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Fecal Zonulin is Elevated in Crohn’s Disease and in Cigarette Smokers

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  • ISCARE a.s.

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Objectives Human zonulin is a protein that increases permeability in the epithelial layer of the small intestine by reversibly modulating the intercellular tight junctions. There is not sufficient information available about zonulin's participation in inflammatory bowel diseases (IBD). The aim of this study was therefore to investigate fecal and serum zonulin in IBD patients and its relation to the disease localization, behavior and smoking status. Design and methods Forty IBD patients and forty healthy persons were examined for fecal and serum zonulin concentrations by competitive ELISA (DRG International Inc). Values were correlated to IBD type, localization and behavior, and smoking. Results Serum and fecal zonulin were significantly higher in patients with Crohn’s disease compared to ulcerative colitis (p = 0.038 for fecal zonulin, and p = 0.041 for serum zonulin concentrations). No association of serum or fecal zonulin was found with respect to IBD localization and behavior. The only difference was found with respect to smoking. Both the IBD cohort and healthy smokers showed significantly higher fecal zonulin levels (median 203 ng/mL) compared to non-smokers (median 35.8 ng/mL), p < 0.001. Conclusions Fecal and serum zonulin levels are elevated in patients with active Crohn’s disease but not with ulcerative colitis. High fecal zonulin levels in smokers irrespective of IBD point to the significant and undesirable up-regulation of gut permeability in cigarette smokers.
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Practical Laboratory Medicine
journal homepage: www.elsevier.com/locate/plabm
Fecal zonulin is elevated in Crohns disease and in cigarette
smokers
Karin Malíčková
a,
, Irena Francová
a
, Milan Lukáš
b
, Martin Kolář
b
, Eva Králíková
c
,
Martin Bortlík
b
, Dana Ďuricová
b
, Lenka Štěpánková
c
, Kamila Zvolská
c
,
Alexandra Pánková
c
, TomášZima
a
a
Institute of Medical Biochemistry and Laboratory Diagnostics, General University Hospital & 1st Faculty of Medicine of the Charles University, U
Nemocnice 2, Prague 2 12800, Czech Republic
b
IBD Clinical and Research Centre ISCARE, Jankovcova 1569, Prague 7 17000, Czech Republic
c
The Centre for Tobacco-Dependent of the 3rd Medical Department Department of Endocrinology and Metabolism, General University Hospital & 1st
Faculty of Medicine of the Charles University, U Nemocnice 1, Prague 2 12800, Czech Republic
ARTICLE INFO
Keywords:
Zonulin
Inammatory bowel disease
Crohn's disease
Ulcerative colitis
Smoking
ABSTRACT
Objectives: Human zonulin is a protein that increases permeability in the epithelial layer of the
small intestine by reversibly modulating the intercellular tight junctions. There is not sucient
information available about zonulin's participation in inammatory bowel diseases (IBD). The
aim of this study was therefore to investigate fecal and serum zonulin in IBD patients and its
relation to the disease localization, behavior and smoking status.
Design and methods: Forty IBD patients and forty healthy persons were examined for fecal and
serum zonulin concentrations by competitive ELISA (DRG International Inc). Values were cor-
related to IBD type, localization and behavior, and smoking.
Results: Serum and fecal zonulin were signicantly higher in patients with Crohns disease
compared to ulcerative colitis (p = 0.038 for fecal zonulin, and p = 0.041 for serum zonulin
concentrations). No association of serum or fecal zonulin was found with respect to IBD locali-
zation and behavior. The only dierence was found with respect to smoking. Both the IBD cohort
and healthy smokers showed signicantly higher fecal zonulin levels (median 203 ng/mL)
compared to non-smokers (median 35.8 ng/mL), p < 0.001.
Conclusions: Fecal and serum zonulin levels are elevated in patients with active Crohns disease
but not with ulcerative colitis. High fecal zonulin levels in smokers irrespective of IBD point to
the signicant and undesirable up-regulation of gut permeability in cigarette smokers.
1. Introduction
Human zonulin is a 47-kDa human protein that increases permeability in the epithelial layer of the small intestine [1]. It is the
only physiological mediator known that increases gut permeability by reversibly modulating the intercellular tight junctions, whereas
proper functioning of the tight junctions is crucial for maintaining normal physiologic processes in the intestinal tract [2].
Increased serum/plasma zonulin levels have been described in celiac disease [3], type 1 and 2 diabetes [4,5] or in obesity-
associated insulin resistance [6,7]; and circulating plasma zonulin has been suggested as a potential marker of intestinal permeability
[810]. However, there is insucient information about zonulin's participation in some important states of intestinal inammation
http://dx.doi.org/10.1016/j.plabm.2017.09.001
Received 4 May 2017; Received in revised form 10 September 2017; Accepted 13 September 2017
Corresponding author.
Practical Laboratory Medicine 9 (2017) 39–44
Available online 23 September 2017
2352-5517/ © 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/BY-NC-ND/4.0/).
MARK
(e.g., inammatory bowel diseases, IBD), and there is ambiguous information about serum and fecal zonulin in IBD [11].
The aim of this study was to investigate fecal and serum zonulin in IBD patients and its relation to the disease localization and
behavior. Moreover, the relationship between fecal and serum zonulin and smoking status was examined.
2. Materials and methods
2.1. Specimen characteristics
Forty consecutive IBD patients 32 with Crohns disease (CD) and 8 with ulcerative colitis (UC) in whom fecal and blood samples
were available were enrolled from a tertiary IBD clinical center. All IBD subjects were patients on induction iniximab therapy, and
were examined before the second iniximab dose. Therefore, it was a relatively homogenous cohort of patients with severe acute gut
inammation or chronic disease resistant to corticosteroids and/or immunosuppressants. Patients´ baseline demographic and clinical
characteristics are presented in Table 1. Disease behavior and localization was classied according to the Montreal classication [12].
Forty healthy persons (laboratory technicians and their family members) without personal or family history of IBD were matched
by age and gender and examined as a control (CTRL) group. There were 27 active smokers and 13 non-smokers in the CTRL group.
None of 80 examined persons (IBD patients or healthy controls) had been noted to have celiac disease or diabetes during previous
clinical examinations.
The study was approved by the Institutional Ethical Committee. The purpose and procedures of the study were explained to
participants, who signed informed consent forms.
2.2. Fecal samples
Raw stool samples from the IBD and CTRL groups were frozen and stored at 80 °C within 12 h after the sampling. Before the
laboratory analysis, stool samples were thawed, and mechanical homogenization was performed using an inoculation loop. The Fecal
Sample Preparation kit (Roche Diagnostics, Germany) for the preparation of fecal eluates was used. In this system, 100 mg of stool
sample is suspended in 5 mL of appropriate extraction buer using a vortex and subsequently centrifuged for 5 min at 2000gusing a
refrigerated centrifuge. For subsequent ELISA analysis, stool sample supernatants (eluates) were used immediately after their pre-
paration.
2.3. Serum samples
Blood samples were collected into commercially available serum-separating tubes (Vacutainer, Becton Dickinson, USA). After
collection, the blood was allowed to clot at room temperature for 30 min. The clot was removed by centrifugation for 10 min at
2000 g using a refrigerated centrifuge. Serum samples were stored at 80 °C immediately after their preparation.
Table 1
Descriptive characteristics of examined IBD patients.
Diagnosis Crohn's disease 32
Ulcerative colitis 8
Gender Male 19
Female 21
Disease duration, years Mean 6
Range 2 15
Behavior of CD B1, non-stricturing non-penetrating Crohns disease 16
B2, stricturing Crohns disease 12
B3, penetrating Crohns disease 4
Localization L1, ileal Crohns disease 8
L2, colonic Crohns disease 6
L3, ileocolonic Crohns disease 14
L4, upper digestive Crohns disease 4
E1, ulcerative proctitis 1
E2, left-sided ulcerative colitis 3
E3, extensive ulcerative colitis 4
Concomitant medication Systemic corticosteroids 14
Local corticosteroids 6
Azathioprine 20
Previous bowel surgery No 31
Yes 9
Smoking No 31
Yes 9
K. Malíčková et al. Practical Laboratory Medicine 9 (2017) 39–44
40
2.4. Laboratory analysis
Fecal and serum zonulin concentrations were measured by competitive ELISA assays: Zonulin (Serum) EIA and Zonulin (Stool)
EIA (both DRG International Inc, USA, catalog numbers EIA-5515 and EIA-5418, respectively). Briey, as a rst preparation step, a
biotinylated zonulin tracer was added to the samples, standards and calibrators. Afterwards, aliquots of the treated preparations were
transferred and incubated in microtiter plate wells coated with polyclonal anti-zonulin antibodies. During the incubation, the free
target antigen in the samples competed with the biotinylated zonulin tracer for the binding of the polyclonal anti-zonulin antibodies
immobilized on the microtiter plate wells. The unbound components were removed by a washing step. During a second incubation
step, a streptavidin-labeled-peroxidase antibody, which binds to the biotinylated zonulin tracer, was added into each microtiter well.
After a washing step to remove the unbound components, the peroxidase substrate tetramethylbenzidine (TMB) was added. Finally,
the enzymatic reaction was terminated by an acidic stop solution.
Fecal calprotectin as a marker of gut inammation was measured by the Calprotectin Alegria ELISA kit from OrgenTec, Germany.
According to the manufacturer, a median concentration of 61 ng/mL ( ± 46 ng/mL) fecal zonulin was estimated as normalfor
healthy persons. For serum zonulin, a median value of 34 ng/mL ( ± 14 ng/mL) was declared as normal for healthy persons. A
reference value of 50 µg/g for normal fecal calprotectin values was taken as normal.
2.5. Statistical analysis
Statistical analysis was performed using Statisctica CZ 12.0 (StatSoft, USA). Standard descriptive statistical analyses were per-
formed, including frequency distributions for categorical data and calculation of median and interquartile range (IQR) for continuous
variables. The non-parametric KruskalWallis (KW) test was used for the comparison of zonulin serum and fecal concentrations in
dierent subgroups of patients. Spearmans rank correlation coecient was used as a nonparametric measure of dependence between
the variables examined. A p-value less than 0.05 was considered signicant.
3. Results
As anticipated, fecal calprotectin concentrations were signicantly higher in IBD patients compared to healthy controls (Fig. 1).
Calprotectin is a strong and potent biomarker of gut inammation, so this fact conrms organic inammatory gut involvement in IBD
patients. Serum and fecal zonulin was signicantly higher in persons with CD compared to UC (Fig. 2).
In the IBD group, no association of serum or fecal zonulin was found with respect to the disease localization and behavior
(Table 2). In upper digestive tract Crohns disease, fecal zonulin seems to tend towards higher values compared to other CD groups;
however, the p-value did not reach signicance in the KW non-parametric test. The only dierence was found with respect to
smoking, while IBD smokers showed signicantly higher fecal zonulin levels than non-smokers (Table 2).
Fig. 1. Box and whisker plots of the fecal calprotectin in IBD patients and healthy controls. CTRL, healthy controls; IBD, inammatory bowel disease; KW-H, Kruskal-
Wallis test. The vertical line within the box indicates the median, boundaries of the box indicate the 25th- and 75th percentile, and the whiskers indicate the highest
and lowest values of the results. Each individual fecal calprotectin value is depicted as a point.
K. Malíčková et al. Practical Laboratory Medicine 9 (2017) 39–44
41
Fecal calprotectin, as a biomarker of intestinal inammation, was measured in both the IBD and CTRL groups. In the IBD group, a
positive correlation of fecal calprotectin with fecal zonulin was proven (r = 0.430, p = 0.006). In the CTRL group, which showed low
fecal calprotectin levels (median of concentrations 20.5 µg/g), no association of calprotectin and zonulin levels was observed in stool
samples (r = 0.201, p = 0.216).
Interestingly, the only strong association in both groups examined was found between active cigarette smoking and fecal zonulin
levels: smokers showed conclusively higher fecal zonulin values, irrespective of whether IBD diagnosis was present or not (see Fig. 3).
There were no signicant dierences in fecal zonulin concentrations in IBD and healthy smokers (medians 207.9 and 198.0 ng/mL,
respectively, p = 0.324). No association with smoking was found either for fecal calprotectin or serum zonulin levels.
Fig. 2. Box and whisker plots of the fecal and serum zonulin in IBD patients. UC, ulcerative colitis; CD, Crohns disease; KW-H, Kruskal-Wallis test. The horizontal line
within the box indicates the median, boundaries of the box indicate the 25th- and 75th percentile, and the whiskers indicate the highest and lowest values without
outliers. Each individual zonulin value is depicted as a point. Transparent boxes represent fecal zonulin values, and striped boxes represent serum zonulin values.
Table 2
Fecal and serum zonulin concentrations in IBD patients with respect to disease characteristics.
Fecal zonulin ng/Ml median [IQR] Serum zonulin ng/mL median [IQR]
Behavior of Crohn's disease
B1, non-stricturing non-penetrating Crohns disease 92.6 [34.0;168.4] 39.5 [16.9; 63.1]
B2, stricturing Crohns disease 65.8 [21.8; 87.3] 22.2 [10.3; 51.0]
B3, penetrating Crohns disease 130.8 [67.1; 203.1] 18.1 [10.5; 31.7]
P - value 0.355, NS 0.0769, NS
Localization of Crohn's disease
L1, ileal Crohns disease 48.6 [27.9; 76.9] 35.1 [16.4; 70.8]
L2, colonic Crohns disease 57.2 [22.5; 103.8] 21.5 [9.0; 38.1]
L3, ileocolonic Crohns disease 89.8 [37,8; 204.5] 31.1 [16.9; 64.8]
L4, upper digestive Crohns disease 120.3 [55.2; 206.9] 18.0 [6.3; 20.3]
P - value 0.053, NS 0.166, NS
Localization of ulcerative colitis
E1, ulcerative proctitis ––
E2, left-sided ulcerative colitis 72.5 [52.9; 76.2] 7.9 [4.5; 29.8]
E3, extensive ulcerative colitis 59.1 [20.6; 78.9] 11.2 [ 3.3; 23.3]
P - value 0.354, NS 0.245, NS
Previous bowel surgery
no 72.5 [28.5; 121.4] 18.8 [9.1; 47.1]
yes 53.2 [22.9; 87.0] 32.5 [7.5; 47.3]
P - value 0.974, NS 0.987, NS
Smoking
no 36.8 [21.6; 71.3] 18.8 [7.8; 41.0]
yes 207.9 [178.6; 226.7] 27.3 [11.6; 56.9]
P-value < 0.0001 0.237, NS
K. Malíčková et al. Practical Laboratory Medicine 9 (2017) 39–44
42
4. Discussion
As far as we know, this is the rst work that describes fecal and serum zonulin levels in IBD patients with respect to IBD
localization and behavior. Our results showed higher fecal and serum zonulin levels only in patients with Crohns disease and not in
patients with ulcerative colitis, and there was a tendency towards higher fecal zonulin concentrations in Crohns disease with upper
digestive tract involvement. Moreover, our work surprisingly noted high fecal zonulin levels in active smokers regardless of the gut
inammatory involvement.
Zonulin was rstly described by Fasano as a human protein analogue to the Vibrio cholerae -derived Zonula occludens toxin, which
induces the disassembly of tight junctions and subsequently increases intestinal permeability [13]. According to Fasanos workgroup,
zonulin expression is raised in intestinal tissues during the acute phase of celiac disease [14]. Fasano had foretold, in 2000 [15], that
dysregulation of zonulin might contribute to the perturbation of the intestinal barrier functions, leading to the passage of antigens
involved in the pathogenesis of dierent immunopathological diseases such as food allergies, infections of the gastrointestinal tract,
systemic autoimmune diseases and inammatory bowel diseases. Bacteria were identied as powerful triggers of zonulin release
[16].
Although the pathogenesis of IBD remains unknown, an important role can be attributed to increased intestinal permeability. It
was proven that zonulin up-regulation is detected in acute phase IBD [11]. Dysmicrobia has been implicated in the pathogenesis of
IBD, and small intestines exposed to dierent enteric bacteria secrete zonulin to the intestinal lumen and/or to the blood circulation.
Our nding that zonulin levels are elevated in stool and serum only in Crohns disease may be in accordance with this theory. We
were not able to prove any association between zonulin levels and IBD extent, stulizing and/or penetrating behavior or previous gut
surgery.
Zonulin is the fecal protein that best reects the intestinal permeability. Its increased fecal levels are considered to be a marker of
an impaired intestinal barrier, and reect reactions secondary to inammation. Elevated calprotectin levels in our IBD cohort reect
an inammatory state. However, elevated fecal zonulin is suspected to reect not only the presence of inammation, but an increased
intestinal permeability caused by other factors.
Fecal zonulin was signicantly raised in Crohns disease, but not in ulcerative colitis patients. It could be hypothesized, that there
isadierent permeability abnormality in Crohn's disease compared to ulcerative colitis, and that this abnormality could be important
in the genesis of disease. At least some of the reported genetic associations of Crohn's disease appear to involve these pathways [17].
Environmental components such as food may have an important role in regulating intestinal permeability. In addition, gut
microbiota have also been shown to inuence intestinal permeability. Our nding of signicantly higher fecal zonulin levels in IBD
and healthy smokers points to the important inuence of gut homeostasis induced by the cigarette smoking. Smoking is considered to
be one of the most important environmental risk factors in IBD pathogenesis and is to be included in the list of relevant factors that
inuence the composition of intestinal microbiota [1820].The proper mechanisms by which smoking interferes with the patho-
genesis of IBD are, as yet, only poorly understood. While several potential mechanisms have been proposed - for example, modulation
Fig. 3. Box and whisker plots of the fecal zonulin in active smokers and non-smokers in both groups (IBD and CTRLs). IBD, inammatory bowel disease; CTRLs,
healthy controls. The vertical line within the box indicates the median, boundaries of the box indicate the 25th- and 75th percentile, and the whiskers indicate the
highest and lowest values without outliers, each individual fecal zonulin value is depicted as a point. Median values and interquartile ranges of fecal zonulin
concentrations are given for all groups.
K. Malíčková et al. Practical Laboratory Medicine 9 (2017) 39–44
43
of mucosal immune responses, alterations in intestinal cytokine and eicosanoid levels or modications in gut permeability - none of
these hypotheses give a satisfying explanation [21]. As the importance of zonulin in gut inammation is well established, high fecal
zonulin levels in smokers may explain a potential pathogenetic link of cigarette smoking, intestinal dysmicrobia, leaky gut and the
course of disease in IBD. We consider that the results of our study, which demonstrate high fecal zonulin levels even in apparently
healthy persons without any signs of intestinal inammation, point to a large complex interplay between the gut microenvironment
and environmental factors such as smoking, for example, concerning possible weight gain after stopping smoking [22].
The design of our study produces potential limitations. Firstly, this is a pilot study, and as such serves as a rst step in exploring a
novel laboratory marker. The cohort sample size is small and based on the pragmatics of recruitment and the necessities for ex-
amining feasibility. Further research may be advisable in a larger population. Secondly, as we hypothesized that elevated zonulin
levels serve as a mirror of gut dysmicrobia, we do not have sucient information regarding the fecal microbiology to exclude
infection or small intestinal bacterial overgrowth, and the antibiotic or other immunomodulatory treatments in our examined co-
horts, which is an important factor that may potentially inuence gut microbiota. Thirdly, as the clinical utility of stool and serum
zonulin was not evaluated during the initial decision to perform endoscopic examination in IBD patients, we were unable to de-
termine whether or not these laboratory examinations could contribute to the gastroenterologist's choice to perform an endoscopy.
In conclusion, zonulin as a marker of intestinal permeability is increased in stool and serum samples of patients with Crohns
disease. However, zonulin levels in IBD patients are not inuenced by disease location or behavior. High fecal zonulin levels in
smokers with and without intestinal disease point to the signicant and undesirable up-regulation of gut permeability in cigarette
smokers.
Acknowledgement
This work was supported by the RVO VFN 64165 project provided by the Ministry of Health, Czech Republic.
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... Our study showed that factors such as maternal education, smoking and the presence of allergies in the family history did not show any significant influence. Other studies have shown that cigarette smokers have high levels of fecal zonulin, which is associated with significantly increased intestinal permeability [26]. However, these studies did not analyze other markers of impaired intestinal permeability and fecal battery endoxemia, such as occludin and LPS concentrations [26]. ...
... Other studies have shown that cigarette smokers have high levels of fecal zonulin, which is associated with significantly increased intestinal permeability [26]. However, these studies did not analyze other markers of impaired intestinal permeability and fecal battery endoxemia, such as occludin and LPS concentrations [26]. ...
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Background: The intestinal microbiota of pregnant women and factors disturbing the microbial balance of their gastrointestinal tract during the perinatal period may be the cause of dysbiosis and thus intestinal permeability syndrome in their children. The purpose of this study was to analyze the implications of intestinal permeability parameters in the stools of newborns and infants with perinatal risk factors for intestinal colonization disorders (the route of delivery, antibiotic therapy in the neonatal period and the abandonment of breastfeeding). Methods: The study included 100 mother-child pairs. All children were born from uncomplicated and term pregnancies (between 37 and 42 weeks of gestation). In order to determine the parameters of dysbiosis and intestinal permeability, we determined the concentrations of zonulin and occludin in stool samples taken from all children at 0 (i.e., at birth), 3, 6 and 12 months of age. Elevated levels of lipopolysaccharide (LPS) are associated with metabolic diseases and its presence may be indicative of TJ injury and the onset of leaky gut syndrome. To indirectly determine the presence of endotoxemia, the concentrations of lipopolysaccharide were also measured in stool samples taken from all children at 0, 3, 6 and 12 months of age. We analyzed the relationship between the markers studied and perinatal risk factors for impaired intestinal colonization, including the mode of delivery, the method of feeding, and a family history of allergy. Results: During the first 3 months of infant life, higher concentrations of fecal occludin and zonulin were most often accompanied by higher values of fecal LPS. Similarly, higher concentrations of zonulin were accompanied by higher values of occludin. There were no significant differences in the stool concentrations of the studied markers during the first year of life between children born by caesarean section and those born naturally. In addition, the method of feeding had no significant effect on the changes in the concentrations of the determined fractions. Antibiotic therapy was associated only with an increase in the fecal occludin concentration after birth, without any effect on zonulin, occludin or LPS levels. The use of probiotic therapy in infants resulted in a decrease in only LPS concentrations at 3 months of age, with no effect on zonulin or occludin concentrations at 0, 6 and 12 months. Conclusions: Perinatal factors related to intestinal permeability are important during the first 3 months of infant life. However, we found that the mode of delivery had no influence on the parameters of infant intestinal leakage during the first year of life. In addition, the mode of infant feeding-breast or exclusively formula-did not significantly affect the changes in the concentrations of LPS, zonulin or occludin in the stools of children. A short-term increase in occludin concentrations after delivery in the stools of children from mothers undergoing antibiotic therapy indicates a negative but reversible influence of intrapartum antibiotics on the intestinal integrity of children in the perinatal period. Probiotic therapy seems to have a positive effect on reducing endotoxemia in children during the first 3 months of life. The presence of LPS at 3 months did not affect intestinal tightness at any of the later measured periods of the infants' lives.
... For those having donated fecal samples (n = 57), measured zonulin and calprotectin levels were used as indicators of gastrointestinal permeability and inflammation (Walsham and Sherwood, 2016;Malíčková et al., 2017). Zonulin was dichotomized at their median levels. ...
... In contrast, though with weaker associations, a longer half-life was associated with higher levels of zonulin. Zonulin has been suggested as a marker of intestinal permeability (Malíčková et al., 2017), as it has been found to be associated with increased intestinal permeability in in vitro studies (Fasano, 2012;Sapone et al., 2006). However, zonulin is not commonly used for in vivo studies or as a clinical marker, so its use in understanding these results is limited. ...
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Background Per- and polyfluoroalkyl substances (PFAS) are persistent substances with surfactant and repellent properties. Municipal drinking water contaminated with PFAS had been distributed for decades to one third of households in Ronneby, Sweden. The source was firefighting foam used in a nearby airfield since the mid-1980s. Clean water was provided from December 16, 2013. Aims The purpose was to estimate serum half-lives and their determinants in the study population for different PFAS. Methods Up to ten blood samples were collected between 2014 and 2018 from 114 participants (age 4–84 years at entry, 53% female). 19 PFAS were analysed. Linear mixed models were used to estimate the half-lives. Results Eight PFAS were increased in Ronneby: perfluorooctanoic acid (PFOA), perfluoropentane sulfonate (PFPeS), perfluorohexane sulfonate (PFHxS), perfluoroheptane sulfonate (PFHpS), linear perfluorooctane sulfonate (L-PFOS) and three branched perfluorooctane sulfonates (1 m-PFOS, 3/4/5m-PFOS and 2/6m-PFOS). The mean estimated half-lives (in years) were 0.94 (95 %CI 0.86–1.02) for PFPeS, 2.47 (2.27–2.7) for PFOA, 2.67 (2.51–2.85) for 2/6m-PFOS, 2.73 (2.55–2.92) for L-PFOS, 3.43 (3.19–3.71) for 3/4/5m-PFOS, 4.52 (4.14–4.99) for PFHxS, 4.55 (4.14–5.06) for PFHpS, and 5.01 (4.56–5.55) for 1 m-PFOS. The most important determinants of a shorter half-life were young age, and better kidney function measured by estimated glomerular filtration rate and ratio of paired urine and serum PFAS levels, followed by female sex during their fertile period aged 15–50. Markers of gut inflammation and reduced permeability i.e. zonulin and calprotectin were also possibly associated with shorter half-life. The results also suggested a time-dependent PFAS elimination process, with more rapid elimination in the first year after the end of exposure. Conclusion The half-life estimates are in line with past estimates for some PFAS such as PFOA, and the novel results for different PFOS isomers. These results provide observational support for elimination routes – renal, fecal and maternal.
... One factor, the protein zonulin, has been proposed to be a major pathophysiological regulator [2,3]. Zonulin has been shown to be elevated in diabetes [4][5][6], IBS and irritable bowel disease (IBD) [7][8][9], Colitis [10,11], and Celiac disease [12][13][14]. Zonulin plays a role in these disease states as the gatekeeper of permeability. ...
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Background: Zonulin is observed in animal models to regulate intestinal permeability and influenced by dietary intake, gut microbiota, and inflammation. We conducted a secondary analysis of a randomized controlled crossover trial (NCT03582306) in individuals with a BMI greater than 30 kg/m2 and high habitual red meat intake and low habitual green leafy vegetable (GLV) intake. Methods: Participants were provided with frozen GLV during the first or last four weeks (immediate or delayed intervention) of the twelve-week trial. Biological and anthropometric measures were taken at the beginning and at each four-week interval. A subset of 20 participants was selected for this secondary analysis of the intestinal permeability and inflammation-related biomarkers: serum and fecal zonulin; serum lipopolysaccharide binding protein (LBP), Alpha-1-acid glycoprotein 1 (ORM-1), tumor necrosis factor α (TNFα), interleukin-6 (IL-6), and C-reactive protein; 8-hydroxy-2'-deoxyguanosine (8OHdG) and plasma Vitamin K1 as a marker of protocol adherence. Nutrient and food group intake from two-24-h dietary recalls collected at each time point were assessed. Fecal microbiota was measured by 16 s rRNA PCR sequencing. Changes in biological markers, dietary factors, and microbial taxa were assessed with Wilcoxon Sign Ranks Tests. Exploratory analyses of the relationship between changes in outcome variables were conducted with Spearman correlations. Results: No changes in serum and fecal zonulin and serum LBP were observed. Plasma Vitamin K (p = 0.005) increased, while plasma 8OHdG (p = 0.023) decreased during the intervention compared to the control. The only dietary factors that changed significantly were increases during intervention in Vitamin K and Dark GLV (p < 0.001 for both) compared to control. Fecal microbiota did not change significantly across all times points; however, change in serum zonulin was associated with change in Proteobacteria (ρ = - 0.867, p = 0.001) in females and Bifidobacterium (ρ = - 0.838, p = 0.009) and Bacteroidaceae (ρ = 0.871, p = 0.005) in men. Conclusions: A high GLV dietary intervention increased serum zonulin levels and had no effect on fecal zonulin. Lack of concordance between several inflammation-associated biomarkers and zonulin corroborate recent reports of limited utility of zonulin in obese adults free of lower gastrointestinal disease. Trial Registration information: https://clinicaltrials.gov/ct2/show/NCT03582306 (NCT03582306) registered on 07/11/2018.
... In agreement with our results, Caviglia et al. [33] reported higher serum ZRP levels in IBD patients compared to healthy controls. Another study by Malickova found that serum / fecal ZRP levels were higher only in Crohn's disease but not in ulcerative colitis [34]. ZRP upregulation has been detected in both the acute phase and after anti-inflammatory treatment of IBD [25]. ...
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Background Current evidence regarding the association of serum zonulin-related proteins (ZRP) levels with prevalent inflammatory bowel disease (IBD) is contradictory. Moreover, the association with the subsequent risk of incident IBD is still unexplored. This study aimed to investigate the association of serum ZRP levels with both prevalent and incident IBD. Method The study included a total of 130 women (51–61 years) from the Women’s Health in Lund Area (WHILA) study, which included 18 prevalent IBD (diagnosed before baseline) and 47 incident IBD diagnosed during the 17 years (median) follow-up and age- and sampling time-matched controls. Serum ZRP was tested in all participants by ELISA. Results The serum ZRP levels were significantly higher in prevalent IBD compared to their matched controls (63.2 ng/ml vs 57.0 ng/ml, p = 0.02), however, no evidence of a difference in ZRP levels was found between the women who developed IBD during the follow-up period and their matched controls (61.2 ng/ml vs 59.7 ng/ml, p = 0.34). Using linear mixed models, we found that the association between serum ZRP levels and prevalent IBD (β = 6.2, p = 0.01), remained after adjusting for potential confounders. Conditional logistic regression models showed no evidence of an association between ZRP level and incident IBD (OR 1.03, p = 0.34). Conclusion Higher serum ZRP levels were associated with prevalent IBD, but not with incident IBD in our study samples.
... We also introduced the cessation of smoking and report an alteration in BMI during PR regime. Previous reports indicate that the plasma zonulin levels are affected by smoking [25] and BMI [26] independent of exercise therapy. Thus, it is possible that the alterations in plasma zonulin following PR in COPD are partly due to altered BMI and the smoking cessation. ...
Article
Purpose Sarcopenia or age-related muscle loss is a common finding in patients with chronic obstructive pulmonary disease (COPD) and may lead to functional compromise. The contribution of an increased gut permeability to muscle decline in COPD may be of primary relevance. We measured the plasma zonulin levels (a marker of intestinal permeability) as potential predictors of sarcopenia in COPD patients during pulmonary rehabilitation (PR). Method We recruited male, 56—73 years healthy controls and patients with COPD (N=70—76/group) to measure plasma zonulin, handgrip strength (HGS), body composition and biochemical parameters. All measurements were performed before and one year following the PR. Results COPD patients had elevated plasma zonulin levels at baseline (22.8% higher vs healthy controls, p < 0.05), which were partially reduced (12.1% reduction vs baseline, p < 0.05) with PR. PR also resulted in improved HGS (8.5% increase, p < 0.05) as well as plasma c-reactive protein (CRP) (11.1% reduction, p < 0.05) and 8-isoprostanes (22.1% reduction, p < 0.05) as markers of inflammation and oxidative stress, respectively. Simple regression analysis revealed dynamic correlations of the alterations in zonulin levels with HGS, CRP and 8-isoprostanes during PR (all p < 0.05). These changes were associated with a reduction in sarcopenia incidence following PR. Conclusion Altogether, increased intestinal permeability may contribute to muscle decline in COPD, which is partially restored by PR. Plasma zonulin may be a useful marker to evaluate sarcopenia phenotype in COPD.
... One pilot study has shown that serum ZRP is very sensitive for the assessment of intestinal permeability in IBD flares for both CD and UC, but no correlation between serum and fecal ZRP values was found [8]. On the other hand, the study conducted by a Czech team has demonstrated that both serum and fecal ZRP were elevated among CD but not UC, patients [9]. So far, there are no studies on ZRP in children with IBD. ...
Article
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Background: Recent data indicate that increased intestinal permeability plays a key role in the pathogenesis of inflammatory bowel diseases (IBD) and correlates with disease flare. Since zonulin related proteins (ZRP) are the proteins that increase permeability in the epithelial layer of the small intestine by reversibly modulating the intercellular tight junctions, they may serve as a new, noninvasive biomarker of disease activity. The aim of this study was to investigate fecal ZRP in pediatric IBD patients as well as its correlation with disease activity and fecal calprotectin (FCP). Methods: Ninety-four individuals: 47 Crohn's disease (CD) patients, 41 ulcerative colitis (UC) patients, and 6 healthy controls were examined for fecal ZRP. Values were correlated to IBD type, disease activity for IBD patients, and FCP for all children included in the study. A stool specimen was collected the day before the visit to the hospital, then fecal ZRP and FCP were tested using the ELISA test. Non-parametric statistical tests were used for data analysis. Results: The level of fecal ZRP was higher among IBD patients compared to the control group (CG): medians for CD-113.3 (53.6-593.6) ng/mL; UC-103.6 (50.7-418.3) ng/mL; and CG-46.9 (31.8-123.0) ng/mL (p < 0.05). No difference in fecal ZRP concentration was observed between children with CD and those with UC (p = 0.55). A slight correlation between disease activity (PCDAI for CD and PUCAI for UC) and the fecal ZRP level was found for CD (p = 0.03/R = 0.33), but not UC (p = 0.62/R = 0.08), patients. A correlation between fecal ZRP and FCP was observed (R = 0.73, p = 0.00). Conclusions: Fecal ZRP levels are increased among those with IBD, are associated with CD activity, and strongly correlate with FCP. Further research into the role of intestinal permeability in IBD and the clinical usefulness of ZRP in IBD is warranted.
... Increased intestinal permeability causing a leaky gut phenomenon has been shown to play a crucial role in the pathogenesis of IBDs. In humans, serum and fecal zonulin were found to be elevated in patients with active Crohn's disease but not with ulcerative colitis (47). In a recent study, serum zonulin concentration was found to be higher in both diseases, and an inverse correlation was observed between serum zonulin concentration and disease duration (48). ...
Article
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Background and Aims: Vitamin D (VD) plays an important role not only in mineral balance and skeletal maintenance but also in immune modulation. VD status was found correlated with the pathophysiology and severity of inflammatory bowel diseases and other autoimmune disorders. Epithelial barrier function is primarily regulated by the tight-junction (TJ) proteins. In this study, we try to establish an animal model by raising mice fed VD-deficient diet and to investigate the effects of VD-deficient diet on gut integrity and zonulin expression. Methods: Male C57BL/6 mice were administered either VD-deficient [VDD group, 25(OH) 2 D 3 0 IU/per mouse] or VD-sufficient [VDS group, 25(OH) 2 D 3 37.8 IU/per mouse] special diets for 7 weeks. Body weight and diet intake were recorded weekly. Serum VD levels were detected. After sacrifice, jejunum and colon specimens were collected. The villus length and crypt depth of the jejunum as well as mucosa thickness of the colon were measured. Various serum pro-inflammatory cytokines and intestinal TJ proteins were assessed. The serum level of zonulin and the mRNA expression of jejunum zonulin were also investigated. Results: We found that mice fed a VDD diet had a lower serum level of VD after 7 weeks ( p < 0.001). VDD mice gained significant less weight ( p = 0.022) and took a similar amount of diet ( p = 0.398) when compared to mice raised on a VDS diet. Significantly decreased colon mucosa thickness was found in VDD mice compared with the VDS group ( p = 0.022). A marked increase in serum pro-inflammatory cytokine levels was demonstrated in VDD mice. All relative levels of claudin (CLD)-1 ( p = 0.007), CLD-3 ( p < 0.001), CLD-7 ( p < 0.001), and zonulin-1 (ZO-1, p = 0.038) protein expressions were significantly decreased in the VDD group when compared to the VDS group. A significant upregulation of mRNA expression of jejunum zonulin ( p = 0.043) and elevated serum zonulin ( p = 0.001) were found in the VDD group. Conclusions: We successfully demonstrated that VDD could lead to impaired barrier properties. We assume that sufficient VD could maintain intestinal epithelial integrity and prevent mucosal barrier dysfunction. VD supplementation may serve as part of a therapeutic strategy for human autoimmune and infectious diseases with intestinal barrier dysfunction (leaky gut) in the future. To our knowledge, this is the first study to demonstrate that VDD could lead to a significant upregulation in mRNA expression of the jejunum zonulin level and also a marked elevation of serum zonulin in a mouse model.
... Lastly, nicotine may contribute to increased gut permeability and has been implicated in poor outcomes in IBD patients (174). Miele and colleagues showed that patients with biopsy-proven NAFLD also experienced significantly greater gut permeability due to the disruption of intercellular tight junctions in the intestine compared to healthy volunteers (175). ...
Article
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The study of the intestinal or gut microbiome is a newer field that is rapidly gaining attention. Bidirectional communication between gut microbes and the host can impact numerous biological systems regulating immunity and metabolism to either promote or negatively impact the host’s health. Habitual routines, dietary choices, socioeconomic status, education, host genetics, medical care and environmental factors can all contribute to the composition of an individual’s microbiome. A key environmental factor that may cause negative outcomes is the consumption of nicotine products. The effects of nicotine on the host can be exacerbated by poor dietary choices and together can impact the composition of the gut microbiota to promote the development of metabolic disease including non-alcoholic fatty liver disease. This review explores the contribution of nicotine, poor dietary choices and other unhealthy lifestyle factors to gut dysbiosis.
Article
Zonulin content in blood serum of patients with colorectal cancer (CRC; n=152; 30-84 years) and patients with large bowel adenomas (n=32; 39-82 years) was measured by standardized kit IDK Zonulin ELISA (Immundiagnostik AG). The healthy control group (n=50) comprised volunteers (27 women, 23 men; 25-68 years); pathological control group (n=84) - patients (55 women, 29 men;18-84 years) with irritable bowel syndrome (n=29), Crohn's disease (n=5), and ulcero-necrotic colitis (n=50). In comparison to healthy control group, the level of zonulin was significantly increased in CRC patients (p<0.0000001) and in patients with benign large bowel tumors (p<0.004), as well as in patients with inflammatory intestine diseases and with irritable bowel syndrome (p<0.0002). Zonulin level in blood serum of CRC patients was slightly, but significantly higher (p<0.05) than in the group of pathological control. ROC curve construction revealed that at optimal zonulin cut-off level (52.2 ng/ml), the diagnostic sensitivity of CRC detection was 66.7% and specificity relative to healthy control was 81.8%. The specificity relative to the combined control group (healthy control+non-tumor bowel diseases) was only 68.9%. Thus, no acceptable cut-off levels for differentiation between malignant and benign tumors, as well as between tumor and non-tumor large bowel pathologies were found. Analysis of the associations between serum zonulin level and the main clinical and pathological characteristics of CRC demonstrated that the level of this marker increased with disease progression (p<0.01; Kruskal-Wallis test), but was not associated with individual criteria of the TNM system, tumor localization, histological structure, and malignancy grade.
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Background Dysbiosis has been recently demonstrated in patients with ankylosing spondylitis (AS) but its implications in the modulation of intestinal immune responses have never been studied. The aim of this study was to investigate the role of ileal bacteria in modulating local and systemic immune responses in AS. Methods Ileal biopsies were obtained from 50 HLA-B27⁺ patients with AS and 20 normal subjects. Silver stain was used to visualise bacteria. Ileal expression of tight and adherens junction proteins was investigated by TaqMan real-time (RT)-PCR and immunohistochemistry. Serum levels of lipopolysaccharide (LPS), LPS-binding protein (LPS-BP), intestinal fatty acid-BP (iFABP) and zonulin were assayed by ELISA. Monocyte immunological functions were studied in in vitro experiments. In addition the effects of antibiotics on tight junctions in human leukocyte antigen (HLA)-B27 transgenic (TG) rats were assessed. Results Adherent and invasive bacteria were observed in the gut of patients with AS with the bacterial scores significantly correlated with gut inflammation. Impairment of the gut vascular barrier (GVB) was also present in AS, accompanied by significant upregulation of zonulin, and associated with high serum levels of LPS, LPS-BP, iFABP and zonulin. In in vitro studies zonulin altered endothelial tight junctions while its epithelial release was modulated by isolated AS ileal bacteria. AS circulating monocytes displayed an anergic phenotype partially restored by ex vivo stimulation with LPS+sCD14 and their stimulation with recombinant zonulin induced a clear M2 phenotype. Antibiotics restored tight junction function in HLA-B27 TG rats. Conclusions Bacterial ileitis, increased zonulin expression and damaged intestinal mucosal barrier and GVB, characterises the gut of patients with AS and are associated with increased blood levels of zonulin, and bacterial products. Bacterial products and zonulin influence monocyte behaviour.
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Background: Increased intestinal permeability with subsequent metabolic endotoxemia, i.e., elevated circulating levels of bacterial lipopolysaccharide, LPS, has been introduced as a novel initiator of obesity related metabolic disturbances in non-pregnant individuals. The objective was to investigate the extent to which intestinal permeability, measured by serum zonulin concentration, is related to metabolic endotoxemia and metabolic risk markers in overweight pregnant women. Methods: This was a cross-sectional study including 100 pregnant overweight women in early pregnancy. Serum zonulin was analyzed using ELISA, and markers for metabolic endotoxemia (LPS), inflammation (high-sensitive C-reactive protein and glycoprotein acetylation GlyA), glucose metabolism (fasting glucose and insulin), and lipid metabolism were measured. Results: Higher serum zonulin concentration associated positively with LPS (P=0.02), inflammatory markers (P<0.001), insulin (P<0.001), insulin resistance (P<0.001), and triglycerides (P=0.001), and negatively with insulin sensitivity (P=0.001) (ANOVA with Tukey's corrections or Kruskal-Wallis nonparametric test with Bonferroni correction for zonulin quartiles). All the observed associations were confirmed (P<0.015) in a linear regression model adjusted with potential confounding factors. Both LPS and GlycA showed positive relationship with insulin resistance, serum insulin, triglycerides, total and LDL-cholesterol and negative relationship with insulin sensitivity (P≤0.03) in the univariate linear regression. Positive relationship was also found between LPS and HDL-cholesterol (P=0.03). Conclusions: Our findings suggest that increased serum zonulin concentration, i.e., increased intestinal permeability, contributes to metabolic endotoxemia, systemic inflammation, and insulin resistance in overweight pregnant women. By reinforcing intestinal barrier, it may be possible to manipulate maternal metabolism during pregnancy with subsequent health benefits.
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Objective: The aim of this study was to investigate the relationship between zonulin and clinical laboratory parameters in childhood obesity. Methods: The study included obese children with a body mass index >95th percentile and healthy children who were similar age and gender distribution. Clinical (body mass index, waist circumferences, mid arm circumference, triceps skin fold, percentage of body fat, systolic blood pressure, diastolic blood pressure) and biochemical (glucose, insulin, lipids, thyroid function tests, cortisol, zonulin and leptin levels) parameters were measured. Results: A total of 43 obese subjects (23 males, mean age: 11.1±3.1 yrs) and 37 healthy subjects (18 males, mean age: 11.5±3.5 yrs) were included in this study. Obese children had significantly higher insulin, HOMA-IR, TG, TC, LDL-C, HDL-C, zonulin and leptin levels than those of the healthy children (p < 0.05), while glucose levels were not different (p > 0.05). Comparison of the obese children regarding the insulin resistance showed no statistically significant differences for zonulin levels (p > 0.05). Conclusion: To the best of our knowledge, the present study is the first study to compare serum zonulin levels between obese and non-obese children. The results of the study showed that zonulin was significantly higher in obese children when compared to healthy children, which is indicating a potential role of zonulin in the obesity etiopathogenesis and related disturbances.
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Several studies have reported an association between enteric bacteria and atherosclerosis. Bacterial 16S ribosomal RNA (rRNA) gene belong to Enterobacteriaceae have been detected in atherosclerotic plaques. How intestinal bacteria go into blood is not known. Zonulin reversibly modulate intestinal permeability (IP), the circulating zonulin levels were increased in diabetes, obesity, all of which are risk factors for atherosclerosis. It is unclear whether the circulating zonulin levels were changed in coronary artery disease (CAD) patients and modulate IP. The 16S rRNA gene of bacteria in blood sample was checked by 454 pyrosequencing. The zonulin levels were determined by enzyme-linked immunosorbent assay (ELISA) methods. The distribution of zonulin was detected by confocal immunofluorescence microscopy. Bacteria and Caco-2 cell surface micro-structure were checked by transmission electron microscopy. A high diversity of bacterial 16S rRNA gene can be detected in samples from CAD patients, most of them (99.4%) belong to Enterobacteriaceaes, eg. Rahnella. The plasma zonulin levels were significantly higher in CAD patients. Pseudomonas fluorescens exposure significantly increased zonulin expression and decreased IP in a time dependent manner. The elevated zonulin increase IP and may facilitate enteric translocation by disassembling the tight junctions, which might explain the observed high diversity of bacterial 16S rRNA genes in blood samples.
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Background and aims: Smoking affects the course of disease in patients with ulcerative colitis (UC) and Crohn's disease (CD). We aimed to study the association between smoking and extraintestinal manifestations (EIMs) in inflammatory bowel disease (IBD). Methods: We cross-sectionally explored the association between smoking and EIMs in IBD in three cohort studies: (1) the COIN study, designed to estimate healthcare expenditures in IBD; (2) the Groningen study, focused on cigarette smoke exposure and disease behaviour in IBD; and (3) the JOINT study, evaluating joint and back manifestations in IBD. Results: In the COIN, Groningen and JOINT cohorts, 3030, 797 and 225 patients were enrolled, of whom 16, 24 and 23.5% were current smokers, respectively. Chronic skin disorders and joint manifestations were more prevalent in smoking IBD patients than in non-smokers (COIN, 39.1 vs 29.8%, p <0.01; Groningen, 41.7 vs 30.0%, p <0.01) in both CD and UC. In the JOINT cohort, smoking was more prevalent in IBD patients with joint manifestations than in those without (30.3 vs 13.0%, p <0.01). EIMs appeared to be more prevalent in high- than in low-exposure smokers (56.0 vs 37.1%, p = 0.10). After smoking cessation, the prevalence of EIMs in IBD patients rapidly decreased towards levels found in never smokers (lag time: COIN cohort, 1-2 years; Groningen cohort, within 1 year). Conclusions: There is a robust dose-dependent association between active smoking and EIMs in both CD and UC patients. Smoking cessation was found to result in a rapid reduction of EIM prevalence to levels encountered in never smokers.
Article
Background: Obesity and associated metabolic disorders are related to impairments of the intestinal barrier. Objective: We examined lactulose:mannitol (Lac:Man) permeability in obese individuals with and without liver steatosis undergoing a weight-reduction program to test whether an effective weight-loss program improves gut barrier function and whether obese patients with or without liver steatosis differ in this function. Design: Twenty-seven adult, nondiabetic individuals [mean ± SD body mass index (BMI; in kg/m(2)): 43.7 ± 5.2; 78% with moderate or severe liver steatosis] were included in the follow-up intervention study (n = 13 by month 12). All patients reduced their weight to a mean ± SD BMI of 36.4 ± 5.1 within 12 mo. We assessed barrier functions by the oral Lac:Man and the fecal zonulin tests. Insulin resistance was assessed by the homeostatic model assessment index (HOMA), and liver steatosis by sonography and the fatty liver index (FLI). Results: The Lac:Man ratio and circulating interleukin (IL) 6 concentration decreased during intervention from 0.080 (95% CI: 0.073, 0.093) to 0.027 (95% CI: 0.024, 0.034; P < 0.001) and from 4.2 ± 1.4 to 2.8 ± 1.6 pg/mL (P < 0.01), respectively. At study start, the Lac:Man ratio was higher in patients with moderate or severe steatosis than in those without any steatosis (P < 0.001). The Lac:Man ratio tended to correlate with HOMA (ρ = 0.55, P = 0.052), which correlated with FLI (ρ = 0.75, P < 0.01). A multiple-regression analysis led to a final model explaining FLI best through BMI, waist circumference, and the Lac:Man ratio. Conclusions: Intestinal permeability is increased in obese patients with steatosis compared with obese patients without. The increased permeability fell to within the previously reported normal range after weight reduction. The data suggest that a leaky gut barrier is linked with liver steatosis and could be a new target for future steatosis therapies. This trial was registered at clinicaltrials.gov as NCT01344525.
Article
The digestive tract is colonized from birth by a bacterial population called the microbiota which influences the development of the immune system. Modifications in its composition are associated with problems such as obesity or inflammatory bowel diseases. Antibiotics are known to influence the intestinal microbiota but other environmental factors such as cigarette smoking also seem to have an impact on its composition. This influence might partly explain weight gain which is observed after smoking cessation. Indeed there is a modification of the gut microbiota which becomes similar to that of obese people with a microbiotical profile which is more efficient to extract calories from ingested food. These new findings open new fields of diagnostic and therapeutic approaches through the regulation of the microbiota.
Conference Paper
Background and aims: Smoking affects the course of disease both in patients with ulcerative colitis (UC) and Crohn's disease (CD). We aimed to study the association between smoking and extra-intestinal manifestations (EIMs) in Inflammatory Bowel Disease (IBD). Methods: We cross-sectionally explored the association between smoking and EIMs in IBD in three cohort studies: 1. the COIN-cohort, designed to estimate healthcare expenditures in IBD, 2. the Groningen-cohort, focused on cigarette smoke exposure and disease behaviour in IBD and 3. the JOINT-cohort, evaluating joint and back manifestations in IBD. Results: In the COIN-, Groningen-, and JOINT-cohort, 3,030, 797 and 225 patients were enrolled of whom 16%, 24% and 23.5% were current smokers, respectively. Chronic skin disorders and joint manifestations were more prevalent in smoking IBD patients than in non-smokers (COIN-cohort: 39.1% vs. 29.8%, p <0.01; Groningen-cohort: 41.7% vs. 30.0%, p <0.01), in both CD and UC. In the JOINT-cohort, smoking was more prevalent in IBD patients with joint manifestations than in those without (30.3% vs. 13.0%, p <0.01). EIMs appeared to be more prevalent in high than in low-exposure smokers (56.0% vs. 37.1%, p = 0.10). After smoking cessation, the prevalence of EIMs in IBD patients rapidly decreased towards levels of never smokers (lag time COIN-cohort: 1-2 years, Groningen-cohort: within one year). Conclusions: There is a robust dose-dependent association between active smoking and EIMs in both CD and UC patients. Smoking cessation was found to result in a rapid reduction of EIM prevalence to levels encountered in never smokers.
Article
The relationship between smoking behavior and inflammatory bowel disease (IBD) is complex. While Crohn’s disease (CD) is associated with smoking and smoking has detrimental effects on the clinical course of the disease, ulcerative colitis (UC) is largely a disease of nonsmokers and former smokers. Furthermore, cigarette smoking may even result in a beneficial influence on the course of ulcerative colitis. The potential mechanisms involved in this dual relationship include changes in humoral and cellular immunity, cytokine and eicosanoid levels, gut motility, permeability, and blood flow, colonic mucus, and oxygen free radicals. Nicotine is assumed to be the active moiety. The differential therapeutic consequences comprise the cessation of smoking in CD and, so far, clinical trials using nicotine in different forms of application for UC. In this article, we review the relationship between cigarette smoking and IBD, considering epidemiological, pathogenetic, and clinical aspects.