forcing the consumption of fats as
the primary energy source, with a resulting increase in fatty
acids, ketone bodies, and pyruvic acid. However, weight loss
and the increase in ketone bodies were not associated with any
alteration of those biochemical parameters that initially were in
the average concentration range, thus proving the safety of the
proposed dietary intervention.
In contrast, biochemical and clinical parameters previously
found in abnormal concentrations and related to carbohydrate
and lipid metabolism, such as glucose, total cholesterol, LDL,
Apo A1 and B, AST, γGT, insulin, and HOMA-I, returned to
healthy average ranges (see Table S6,Supporting Informa-
tion). A decrease in HDL was also observed due to the drop in
total cholesterol (from 52.07 ±18.23 to 44.20 ±14.22 mg/dL;
P= 0.079). Last, the reduction in the aortomesenteric fat
thickness (AMFT) proved a substantial decrease in VAT.
The ketogenic nutritional regimen aims to minimize insulin
levels and to increase GH secretion. The nal eect is the
almost complete reduction of the visceral adipose tissue
responsible for insulin resistance and the insurgence of
inammatory status. Insulin and estrogen act at the PPAR
(peroxisome proliferator-activated receptor) level by activating
the transcriptase for adipogenesis. Conversely, GH phosphor-
ylates PPAR and inhibits adipogenesis. As a result, reduced
insulin concentration favors a lipolytic route with the
mobilization of visceral localized fat deposits.
Earlier scientic studies have identied lactic acid as a
possible biomarker of psoriasis.
Conrming this evidence,
the VIP analysis (Figure 3) indicated increased lactic acid
concentration in psoriatic patients. On the contrary, the
concentrations of lactic acid and L-isoleucine, although
decreasing, do not fall into the physiological range of healthy
subjects, perhaps due to the short-term treatment.
The conrmationthattheketogenicdietinducesa
correction of the dysmetabolic condition related to psoriasis
disease results from the NMR metabolomics study performed
on psoriasis patientsblood sera. NMR metabolomics data on
the patient sera collected before the diet indicated abnormal
concentrations of metabolites that are related to the condition
of psoriasis,
and these concentrations were found in the
ranges of the healthy controls at T1, suggesting a rebalancing
of the metabolome after the ketogenic regimen.
Abnormally high concentrations of L-alanine and L-leucine
and a lower concentration of L-glutamine were previously
identied as biomarkers of psoriasis.
VIP score analysis based
on the multivariate statistical analysis of the NMR metab-
olomics data shows a decrease in L-leucine and L-alanine and
an increase in glutamine and glutamate at T1.
Moreover, signicant variations in L-arginine, L-phenyl-
alanine, L-aspartic acid, and L-proline concentrations at T1
were also observable.
An interpretation of these metabolic
changes according to the pathway and enrichment analysis
(Figures 6 and 7) indicated that the regression of psoriasis was
related to the correction of amino acid metabolic pathways, in
particular, those of alanine, aspartate, and glutamate metabo-
lism; arginine and proline metabolism; valine, leucine, and
isoleucine degradation; valine, leucine, and isoleucine biosyn-
thesis; and tyrosine metabolism. Therefore, these data,
considered from a pathognomonic perspective, suggest that
important modications in amino acid and glycolysis pathways
for psoriasis patients are ascribed to an increase in amino acid
and energy demand for protein biosynthesis and keratinocyte
NMR metabolomics data showed that choline levels were
decreased in psoriasis patients at T1 compared to T0. The
decrease in choline and nicotine concentrations is additional
evidence that the regression of psoriasis corresponds to the
regression of the inammatory process: previous data showed
high choline and nicotine levels in psoriasis patients due to
mast cell degranulation.
Additionally, we measured the concentration of the
cytokines IL-4, TNF-α, INF-γ, IL-2, and IL-1βthat are
considered markers of inammatory status. In agreement with
previous scientic studies pointing to altered interleukin serum
concentrations in psoriasis patients,
we found decreased
IL-2 and IL-1βconcentrations at T1 compared to T0
Figure 8. Mean resultant signicant cytokine concentrations (P< 0.05) at T0 (before diet) and T1 (after 4 weeks of the diet).
Journal of Proteome Research Article
J. Proteome Res. 2021, 20, 15091521
(Figure 3). The concentrations of IL-4, TNF-α, and INF-γ
were not signicantly decreased, probably due to the
insucient 4 week period to induce a signicant variation of
pro-inammatory cytokine concentrations.
Taken together, our data suggest that a low-calorie ketogenic
diet can be considered a successful strategy and therapeutic
option for the management of psoriasis. IL-2 and IL-1β,
together with the concentrations of leucine, alanine, glutamine,
glutamate, and choline, can be considered promising
biomarkers for the early diagnosis and correct prognosis of
psoriasis patients.
Our data suggest that a low-calorie ketogenic diet can be
considered a successful strategy and therapeutic option for
psoriasis management. IL-2 and IL-1β, together with the
concentrations of L-leucine, L-alanine, L-glutamine, L-glutamate,
and choline, can be considered promising biomarkers for the
early diagnosis and correct prognosis of psoriasis patients. The
dietary program is feasible, with high compliance, and safe.
The main eects depend on reducing VAT, disrupting the
inammatory environment, and the source of inammatory
sıSupporting Information
The Supporting Information is available free of charge at
Figure S1: green line on top showing the accumulated
variance explained and blue line underneath showing the
variance explained by individual PC; Figure S2: pairwise
score plots among the selected PCs; Figure S3: PLS-DA
classication using dierent numbers of components;
Table S1: important features identied by fold change
and logarithmic fold change (log2(FC)) parameters
calculated; Table S2: important features identied by t-
test values, Pvalues (threshold, <0.05), logarithmic P
values and false discovery rate (FDR) parameters
calculated for the most statistically signicant com-
pounds; Table S3: important features identied by PLS-
DA and relative component VIP score; Table S4: results
from quantitative enrichment analysis; Table S5: path-
way analysis by Reactome and relative Pvalue and
number of hits; Table S6: clinical features of the patients
during the follow-up (PDF)
Corresponding Authors
Anna Maria DUrsi Department of Pharmacy, University of
Salerno, 84084 Fisciano, Salerno, Italy;
0001-6814-8472; Phone: +39089969748; Email: dursi@
Luca Rastrelli NutriKeto_LAB UnisaSan Giuseppe
MoscatiNational Hospital (AORN), 83100 Avellino,
Avellino, Italy; Department of Pharmacy, University of
Salerno, 84084 Fisciano, Salerno, Italy;
0003-0718-5450; Phone: +39089969766;
Giuseppe Castaldo NutriKeto_LAB UnisaSan Giuseppe
MoscatiNational Hospital (AORN), 83100 Avellino,
Avellino, Italy;
Imma Pagano NutriKeto_LAB UnisaSan Giuseppe
MoscatiNational Hospital (AORN), 83100 Avellino,
Avellino, Italy; Department of Pharmacy, University of
Salerno, 84084 Fisciano, Salerno, Italy;
Manuela Grimaldi Department of Pharmacy, University of
Salerno, 84084 Fisciano, Salerno, Italy;
Carmen Marino Department of Pharmacy, University of
Salerno, 84084 Fisciano, Salerno, Italy
Paola Molettieri NutriKeto_LAB UnisaSan Giuseppe
MoscatiNational Hospital (AORN), 83100 Avellino,
Avellino, Italy;
Angelo Santoro Department of Pharmacy, University of
Salerno, 84084 Fisciano, Salerno, Italy;
Ilaria Stillitano Department of Pharmacy, University of
Salerno, 84084 Fisciano, Salerno, Italy
Rocco Romano Department of Pharmacy, University of
Salerno, 84084 Fisciano, Salerno, Italy
Paola Montoro Department of Pharmacy, University of
Salerno, 84084 Fisciano, Salerno, Italy
Complete contact information is available at:
Author Contributions
G.C. designed research. I.P., P.M., A.S., I.S., and M.G.
conducted research and analyzed the data. C.M., R.R., and
P.M. performed the statistical analysis. A.M.D. and L.R. wrote
the paper.
The authors declare no competing nancial interest.
PASI, psoriasis area and severity index; BSA, body surface area;
DLQI, dermatology life quality index; BMI, body mass index;
NMR, nuclear magnetic resonance; GH, growth hormone;
HDL, high-density lipoprotein; LDL, low-density lipoprotein;
AST, aspartate aminotransferase; γGT, gamma glutamyl
transferase; HOMA-IR, homeostasis model assessment insulin
resistance; VAT, visceral adipose tissue; AMFT, aortomesen-
teric fat thickness; CPMG, CarrPurcellMeiboomGill;
HMDB, Human Metabolome Database; MVA, multivariate
analysis; PCA, principal component analysis; PLS-DA, partial
least-squares discriminant analysis; TSP, trimethylsilyl pro-
pionic-2,2,3,3-d4acid, sodium salt; PRICONA, PRincipal
COmponent Normalization Algorithm; ELISA, enzyme-linked
immunosorbent assay; VIP, variable inuence on projection;
VAS, visual analogue scale; FDR, false discovery rate; PPAR,
peroxisome proliferator-activated receptor
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... Clinical parameters associated with the metabolic profile and the inflammatory state of patients subjected to various diet regimens were evaluated. A low-calorie diet and a ketogenic diet, among others, improved all the tested parameters and clinically alleviated the psoriatic status of the patients [7,8]. ...
... New data that evaluated caloric restriction in Ps patients have shown a regression in the lesions after 4 weeks of dieting. Moreover, a significant reduction in the standard parameters was recorded (DLQI, VAS pain, and VAS pruritus), while PASI scores showed a significant 50% reduction [7]. Ps is known to lead to deregulated biochemical parameters in terms of folic acid, vitamin B12, calcium, bilirubin, cortisol, LDL, and total cholesterol [143]. ...
... Hypocalcemia is another risk factor in Ps. The low-calorie diet [7] indicated an increase in calcium. An antioxidant metabolite, bilirubin, is registered in low concentrations in Ps patients [144], and after dieting, its concentration increases. ...
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Psoriasis, an autoimmune chronic inflammatory skin condition, has a high incidence in the general population, reaching 2-4%. Its pathogenesis involves an interplay of genetic factors, immune disturbances, and environmental factors. Within the environmental factors that aid the appearance of this autoimmune skin disease, the Western lifestyle and overall diet play important roles in the steady growth in psoriasis prevalence. Furthermore, psoriasis is associated with comorbidities such as psoriatic arthritis, cardiovascular disease, metabolic syndrome, and obesity. Accumulating evidence suggests that obesity is an important risk factor for psoriasis. Moreover, obesity aggravates established psoriasis, and a reduction in the body mass index can improve the clinical outcomes of psoriasis and increase the efficacy of standard psoriasis therapies. The possible connection between this autoimmune disease and obesity relies on the fact that white adipose tissue is an essential en-docrine organ that secretes an array of immune mediators and inflammatory and metabolic factors with pro-inflammatory action. Thus, immune-mediated mechanisms in both psoriasis and obesity conditions are common factors. This paper describes the factors that link obesity with skin autoim-mune disease and highlights the importance of the stimulatory or regulatory effects of nutrients and food in psoriasis and the possible improvement of psoriasis through nutritional strategies.
... A randomized controlled trial in those with acne found that intervention with a low-glycemic load diet improved insulin sensitivity and reduced total inflammatory lesion counts compared to control [4]. Furthermore, psoriasis has been associated with increased adiposity, with excess adipose tissue that contributes to a pro-inflammatory state [5]. A study was conducted to investigate the role of weight reduction on psoriasis with the use of a low-calorie, protein-based diet [5]. 2 ...
... Furthermore, psoriasis has been associated with increased adiposity, with excess adipose tissue that contributes to a pro-inflammatory state [5]. A study was conducted to investigate the role of weight reduction on psoriasis with the use of a low-calorie, protein-based diet [5]. 2 ...
... After four weeks, a significant improvement was found in measures of quality of life, pain, itch, and the extent and severity of psoriasis [5]. ...
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Diet and nutrition have been shown to impact dermatological conditions. This has increased attention toward integrative and lifestyle medicine in the management of skin health. Emerging research around fasting diets, specifically the fasting-mimicking diet (FMD), has provided clinical evidence for chronic inflammatory, cardiometabolic, and autoimmune diseases. In this randomized controlled trial, we evaluated the effects of a five-day FMD protocol, administrated once a month for three months, on facial skin parameters, including skin hydration and skin roughness, in a group of 45 healthy women between the ages of 35 to 60 years old over the course of 71 days. The results of the study revealed that the three consecutive monthly cycles of FMD resulted in a significant percentage increase in skin hydration at day 11 (p = 0.00013) and at day 71 (p = 0.02) relative to baseline. The results also demonstrated maintenance of skin texture in the FMD group compared to an increase in skin roughness in the control group (p = 0.032). In addition to skin biophysical properties, self-reported data also demonstrated significant improvement in components of mental states such as happiness (p = 0.003) and confidence (0.039). Overall, these findings provide evidence for the potential use of FMD in improving skin health and related components of psychological well-being.
... Among the studies, 13 studies included KD as an intervention (Bock et al., 2018;Bosco et al., 2018;Castaldo et al., 2021;Rhyu and Cho, 2014;Cipryan et al., 2020aCipryan et al., , 2020bPaoli et al., 2021;Bertoli et al., 2015;Kong et al., 2020;Khodabakhshi et al., 2021;Rosenbaum et al., 2019;Monda et al., 2020;Shaw et al., 2020), while only 2 studies employed ketone body administration as an intervention (Shaw et al., 2020;Martin-Arrowsmith et al., 2020). Alteration of multiple cytokines or other inflammatory mediators such as adiponectin, resistin, etc., were reported. ...
... Among the studies, 10 of 15 (66.7%), reported at least one inflammatory mediator (C-reactive protein (CRP), leptin, interleukin (IL)-1β, IL-2, IL-6, IL-12p40, interferon (IFN)-γ and/or tumor necrosis factor (TNF)-α) (Bosco et al., 2018;Castaldo et al., 2021;Cipryan et al., 2020bCipryan et al., , 2020aKong et al., 2020;Shaw et al., 2020;Khodabakhshi et al., 2021, Monda et al., 2020 or the mRNA of the indicated inflammatory mediators (IFN-γ mRNA, Shaw et al., 2020) was decreased by KD or BHB intervention. However, 3 studies reported that no changes were observed (Bock et al., 2018;Rhyu and Cho, 2014;). ...
... Another option for people with psoriasis is the ketogenic diet. It is a dietary regimen characterized by a reduction in carbohydrate intake and a relative increase in protein and fat presence on the menu [54]. On a biochemical level, the ketogenic diet causes a shift to ketone metabolism, forming ketones from fat as the main energy source, followed by a decrease in glucose levels and increasing blood ketones. ...
... Studies have shown that using a low-calorie ketogenic diet in patients with psoriasis decreased the concentration of pro-inflammatory cytokines (including IL-2 and IL-1β). It also decreased the PASI index (psoriasis severity assessment scale, Psoriasis Area and Severity Index) [54,55]. ...
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Psoriasis is an inflammatory disease with strong genetic links and numerous features of autoimmunity that are also influenced by environment and lifestyle, including nutritional factors and physical activity (PA), with regards to the condition of patients. Recent reports in the field of nutrigenomics indicate a significant impact of nutrients in modulating microRNAs. However, few studies have evaluated the effect of nutritional systems and PA on treating psoriasis. This narrative review updates information regarding the current dietary recommendations for individuals with psoriasis and discusses the role of diet and PA in psoriasis prevention and treatment. Application of nutrigenetics in psoriasis therapy is also discussed. The PubMed and Google Scholar databases were searched using the MeSH terms for “nutrigenomics”, “dietetics”, “diet therapy”, “diet”, “physical activity”, and “exercise” in conjunction with the MeSH terms for “psoriasis” and “dermatology”. Evidence has shown that patients with psoriasis should have a personalized anti-inflammatory diet. Psoriasis patients are less physically active; most performed exercises of low-to-moderate intensity and were less likely to undertake regular exercise. Identifying nutrigenomic discoveries and the current lifestyle interventions associated with psoriasis can help physicians and physical therapists develop educational programs to manage and protect against the disease.
... Interestingly, the afternoon MED differences in patients following omnivore, ketogenic or paleo diets disappeared. The ketogenic diet [81], characterized by a low carbohydrate intake along with a high intake of protein and fat, has been demonstrated to improve clinical symptoms and biochemical and inflammatory markers in PsO patients. Similarly, Ramadan fasting, with the corresponding changes in sleep-wake cycles, has been shown to be beneficial in terms of PsO severity [19]. ...
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Abstract Introduction Minimal erythema dose (MED) remains a parameter of paramount importance to orient narrow-band (NB)-UVB phototherapy in psoriatic (PsO) patients. Recently, circadian rhythm and diet were recognized as potential MED modulators, but their mutual interaction remains understudied. Thus, we aimed to evaluate the potential diet modulation of MED circadian oscillations. Methods In the first phase, a cohort study was performed comparing potential MED oscillations (morning, afternoon, and evening) among omnivorous psoriatic patients before and after a phototherapy cycle and omnivorous healthy controls. The two groups were age-, gender-, skin-type-, MED-, and diet-matched. Then, in the second phase, another cohort study was carried out comparing MED oscillations 24 h after the last phototherapeutic session only in psoriatic patients cleared with NB-UVB and undergoing different diets (vegan, vegetarian, paleo , ketogenic, intermittent circadian fasting, and omnivore). Patients with different diets were age-, gender-, and skin-type matched. Results In the first phase, we enrolled only omnivores, specifically 54 PsO patients and 54 healthy individuals. Their MED before and after NB-UVB therapy changed significantly among the three different time-points (morning, afternoon, and evening) (p
... It has been previously shown that a very low carbohydrate ketogenic diet protocol improves the expansion of psoriatic lesions with the concurrent improvement of biochemical and inflammation markers in patients with psoriasis. The nutritional intervention resulted in the reprogramming of several metabolic pathways, to the levels of healthy control, with the most significant being dysmetabolism and amino acid metabolism possibly linked to keratinocytes hyperproliferation (Castaldo et al., 2021). ...
Full-text available
Psoriasis is a common inflammatory disease that affects mainly the skin. However, the moderate to severe forms have been associated with several comorbidities, such as psoriatic arthritis, Crohn’s disease, metabolic syndrome and cardiovascular disease. Keratinocytes and T helper cells are the dominant cell types involved in psoriasis development via a complex crosstalk between epithelial cells, peripheral immune cells and immune cells residing in the skin. Immunometabolism has emerged as a potent mechanism elucidating the aetiopathogenesis of psoriasis, offering novel specific targets to diagnose and treat psoriasis early. The present article discusses the metabolic reprogramming of activated T cells, tissue-resident memory T cells and keratinocytes in psoriatic skin, presenting associated metabolic biomarkers and therapeutic targets. In psoriatic phenotype, keratinocytes and activated T cells are glycolysis dependent and are characterized by disruptions in the TCA cycle, the amino acid metabolism and the fatty acid metabolism. Upregulation of the mammalian target of rapamycin (mTOR) results in hyperproliferation and cytokine secretion by immune cells and keratinocytes. Metabolic reprogramming through the inhibition of affected metabolic pathways and the dietary restoration of metabolic imbalances may thus present a potent therapeutic opportunity to achieve long-term management of psoriasis and improved quality of life with minimum adverse effects.
... Apart from drug therapy, the effects of dietotherapy have also been the focus of recent research. Castaldo et al [40] investigated the serum metabolomic profiles of overweight psoriasis patients before and after a 4-week ketogenic diet using NMR analysis. After the dietary intervention, levels of L-leucine, L-alanine, and choline were decreased, whereas levels of glutamine and glutamate were increased, suggesting a rebalancing of the metabolome. ...
Full-text available
Psoriasis is a chronic inflammatory skin disease with significant physical and psychological burdens. The interplay between the innate and adaptive immune systems is thought to contribute to the pathogenesis; however, the details of the pathogenesis remain unclear. In addition, reliable biomarkers for diagnosis, assessment of disease activity, and monitoring of therapeutic response are limited. Metabolomics is an emerging science that can be used to identify and analyze low molecular weight molecules in biological systems. During the past decade, metabolomics has been widely used in psoriasis research, and substantial progress has been made. This review summarizes and discusses studies that applied metabolomics to psoriatic disease. These studies have identified dysregulation of amino acids, carnitines, fatty acids, lipids, and carbohydrates in psoriasis. The results from these studies have advanced our understanding of: (1) the molecular mechanisms of psoriasis pathogenesis; (2) diagnosis of psoriasis and assessment of disease activity; (3) the mechanism of treatment and how to monitor treatment response; and (4) the link between psoriasis and comorbid diseases. We discuss common research strategies and progress in the application of metabolomics to psoriasis, as well as emerging trends and future directions.
... However, more evidence will be helpful to support this outcome [8]. A low-calorie ketogenic diet could be considered as a promising therapy to improve psoriasis-related dysmetabolism, upon extensive reformation of the inflammatory as well as metabolic state of the subject [9]. Moreover, in a recent study, KD was also shown to inhibit colitis and protect intestinal barrier decay [10]. ...
Full-text available
Interceding nutrients have been acquiring increased attention and prominence in the field of healing and deterrence of various disorders. In this light, the present article encompasses several facets of ketogenic diet as an immunomodulator with respect to its expansive clinical applications. Accordingly, several scientific records, models, and case histories, including viral infections, cancer, chronic diseases, e.g., cardiovascular diseases, epilepsy, as well as numerous other neuro-disorders, are assembled, revealing a profound influence of KD in favor of improvement in the patient’s condition. We accentuate possible manifold mechanisms of KD that require further exploration.
Purpose of review: Psoriatic arthritis (PsA) is a common form of inflammatory arthritis that affects people with psoriasis. Both psoriasis and PsA are associated with metabolic diseases including obesity, hypertension, hyperlipidaemia, diabetes mellitus, fatty liver disease, and cardiovascular disease including myocardial infarction. Dietary interventions for psoriatic disease have been of great interest, particularly among patients with PsA. Recent findings: Herein, we review the evidence for dietary intervention in psoriatic arthritis. To date, weight loss among patients who are obese has the greatest evidence for benefit. We also examine the evidence for fasting, nutrient supplementation, and specific diets as adjunct therapeutic strategies. Summary: While the data do not clearly support a single dietary intervention across the disease, weight loss among those who are obese results in improved PsA disease activity and physical function. Additional studies are needed to better understand the impact of diet on psoriatic arthritis.
Purpose of review: This review provides an overview of most recent research studies employing nuclear magnetic resonance (NMR)-based metabolomics in the assessment of effects of diet and food ingestion. Recent findings: NMR metabolomics is a useful tool in the elucidation of specific diets, for example, the Mediterranean diet, the New Nordic diet types, and also for comparing vegan, vegetarian and omnivore diets where specific diet-linked metabolite perturbations have been identified. Another core area where NMR metabolomics is employed involves research focused on examining specific food components or ingredients, including dietary fibers and other functional components. In several cases, NMR metabolomics has aided to document how specific food components exert effects on the metabolic activity of the gut microbiota. Research has also demonstrated the potential use of NMR metabolomics in assessing diet quality and interactions between specific food components such as meat and diet quality. The implications of these findings are important as they address that background diet can be decisive for if food items turn out to exert either harmful or health-promoting effects. Summary: NMR metabolomics can provide important mechanistic insight and aid to biomarker discovery with implications for compliance and food registration purposes.
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Epilepsy in the pediatric and adolescent populations is a devastating condition where individuals are prone to recurrent epileptic seizures or changes in behavior or movement that is the direct result of a primary change in the electrical activity in the brain. Although many children with epilepsy will have seizures controlled with antiseizure medications (ASMs), a large percentage of patients are refractory to drug therapy and may consider initiating a ketogenic diet. The term Ketogenic Diet or Ketogenic Diet Therapy (KDT) refers to any diet therapy in which dietary composition results in a ketogenic state of human metabolism. Currently, there are 4 major Ketogenic diet therapies—the classic ketogenic diet (cKD), the modified Atkins diet (MAD), the medium chain triglyceride ketogenic diet (MCTKD) and the low glycemic index treatment (LGIT). The compositions of the 4 main KDTs differ and limited evidence to distinguish the efficacy among different diets currently exists. Although it is apparent that more randomized controlled trials (RCTs) and long-term studies are needed to evaluate efficacy, side effects and individual response to the diet, it is imperative to study and understand the metabolic profiles of patients with epilepsy in order to isolate which dietary restrictions are necessary to maximize clinical benefit.
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Background: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women during reproductive age. It is characterised clinically by oligo-ovulation or anovulation, hyper-androgenism, and the presence of polycystic ovaries. It is associated with an increased prevalence of metabolic syndrome, cardiovascular disease and type 2 diabetes. The onset of PCOS has been associated to several hereditary and environmental factors, but insulin resistance plays a key pathogenetic role. We sought to investigate the effects of a ketogenic diet (KD) on women of childbearing age with a diagnosis of PCOS. Methods: Fourteen overweight women with diagnosis of PCOS underwent to a ketogenic Mediterranean diet with phyoextracts (KEMEPHY) for 12 week. Changes in body weight, body mass index (BMI), fat body mass (FBM), lean body mass (LBM), visceral adipose tissue (VAT), insulin, glucose, HOMA-IR, total cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL), triglycerides (TGs), total and free testosterone, luteinizing hormone (LH), follicle stimulating hormone (FSH); dehydroepiandrosterone sulfate (DHEAs), estradiol, progesterone, sex hormone binding globulin (SHBG) and Ferriman Gallwey score were evaluated. Results: After 12 weeks, anthropometric and body composition measurements revealed a significant reduction of body weight (- 9.43 kg), BMI (- 3.35), FBM (8.29 kg) and VAT. There was a significant, slightly decrease of LBM. A significant decrease in glucose and insulin blood levels were observed, together with a significant improvement of HOMA-IR. A significant decrease of triglycerides, total cholesterol and LDL were observed along with a rise in HDL levels. The LH/FSH ratio, LH total and free testosterone, and DHEAS blood levels were also significantly reduced. Estradiol, progesterone and SHBG increased. The Ferriman Gallwey Score was slightly, although not significantly, reduced. Conclusions: Our results suggest that a KD may be considered as a valuable non pharmacological treatment for PCOS. Longer treatment periods should be tested to verify the effect of a KD on the dermatological aspects of PCOS. Trial registration, NCT04163120, registrered 10 November 2019, retrospectively registered,
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Preclinical data provide evidence for synergism between ketogenic diets (KDs) and other oncological therapies. The aim of this systematic review was to summarize data from clinical studies that have tested KDs along with other treatments used within medical oncology. The PubMed database was searched using the key words "ketogenic" AND ("cancer" OR "glioblastoma"). A secondary search was conducted by screening the reference lists of relevant articles on this topic. Relevant studies for this review were defined as studies in which KDs were used complementary to surgery, radio-, chemo-, or targeted therapy and at least one of the following four outcomes were reported: (i) Overall survival (OS); (ii) progression-free survival (PFS); (iii) local control rate; (iv) body composition changes. Twelve papers reporting on 13 clinical studies were identified. Nine studies were prospective and six had a control group, but only two were randomized. KD prescription varied widely between studies and was described only rudimentarily in most papers. Adverse events attributed to the diet were rare and only minor (grade 1–2) except for one possibly diet-related grade 4 event. Studies reporting body composition changes found beneficial effects of KDs in both overweight and frail patient populations. Beneficial effects of KDs on OS and/or PFS were found in four studies including one randomized controlled trial. Studies in high-grade glioma patients were not sufficiently powered to prove efficacy. Evidence for beneficial effects of KDs during cancer therapy is accumulating, but more high-quality studies are needed to assess the overall strength of evidence.
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Very low calorie ketogenic diet (VLCKD) has been proposed as a promising option to achieve a significant weight loss in a short time period. We conducted a systematic review and meta-analysis to evaluate its efficacy and safety in patients with overweight and obesity. Four databases were searched on May 2019. Studies reporting data on body weight, body mass index (BMI), waist circumference, body composition, blood pressure, HbA1c, lipids, and markers of liver and kidney function were selected. Discontinuation was also assessed. Twelve studies were included. VLCKD was associated with weight losses of −10.0 kg (I² = 6%) and − 15.6 kg (I² = 37%) in studies with a ketogenic phase up to and of at least four weeks, respectively. The weight lost during the ketogenic phase was stable in the subsequent follow-up up to two years (p = 0.12). Also, VLCKD was associated with reductions of BMI (−5.3 kg/m²), waist circumference (−12.6 cm), HbA1c (−0.7%), total cholesterol (−28 mg/dl), triglycerides (−30 mg/dl), AST (−7 U/l), ALT (−8 U/l), GGT (−8 U/l), systolic and diastolic blood pressure (−8 and − 7 mmHg, respectively). No changes in LDL cholesterol, HDL cholesterol, serum creatinine, serum uric acid and serum potassium were found. Serum sodium increased during VLCKD (+1.6 mEq/l). The overall prevalence of patients discontinuing VLCKD was 7.5% and this was similar to patients undergoing a low calorie diet (p = 0.83). The present review supports the use of VLCKD as an effective strategy for the management of overweight and obesity. Future guidelines should include a specific recommendation for this intervention.
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Objective The objectives of this study were to delineate the pro and anti-inflammatory cytokine profiles of psoriasis and cytokine profile models that externally validate the diagnosis. Subjects and Methods This study recruited 70 patients with psoriasis and 76 healthy controls. Cytokine profiles were evaluated, including pro-inflammatory M1 (IL-1 + IL-6 + TNF-α), Th1 (IL-2 + IL-12 + IFN-γ), Th17 (IL-6 + IL-17), and immune-inflammatory response system (IRS = M1 + Th1 + Th17) profiles. Moreover, the anti-inflammatory potential included Th2 (IL-4), Th2 + T regulatory (Th2 + Treg, namely IL-4 + IL-10 + TGF-β), anti-inflammatory (Th2 + Treg + adiponectin), and the pro-inflammatory/anti-inflammatory index. Results There was a highly significant association between psoriasis and cytokine levels with an effect size of 0.829 and a particularly strong impact on IL-2 (0.463), IL-12 (0.451), IL-10 (0.532) and adiponectin (0.401). TGF-β and adiponectin were significantly lower while all other cytokines (except IFN-γ) were significantly higher in psoriasis than in controls. In addition, M1, Th1, Th17, Th2 + Treg, and IRS/Anti-inflammatory index were significantly higher in psoriasis patients than in controls. The IRS index, Th2 + Treg, and adiponectin predicted psoriasis with 97.1% sensitivity and 94% specificity. Conclusion In conclusion, psoriasis is characterized by increased M1, Th1, Th2 and Th17 profiles together with lowered TGF-β and adiponectin. In addition, we propose a model based on a higher IRS and Th2 + Treg index coupled with lower adiponectin values, which may be used to externally validate the diagnosis of psoriasis. The most important single biomarker of psoriasis is adiponectin. Because the latter may play a role in the modulation of the chronic inflammatory response in psoriasis, adiponectin could be a new drug target to treat psoriasis.
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Background Psoriasis is a common inflammatory skin disease that has been reported to be associated with obesity. We aimed to investigate a possible causal relationship between body mass index (BMI) and psoriasis. Methods and findings Following a review of published epidemiological evidence of the association between obesity and psoriasis, mendelian randomization (MR) was used to test for a causal relationship with BMI. We used a genetic instrument comprising 97 single-nucleotide polymorphisms (SNPs) associated with BMI as a proxy for BMI (expected to be much less confounded than measured BMI). One-sample MR was conducted using individual-level data (396,495 individuals) from the UK Biobank and the Nord-Trøndelag Health Study (HUNT), Norway. Two-sample MR was performed with summary-level data (356,926 individuals) from published BMI and psoriasis genome-wide association studies (GWASs). The one-sample and two-sample MR estimates were meta-analysed using a fixed-effect model. To test for a potential reverse causal effect, MR analysis with genetic instruments comprising variants from recent genome-wide analyses for psoriasis were used to test whether genetic risk for this skin disease has a causal effect on BMI. Published observational data showed an association of higher BMI with psoriasis. A mean difference in BMI of 1.26 kg/m² (95% CI 1.02–1.51) between psoriasis cases and controls was observed in adults, while a 1.55 kg/m² mean difference (95% CI 1.13–1.98) was observed in children. The observational association was confirmed in UK Biobank and HUNT data sets. Overall, a 1 kg/m² increase in BMI was associated with 4% higher odds of psoriasis (meta-analysis odds ratio [OR] = 1.04; 95% CI 1.03–1.04; P = 1.73 × 10⁻⁶⁰). MR analyses provided evidence that higher BMI causally increases the odds of psoriasis (by 9% per 1 unit increase in BMI; OR = 1.09 (1.06–1.12) per 1 kg/m²; P = 4.67 × 10⁻⁹). In contrast, MR estimates gave little support to a possible causal effect of psoriasis genetic risk on BMI (0.004 kg/m² change in BMI per doubling odds of psoriasis (−0.003 to 0.011). Limitations of our study include possible misreporting of psoriasis by patients, as well as potential misdiagnosis by clinicians. In addition, there is also limited ethnic variation in the cohorts studied. Conclusions Our study, using genetic variants as instrumental variables for BMI, provides evidence that higher BMI leads to a higher risk of psoriasis. This supports the prioritization of therapies and lifestyle interventions aimed at controlling weight for the prevention or treatment of this common skin disease. Mechanistic studies are required to improve understanding of this relationship.
Background: Sex and gender may affect disease prevalence, adverse effects and response to therapy. Aim: To analyse sex- and gender differences in psoriasis outpatients. Methods: A cross-sectional study was conducted at IDI-IRCCS, Rome, over a 3-year period. 3023 psoriasis patients were enrolled. Anthropometric and demographic characteristics were recorded, and a dermatologist evaluated the clinical severity of disease. Quality of life questionnaires were collected. Univariate and multivariate analyses were performed to examine factors associated with sex. Results: We found sex- and gender- differences in clinical characteristics, severity of disease, psychological distress, and quality of life. Male sex was associated with Body Mass Index, smoking, alcohol consumption, Psoriasis Area Severity Index (PASI) ≥10, age at onset ≥20 years. Female sex was associated with family history of diabetes, joint involvement, clinical type other than plaque diffuse, higher psychological distress, and a greater burden on quality of life. Conclusion: Our study identified sex- and gender differences of potential clinical relevance.
Objectives: A very low-calorie ketogenic diet (VLCKD) has been associated with a significant reduction in visceral adipose tissue and ketone bodies that likely possess antiinflammatory properties. We evaluated the efficacy of an aggressive weight-loss (WL) program with a ketogenic induction phase as first-line treatment for chronic plaque psoriasis. Methods: Adult patients who were overweight or obese and drug-naïve (i.e., never treated, excluding the use of topical emollients; n = 37; 30% men; age: 43.1 ± 13.8 y) with stable chronic plaque psoriasis underwent a 10-wk, 2-phase WL program consisting of a 4-wk protein-sparing, VLCKD (<500 kcal/d; 1.2 g of protein/kg of ideal body weight/d) and 6-wk balanced, hypocaloric (25-30 kcal/kg of ideal body weight/d), Mediterranean-like diet. The primary endpoint was the reduction in Psoriasis Area and Severity Index (PASI) score at wk 10. Major secondary endpoints included PASI score responses of ≥50% and ≥75%, reduction in body surface area involved, improvement in itch severity (visual analogue scale), and Dermatology Life Quality Index score at wk 10. Results: With a mean body weight reduction of 12.0% (-10.6 kg), the dietary intervention resulted in a significant reduction in PASI (baseline score: 13.8 ± 6.9; range, 7-32), with a mean change of -10.6 (95% confidence interval, -12.8 to -8.4; P < 0.001). PASI score responses of ≥50% and ≥75% were recorded in 36 patients (97.3%) and 24 patients (64.9%), respectively. Treatment also resulted in a significant reduction (P < 0.001) in the body surface area involved (-17.4%) and an improvement in itch severity (-33.2 points) and Dermatology Life Quality Index score (-13.4 points). Conclusions: In drug-naïve adult overweight patients with stable chronic plaque psoriasis, an aggressive dietary WL program consisting of a VLCKD, followed by a balanced, hypocaloric, Mediterranean-like diet, appeared to be an effective first-line strategy to reduce disease severity.
MetaboAnalyst ( is an easy‐to‐use web‐based tool suite for comprehensive metabolomic data analysis, interpretation, and integration with other omics data. Since its first release in 2009, MetaboAnalyst has evolved significantly to meet the ever‐expanding bioinformatics demands from the rapidly growing metabolomics community. In addition to providing a variety of data processing and normalization procedures, MetaboAnalyst supports a wide array of functions for statistical, functional, as well as data visualization tasks. Some of the most widely used approaches include PCA (principal component analysis), PLS‐DA (partial least squares discriminant analysis), clustering analysis and visualization, MSEA (metabolite set enrichment analysis), MetPA (metabolic pathway analysis), biomarker selection via ROC (receiver operating characteristic) curve analysis, as well as time series and power analysis. The current version of MetaboAnalyst (4.0) features a complete overhaul of the user interface and significantly expanded underlying knowledge bases (compound database, pathway libraries, and metabolite sets). Three new modules have been added to support pathway activity prediction directly from mass peaks, biomarker meta‐analysis, and network‐based multi‐omics data integration. To enable more transparent and reproducible analysis of metabolomic data, we have released a companion R package (MetaboAnalystR) to complement the web‐based application. This article provides an overview of the main functional modules and the general workflow of MetaboAnalyst 4.0, followed by 12 detailed protocols: © 2019 by John Wiley & Sons, Inc. Basic Protocol 1 : Data uploading, processing, and normalization Basic Protocol 2 : Identification of significant variables Basic Protocol 3 : Multivariate exploratory data analysis Basic Protocol 4 : Functional interpretation of metabolomic data Basic Protocol 5 : Biomarker analysis based on receiver operating characteristic (ROC) curves Basic Protocol 6 : Time‐series and two‐factor data analysis Basic Protocol 7 : Sample size estimation and power analysis Basic Protocol 8 : Joint pathway analysis Basic Protocol 9 : MS peaks to pathway activities Basic Protocol 10 : Biomarker meta‐analysis Basic Protocol 11 : Knowledge‐based network exploration of multi‐omics data Basic Protocol 12 : MetaboAnalystR introduction
Background Weight loss is a milestone in the prevention of chronic diseases associated with high morbility and mortality in industrialized countries. Very-low calorie ketogenic diets (VLCKDs) are increasingly used in clinical practice for weight loss and management of obesity-related comorbidities. Despite evidence on the clinical benefits of VLCKDs is rapidly emerging, some concern still exists about their potential risks and their use in the long-term, due to paucity of clinical studies. Notably, there is an important lack of guidelines on this topic, and the use and implementation of VLCKDs occurs vastly in the absence of clear evidence-based indications. Purpose We describe here the biochemistry, benefits and risks of VLCKDs, and provide recommendations on the correct use of this therapeutic approach for weight loss and management of metabolic diseases at different stages of life.