Scandinavian Journal of Gastroenterology

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Solar radiation is inversely associated with

inflammatory bowel disease admissions

Francisca Jaime, Maria C. Riutort, Manuel Alvarez-Lobos, Rodrigo Hoyos-

Bachiloglu, Carlos A. Camargo Jr & Arturo Borzutzky

To cite this article: Francisca Jaime, Maria C. Riutort, Manuel Alvarez-Lobos, Rodrigo Hoyos-
Bachiloglu, Carlos A. Camargo Jr & Arturo Borzutzky (2017) Solar radiation is inversely associated
with inflammatory bowel disease admissions, Scandinavian Journal of Gastroenterology, 52:6-7,
730-737, DOI: 10.1080/00365521.2017.1307444

To link to this article: https://doi.org/10.1080/00365521.2017.1307444

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Published online: 31 Mar 2017.

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SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY, 2017
VOL. 52, NO. 6-7, 730–737
http://dx.doi.org/10.1080/00365521.2017.1307444

ORIGINAL ARTICLE

Solar radiation is inversely associated with inflammatory bowel disease

admissions
Francisca Jaimea , Maria C. Riutorta, Manuel Alvarez-Lobosb, Rodrigo Hoyos-Bachilogluc, Carlos A. Camargo Jrd
and Arturo Borzutzkyc,e
a
Department of Pediatric Gastroenterology and Nutrition, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile;
b
Department of Gastroenterology, School of Medicine, Pontificia Universidad Cat
olica de Chile, Santiago, Chile; cDepartment of Pediatric
Infectious Diseases and Immunology, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile; dDepartment of
Emergency Medicine and Division of Rheumatology, Allergy, and Immunology, Department of Medicine, Massachusetts General Hospital,
Harvard Medical School, Boston, MA, USA; eMillennium Institute on Immunology and Immunotherapy, School of Medicine, Pontificia
Universidad Catolica de Chile, Santiago, Chile

ABSTRACT ARTICLE HISTORY

Objective: To explore the associations between latitude and solar radiation with inflammatory bowel Received 12 January 2017
disease admission rates in Chile, the country with the largest variation in solar radiation in the world. Revised 9 March 2017
Patients and methods: This is an ecological study, which included data on all hospital-admitted popu- Accepted 12 March 2017
lation for inflammatory bowel disease between 2001 and 2012, according to different latitudes and
solar radiation exposures in Chile. The data were acquired from the national hospital discharge data- KEYWORDS
base from the Department of Health Statistics and Information of the Chilean Ministry of Health. Inflammatory bowel
Results: Between 2001 and 2012 there were 12,869 admissions due to inflammatory bowel disease disease; ulcerative colitis;
(69% ulcerative colitis, 31% Crohn’s disease). Median age was 36 years (IQR: 25–51); 57% were female. Crohn’s disease; solar
The national inflammatory bowel disease admission rate was 6.52 (95% CI: 6.40–6.63) per 100,000 radiation; latitude;
inhabitants with increasing rates over the 12-year period. In terms of latitude, the highest admission admissions; vitamin D;
rates for pediatric ulcerative colitis and Crohn’s disease, as well as adult ulcerative colitis, were flares
observed in the southernmost region with lowest annual solar radiation. Linear regression analysis
showed that regional solar radiation was inversely associated with inflammatory bowel disease admis-
sions in Chile (b:
.44, p ¼ .03).
Conclusions: Regional solar radiation was inversely associated with inflammatory bowel disease admis-
sion rates in Chile; inflammatory bowel disease admissions were highest in the southernmost region
with lowest solar radiation. Our results support the potential role of vitamin D deficiency on inflamma-
tory bowel disease flares.

Introduction radiation (SR)-mediated synthesis in the skin. VD can affect

Inflammatory bowel diseases (IBD) comprise two distinct
chronic relapsing-remitting gastrointestinal disorders: ulcera-
tive colitis (UC) and Crohn's disease (CD). The etiology of IBD
has not yet been fully elucidated, but it is thought to be a
multifactorial disease arising in genetically predisposed hosts
as a result of an abnormal interaction between the intestinal
microbiota, the immune system and the environment.
Pollution, increasing industrialization, western diet, smoking,
antibiotic use and prolonged used of anti-inflammatory med-
ications are amongst the multiple factors associated with this
complex group of diseases [1–4]. As a consequence of the
more ‘indoor’ westernized lifestyle, increasing prevalence of
vitamin D (VD) deficiency has been described worldwide
[5–7].
VD is a pleiotropic hormone with multiple effects on the
immune [8] and gastrointestinal systems [9]. The most
important source of VD in humans is by ultraviolet solar
the function of the immune system at different levels and its
receptor is expressed in almost all cells of the immune sys-
tem. The immunosuppressive effects of VD are important for
regulating inflammation and maintenance of the gut epithe-
lial barrier [10]. A growing body of epidemiological evidence
supports the link between VD deficiency and the pathogen-
esis of various immune-mediated diseases [11–13]. Some epi-
demiological studies in the USA and Europe have associated
higher latitudes and low SR, with higher incidence of IBD
[14–19], as well as increased rates and severity of IBD
hospitalizations [20]. However, meta-analyses are inconsistent
and lack sufficient data [21,22]. In support of the epidemio-
logical findings, clinical studies have shown decreased VD
status in IBD patients [23] and an inverse association of VD
levels with disease activity [24–26] and gut inflammation
[27,28].
Chile is a South American country that spans 39 of lati-
tude without significant longitudinal variations and includes

CONTACT Arturo Borzutzky arturobor@med.puc.cl Diagonal Paraguay 362, Santiago 8330077, Chile
Supplemental data for this article can be accessed here.
ß 2017 Informa UK Limited, trading as Taylor & Francis Group

the southernmost populated region in the world. Chile has a
population of 17 million with a relatively homogeneous eth-
nic background composed of a blend of European (mainly
Spanish) and indigenous ethnicities, with a high access to
healthcare, as reflected by a high medical attention of birth
(99.8%) among other indicators [29]. A large gradient of SR
exists in Chile from north to south, being Chile the country
with the widest range in SR in the world [30]. Clinical studies
show that VD deficiency is infrequently observed in the
northernmost region (latitude 17.5 S), affects about half of
the population in Santiago (latitude 33 S), and affects virtu-
ally all the population living in the southernmost region of
Magallanes (latitude 53 S) [31–34]. These characteristics make
Chile an ideal location for studying the association between
latitude and SR, as proxies of VD status, and IBD. The object-
ive of our study was to explore the associations of latitude
and SR with IBD admission rates in Chile. We hypothesized
an association of higher latitude and lower SR with higher
IBD admission rates in Chile.
Materials and methods
Study design
This is an ecological study. We compiled national hospital dis-
charge data from the Department of Health Statistics and
Information of the Chilean Ministry of Health to permit analy-
ses of IBD admissions between 2001 and 2012 [35]. At the
time of data analysis, admissions beyond 2012 were not avail-
able. The annual database is a robust and mandatory by
decree registry of all hospitalizations in the public and private
health systems throughout the country. Chile’s healthcare sys-
tem combines public insurance (middle–low socioeconomic
level population, 80% of population), private insurance (mid-
dle–high socioeconomic level population, 18% of population)
as well as military forces insurance (3% of population) [29].
The unit of analysis of the hospital discharge database is
hospitalizations rather than patients, as the data lack unique
patient identifiers. Thus, we are unable to calculate IBD inci-
dence or prevalence, although we had access to data on the
universe of admissions.
In this database, diagnosis at discharge of every inpatient
hospitalization is registered using ICD-10 codes. Included
admissions were those related to UC and CD. The following
ICD-10 codes were considered as ‘UC’: K51.0 (ulcerative pan-
colitis), K51.2 (ulcerative proctitis), K51.3 (ulcerative rectosig-
moiditis), K51.5 (left sided colitis), K51.8 (other UC) and K51.9
(UC, unspecified). The following ICD-10 codes were consid-
ered as ‘CD’: K50.0 (CD of small intestine), K50.1 (CD of large
intestine), K50.8 (other CD), K50.9 (CD, unspecified). Other
variables included in our analysis were: age and gender of
every patient, place of hospitalization, hospital length of stay,
season of admission (calculated from the date of admission),
type of insurance (public/private), surgery (yes/no) and status
at discharge (alive/dead). Admission rates were expressed as
cases per 100,000 persons per year. Pediatric IBD admission
rates were calculated in the Chilean population younger than
18 years, while the adult IBD rates were calculated for ages
18 years and older. Prolonged hospitalizations were defined
SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY 731
as the top quartile length of stay among all hospitalizations,
which is equivalent to >11 days.
Chile is currently divided into 15 administrative regions
from north to south. Latitude for each region was taken at
its center (e.g., latitude 19 170 S was used for the Tarapaca
Region located between latitudes 18 560 and 21 380 ). Data
on total population for each region were obtained from esti-
mations from the National Institute of Statistics for each year
[36]. Forty percent of the population inhabits the capital city
of Santiago in central Chile, 22% lives in the northern regions
and 38% in the south. Standardized admission ratios (SARs)
were calculated to evaluate excess in IBD-related admissions.
The national average was used as reference for SAR (i.e., SAR
1.0). For analysis, we divided the country into five latitude
ranges of similar size from north to south in order to show
changes in IBD admission rates and SARs.
Average annual SR intensity data, expressed as MJ/m2/
day, was obtained from the Chilean Solarimetric Registry [37].
To assess potential confounders, we also considered percent-
age of population living in poverty, percentage of people
with indigenous ethnicity and the percentage of people liv-
ing in rural area for each administrative region. The two for-
mer variables were obtained from reports from the Chilean
Ministry of Social Development [38] and the latter variable
was extracted from the National Institute of Statistics for the
year 2011 [36]. This study was approved by the Ethics
Committee of the Pontificia Universidad Cato lica de Chile
Medical School, and it is reported according to the RECORD-
STROBE statement [39].
Statistical analyses
Independent variables were latitude of the region of dis-
charge (ROD), solar radiation at the region of discharge, age
of patients (pediatric/adult), gender (male/female), percent-
age of people living in rural areas at ROD, percentage of
people living in poverty at ROD and percentage of people
with indigenous ethnicity at ROD. Dependent variables were
the rate of admissions due to IBD, UC and CD for each ROD
by year, rate of admission length of stay due to IBD, UC and
CD for each ROD and death rate due to IBD, UC and CD for
each ROD. All rates are shown with 95% confidence intervals
(95% CI). Chi-square was used to compare binary variables
between UC and CD admissions and to assess seasonal differ-
ences in IBD admissions. Linear regressions were used to
evaluate the association between the main exposures (years,
regional latitude, SR, poverty, rurality, indigenous ethnicity
percentages) and main outcomes (IBD/UC/CD admission
rates). Unstandardized b coefficients and 95% CI were
reported for each regression. Comparison between two rates
was performed by binomial exact test. A two-sided p < .05
was considered statistically significant. Statistical analyses
were performed using SPSS Statistics 21.0 (SPSS Inc, Chicago,
IL) and OpenEpi software version 2.3.1 (Atlanta, GA).
Results
Between 2001 and 2012, there were 12,869 admissions due
to IBD in Chile; 69% of IBD admissions were due to UC.
732 F. JAIME ET AL.

Table 1. Demographic and seasonal distribution of inflammatory bowel disease admissions in Chile, 2001–2012.
Ulcerative colitis Crohn’s disease
n (%) Admission rate per 100,000 (95% CI) n (%) Admission rate per 100,000 (95% CI)
Age (yrs)
0–9 242 (1.9) 0.80 (0.71–0.91) 256 (2.0) 0.85 (0.75–0.96)
10–19 845 (6.6) 2.50 (2.34–2.68) 481 (3.7) 1.42 (1.30–1.56)
20–29 2035 (16) 6.46 (6.18–6.74) 739 (5.7) 2.35 (2.18–2.52)
30–39 1923 (15) 6.47 (6.19–6.76) 681 (5.3) 2.29 (2.12–2.47)
40–49 1551 (12) 5.52 (5.25–5.80) 733 (5.7) 2.61 (2.24–2.80)
50–59 1037 (8.1) 5.12 (4.81–5.43) 527 (4.1) 2.60 (2.39–2.83)
60–69 605 (4.7) 4.67 (4.31–5.05) 341 (2.6) 2.63 (2.36–2.92)
70–79 380 (3.0) 5.05 (4.56–5.57) 202 (1.6) 2.68 (2.33–3.07)
80–99 197 (1.5) 6.43 (5.58–7.37) 94 (0.7) 3.07 (2.49–3.74)
Sex
Male 3770 (43) 3.86 (3.74–4.00) 1757 (43) 1.80 (1.72–1.89)
Female 5045 (57) 5.07 (4.93–5.21) 2297 (57) 2.31 (2.21–2.40)
Season
Summer 2105 (24) 1.07 (1.02–1.11) 974 (24) 0.49 (0.46–0.53)
Fall 2124 (24) 1.08 (1.03–1.12) 1003 (25) 0.51 (0.48–0.54)
Winter 2159 (25) 1.09 (1.05–1.14) 937 (23) 0.48 (0.45–0.51)
Spring 2305 (26) 1.17 (1.12–1.22)‡ 1048 (26) 0.53 (0.50–0.56)†
Unknown 122 (1.4) 92 (2.3)
p < .001 compared to female.
†p < .05 compared to winter.
‡p < .05 compared to any other season.

Demographic and seasonal distributions of IBD admissions
are shown in Table 1. Briefly, the median age was 36 years
(interquartile range, IQR: 25–51), with no significant differ-
ence between UC- and CD-related admissions (36 [IQR:
25–50] vs. 37 [IQR: 23–52]). Children accounted for 11% of all
IBD admissions. A significantly lower percentage of UC
admissions than CD admissions were due to pediatric admis-
sions (9% vs. 15%, p < .001). Male gender accounted for 43%
of all IBD admissions, no significant gender difference was
found between UC and CD admissions (43.3% vs. 42.8%);
however, female patients had higher odds ratio (OR) of
admission for UC and CD than male patients (1.31 [95% CI:
1.26–1.37] and 1.28 [95% CI: 1.21–1.36], respectively). The
seasonal distribution of IBD admissions showed a significantly
higher rate of UC admissions during spring compared to all
other seasons (OR spring vs. summer: 1.1 [95% CI: 1.03–1.16],
OR spring vs. fall: 1.09 [95% CI: 1.02–1.15], OR spring vs. win-
ter: 1.07 [95% CI: 1.01–1.13]) and for CD admissions during
the spring compared to the winter (OR: 1.11, 95% CI:
1.02–1.22).
With regard to the hospital course, the median length of
stay was 6 days (IQR: 2–11). UC admissions were significantly
longer than CD admissions (7 days [IQR: 3–12] vs. 4 days
[IQR: 1–8], p < .001). Eighty-six patients died during hospital-
izations attributable to IBD, resulting in an in-patient mortal-
ity rate of 0.7%. A surgical intervention was performed in
1649 admissions for IBD (12.9%). A significantly lower per-
centage of UC patients required a surgical procedure during
hospitalization compared to CD patients (12.2% vs. 15.3%,
p < .001).
The national IBD admission rate was 6.52 per 100,000
inhabitants (95% CI: 6.40–6.63); IBD admission rates were sig-
nificantly higher in adults than in children (8.29 [95% CI:
8.14–8.45] vs. 2.47 [95% CI: 2.34–2.60], respectively, p < .001).
The admission rate due to UC was significantly higher than
the CD admission rate (4.47 [95% CI: 4.37–4.56] vs. 2.06 [95%
CI: 1.99–2.12], respectively, p < .001). An increasing trend in
admission rates due to IBD was observed throughout the 12-
year period with an increase of 0.3 admissions per 100,000
inhabitants every year (b: .291, p < .001). Analysis of the
admission trends in the pediatric and adult population
showed a significant increase in admission rates due to UC in
children and adults as well as CD in adults (Figure 1) but not
in children with CD.
In terms of latitude, the highest admission rates for pedi-
atric UC and CD as well as adult UC were observed in the
southernmost region of Magallanes (latitude 48–56 S), which
has the lowest annual SR. To further evaluate the effect of
latitude on IBD admissions throughout Chile, we analyzed
admission rates and SARs for the different latitude ranges
from north to south. IBD admission rates were significantly
higher in the southernmost (latitudes 48.9–56 S) compared
to the northernmost (latitude 17.5–25.9 S) areas of Chile
(9.43 [95% CI: 8.37–10.58] vs. 4.06 [95% CI: 3.55–4.61],
respectively, p < .001). In addition, IBD admissions in the
southernmost area of Chile were significantly higher than the
national IBD admission rate (9.43 [95% CI: 8.37–10.58] vs.
6.52 [95% CI: 6.40–6.63], respectively, p < .001). The effect of
latitude on IBD admissions was more pronounced for UC
than for CD, both in the pediatric and adult population
(Figure 2).
We next analyzed whether latitude and regional SR levels
correlated with IBD admission rates by linear regression.
Unadjusted linear regression analysis showed that higher lati-
tude was associated with IBD admissions in Chile (b:
.165,
[95% CI:
0.31,
0.02], p ¼ .03). Latitude and regional SR
are highly correlated in Chile (r ¼
.96). In consequence,
regional SR was inversely associated with IBD admissions in
Chile (b:
.44, [95% CI:
0.82,
0.05], p ¼ .03). Upon
unadjusted analysis by IBD type, this association remained

Figure 1. Time trends of inflammatory bowel disease related hospital admission rates in Chile, 2001–2012. (A) Overall inflammatory bowel disease admission rates.
(B) Crohn’s disease admission rates. (C) Ulcerative colitis admission rates.
significant for UC (b:
.34, [95% CI:
0.65,
0.03], p ¼ .03)
but not for CD (b:
.1, [95% CI:
0.21, 0.02], p ¼ .09). No
association was observed between regional latitude/SR and
in-patient mortality rates, surgical intervention rates or pro-
longed hospitalization rates (>11 days), although low case-
loads per region for these variables preclude firm
conclusions.
While 26% of overall admissions in Chile during the
studied period had private insurance, a proxy of high socio-
economic status, a significantly higher proportion of
patients admitted to the hospital due to UC and CD sub-
scribed to the private insurance system (39% and 56%,
respectively, p < .001). Although regional poverty and rural-
ity rates consistently had inverse associations with total IBD,
UC and CD admissions in unadjusted linear regressions,
these were not statistically significant (Supplementary Table
1). Indigenous population rates were not associated with
IBD admissions.
We next tested linear regression models to adjust by lati-
tude, SR, rurality and poverty. A model entering both latitude
and SR was not possible due to high collinearity (tolerance
0.07, variance inflation factors 15.2), so we performed linear
regression models including SR, poverty and rurality rates. SR
and rurality had significant independent inverse associations
with total IBD, UC and CD admissions, while poverty was not
associated (Table 2). Upon analyzing by age group, SR and
SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY 733
rurality remained significant for UC admissions in children
and adults, and CD admissions in adults.
Discussion
Our study shows a significant inverse association between
high latitude/low SR and IBD admissions in Chile. A surplus
of IBD admissions was observed at the extreme south of
Chile, where 96% of the pediatric population and 100% of
postmenopausal women have been reported to be VD defi-
cient [31,33].
An association of high latitudes and low SR with IBD inci-
dence has been described previously by others in North
America and Europe [14–20], but this the first report of the
IBD–latitude association in the Southern Hemisphere.
Furthermore, our study found an association between lati-
tude and hospital admissions due to IBD, which may be
related to more severe flares. To our knowledge, the only
other epidemiological study that evaluates the relationship
between latitude and IBD admissions, found that lower SR
was associated with higher IBD admission rates in the USA
[20]. This study also showed an association of lower SR with
higher severity of IBD admissions reflected in higher in-
patient mortality rates, longer hospitalizations and more IBD-
related surgeries [20]. The latter was also replicated in
another recent study [40]. However, some studies of the
734 F. JAIME ET AL.

Figure 2. Increased standardized admission ratios (SARs) of inflammatory bowel disease admissions in the southernmost area of Chile, 2001–2012. (A) Overall
inflammatory bowel disease. (B) Crohn’s disease. (C) Ulcerative colitis.

Table 2. Multivariable regression analysis of regional solar radiation, rurality and poverty rates with inflammatory bowel disease admission rates.
Solar radiation (MJ/m2/day) Rurality Poverty
b 95% CI p b 95% CI p b 95% CI p
IBD
Total IBD (n ¼ 12,869)
.65
1.00 to
0.30 .002
.18
0.31 to
0.05 .01 .13
0.15 to 0.41 .33
Pediatric IBD (n ¼ 1406)
.22
0.35 to
0.09 .003
.07
0.12 to
0.02 .009 .07
0.03 to 0.18 .15
Adult IBD (n ¼ 11,463)
.67
1,12 to
0.23 .007
.22
0.38 to
0.05 .01 .06
0.30 to 0.41 .73
Ulcerative colitis
Total UC (n ¼ 8815)
.50
0.79 to
0.21 .003
.13
0.24 to
0.02 .02 .08
0.16 to 0.3 .49
Pediatric UC (n ¼ 819)
.18
0.26 to
0.10 <.001
.05
0.08 to
0.02 .005 .05
0.01 to 0.12 .10
Adult UC (n ¼ 7996)
.50
0.88 to
0.12 .02
.16
0.30 to
0.02 .03 .01
0.30 to 0.32 .96
Crohn's disease
Total CD (n ¼ 4054)
.16
0.27 to
0.05 .01
.05
0.09 to
0.01 .02 .05
0.04 to 0.14 .21
Pediatric CD (n ¼ 587)
.05
0.12 to 0.03 .21
.02
0.05 to 0.01 .10 .02
0.04 to 0.08 .44
Adult CD (n ¼ 3467)
.17
0.41 to
0.04 .02
.06
0.11 to
0.01 .02 .05
0.06 to 0.02 .34
p < .05 are shown in bold and italics.
IBD: inflammatory bowel disease.

association of SR with IBD incidence have shown a stronger
association of SR with CD than UC [17–19]. In a recent sys-
tematic review, pediatric CD incidence was evaluated in con-
junction with SR, finding a modest increase in pediatric CD
incidence at higher latitudes [41].
Our study showed an association of higher latitudes
and lower SR with IBD admissions, but it did not reveal an
association between lower SR and higher case in-patient
mortality rates, surgical intervention rates or prolonged
hospitalizations. This discrepancy may be due to the lower
number of cases in our study compared to the US study, as
well as regional differences in access to gastroenterologists
and digestive surgeons with expertise in IBD throughout
Chilean regions.
Our data support a possible role of VD deficiency, a modi-
fiable risk factor, on the high IBD admission rates observed in
the southernmost regions of Chile. The effect of latitude on
VD status appears to be mostly through sunlight exposure,

as populations living furthest from the equator are less likely
to have adequate SR exposure and present higher rates of
VD deficiency. Although our study lacks data on VD levels, a
decreasing southward trend in VD levels has been described
in Chile, with the lowest levels being found between lati-
tudes 48.9–56 S [31,33,34,42]. Also, new data in experimental
models has also revealed VD-independent effects from UVR,
some of them similar to those from VD – inhibition of T cell
proliferation – but also a wider inhibition of T cell cytokines,
such as Th1, Th17 and Th2 [43].
Despite a significantly higher proportion of IBD hospital
admissions in patients with private health insurance, a proxy
of high socioeconomic status in Chile, regional poverty levels
were not significantly associated with IBD admissions.
Analysis of CD and UC admission rates separately also
showed a significant increasing trend for both forms of IBD
during the study period. Hospital admissions due to CD were
significantly lower than those due to UC; similar trends have
been previously described worldwide [44].
A linear regression model accounting for regional SR and
rurality provided a significant association between those fac-
tors and admissions due to CD and UC. Previous international
reports have suggested a positive association between higher
educational levels and urban residency with IBD incidence
[45]. A recent hospitalization-based study reported only a
minor contribution of socioeconomic factors such as educa-
tional level and occupation on IBD incidence [46]. These
observations along with our epidemiological findings support
the idea that multiple environmental factors are involved in
the development of IBD, but the relative importance of each
of these factors may vary according to the host's genetic pre-
disposition to develop IBD.
The higher hospital admission rates observed during spring
for UC and CD may be perceived as conflicting evidence for a
potential role of VD deficiency on the pathogenesis of IBD.
Since VD levels associate with disease activity [24,47], it is
plausible that VD depletion occurs during the winter season,
especially in the extreme south of Chile where hours of sun-
light becomes scant, causing an increase in IBD flares in late
winter, which probably leads to increased hospitalizations in
the following spring in patients who have not responded to
outpatient treatment measures in the previous weeks. Further
studies are needed in order to address this hypothesis.
The basic biology underlying the role of VD in the devel-
opment of IBD has not yet been fully clarified. A partial
explanation may be that transcriptional activity of the NOD2
gene is induced by signaling events downstream of the VD
receptor [48–50]. VD can affect the function of the immune
system at different levels and its receptor is expressed in
almost all cells of the immune system [51]. In lymphocytes,
VD has been reported to suppress T cell proliferation, induc-
ing the secretion of immunoregulatory cytokine IL-10, sup-
pressing differentiation into Th17 cells and stimulating the
Treg compartment [52]. The immunosuppressive effects of
VD are important for regulating inflammation and the main-
tenance of the gut epithelial barrier [10]. Nonetheless, a defi-
ciency in the regulatory effects of VD on the immune system
may also play an important role in the development of IBD
in genetically susceptible hosts. The role of VD on the
SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY 735
interaction between the immune and gastrointestinal systems
must be explored further in order to understand its role on
the pathogenesis of IBD.
The main strength of this study is that it includes the uni-
verse of IBD hospital admissions in Chile during a 12-year
period; however, some limitations of this work merit consider-
ation. Most importantly, the current study is ecological and
thus its conclusions may be limited by the ecological fallacy,
the risk of drawing inferences about the nature of individuals
based on inferences about the group to which those individu-
als belong. Although intra-regional differences in sun exposure
of individuals with IBD are possible, considering previous stud-
ies of VD status in Chile, we believe regional SR is a good proxy
of VD status of the inhabitants of each region, which is sup-
ported by the studies previously cited. Despite the fact that
latitude and regional SR reflect a decreasing gradient in VD sta-
tus from north to south in Chile, these may also be associated
with other factors such as colder climate, indoor crowding and
differences in microbial exposure. Some inter-regional differen-
ces in diet also exist. Inhabitants from the southern part of
Chile have shown a higher consumption of red and processed
meat, as well as saturated and polyunsaturated fats [53]. In
addition, the databases do not provide access to patient infor-
mation other than the reported sociodemographic data;
important clinical information, such as confounder diagnoses
and serum 25-hydroxyvitamin D levels, is therefore missing.
In summary, our study demonstrates an inverse associ-
ation between regional SR and IBD admission rates in Chile,
providing additional evidence of a potential role of VD defi-
ciency in IBD flares requiring hospital admission. Further
studies are needed to confirm the role of VD deficiency on
the pathogenesis and natural history of IBD, including cohort
studies with population from different latitudes and cross-
sectional population sampling at different latitudes to dir-
ectly distinguish the association of VD with IBD incidence
and disease severity. Chile provides a unique setting for such
lines of research.
Disclosure statement
The authors have no potential conflict of interest to declare.
Funding
This work was supported by Fondo Nacional de Desarrollo Cientıfico y
gico under [grant No. 1130615] to AB and [grant No. 1131012] to
Tecnolo
MA; and Iniciativa Cientıfica Milenio under [grant No. P09/016-F] to AB.
Funders had no role on the results or the report of this study.
ORCID
Francisca Jaime http://orcid.org/0000-0002-8411-8537
Carlos A. Camargo Jr http://orcid.org/0000-0002-5071-7654
Arturo Borzutzky http://orcid.org/0000-0002-7904-262X
References
[1] Abraham C, Cho JH. Inflammatory bowel disease. N Engl J Med.
2009;361:2066–2078.
736 F. JAIME ET AL.
[2] Ko Y, Butcher R, Leong RW. Epidemiological studies of migration
and environmental risk factors in the inflammatory bowel dis-
eases. World J Gastroenterol. 2014;20:1238–1247.
[3] Ekbom A. The epidemiology of IBD: a lot of data but little
knowledge. How shall we proceed? Inflamm Bowel Dis.
2004;10(Suppl 1):S32–S34.
[4] Molodecky NA, Soon IS, Rabi DM, et al. Increasing incidence
and prevalence of the inflammatory bowel diseases with time,
based on systematic review. Gastroenterology. 2012;142:46–54
e42. quiz e30.
[5] Cashman KD, Dowling KG, Skrabakova Z, et al. Vitamin D defi-
ciency in Europe: pandemic? Am J Clin Nutr. 2016;103:1033–1044.
[6] Gordon CM, Feldman HA, Sinclair L, et al. Prevalence of vitamin D
deficiency among healthy infants and toddlers. Arch Pediatr
Adolesc Med. 2008;162:505–512.
[7] Gordon CM, DePeter KC, Feldman HA, et al. Prevalence of vitamin
D deficiency among healthy adolescents. Arch Pediatr Adolesc
Med. 2004;158:531–537.
[8] Hewison M. Vitamin D and the immune system: new perspectives
on an old theme. Rheum Dis Clin North Am. 2012;38:125–139.
[9] Stumpf WE. Vitamin D and the digestive system. Eur J Drug
Metab Pharmacokinet. 2008;33:85–100.
[10] Reich KM, Fedorak RN, Madsen K, et al. Vitamin D improves
inflammatory bowel disease outcomes: basic science and clinical
review. World J Gastroenterol. 2014;20:4934–4947.
[11] Yang CY, Leung PS, Adamopoulos IE, et al. The implication of
vitamin D and autoimmunity: a comprehensive review. Clin Rev
Allergy Immunol. 2013;45:217–226.
[12] Iruretagoyena M, Hirigoyen D, Naves R, et al. Immune response
modulation by vitamin D: role in systemic lupus erythematosus.
Front Immunol. 2015;6:513.
[13] Vassallo MF, Camargo CA Jr. Potential mechanisms for the
hypothesized link between sunshine, vitamin D, and food allergy
in children. J Allergy Clin Immunol. 2010;126:217–222.
[14] Khalili H, Huang ES, Ananthakrishnan AN, et al. Geographical vari-
ation and incidence of inflammatory bowel disease among US
women. Gut. 2012;61:1686–1692.
[15] Sonnenberg A, Genta RM. Geographic distributions of microscopic
colitis and inflammatory bowel disease in the United States.
Inflamm Bowel Dis. 2012;18:2288–2293.
[16] Nerich V, Monnet E, Etienne A, et al. Geographical variations of
inflammatory bowel disease in France: a study based on national
health insurance data. Inflamm Bowel Dis. 2006;12:218–226.
[17] Armitage EL, Aldhous MC, Anderson N, et al. Incidence of juven-
ile-onset Crohn's disease in Scotland: association with northern
latitude and affluence. Gastroenterology. 2004;127:1051–1057.
[18] Jantchou P, Clavel-Chapelon F, Racine A, et al. High residential
sun exposure is associated with a low risk of incident Crohn's dis-
ease in the prospective E3N cohort. Inflamm Bowel Dis.
2014;20:75–81.
[19] Nerich V, Jantchou P, Boutron-Ruault MC, et al. Low exposure to
sunlight is a risk factor for Crohn's disease. Aliment Pharmacol
Ther. 2011;33:940–945.
[20] Limketkai BN, Bayless TM, Brant SR, et al. Lower regional and tem-
poral ultraviolet exposure is associated with increased rates and
severity of inflammatory bowel disease hospitalisation. Aliment
Pharmacol Ther. 2014;40:508–517.
[21] Lu C, Yang J, Yu W, et al. Association between 25(OH)D level,
ultraviolet exposure, geographical location, and inflammatory
bowel disease activity: a systematic review and meta-analysis.
PLoS One. 2015;10:e0132036.
[22] Del Pinto R, Pietropaoli D, Chandar AK, et al. Association between
inflammatory bowel disease and vitamin D deficiency: a system-
atic review and meta-analysis. Inflamm Bowel Dis.
2015;21:2708–2717.
[23] Ardesia M, Ferlazzo G, Fries W. Vitamin D and inflammatory
bowel disease. Biomed Res Int. 2015;2015:470805.
[24] Torki M, Gholamrezaei A, Mirbagher L, et al. Vitamin D deficiency
associated with disease activity in patients with inflammatory
bowel diseases. Dig Dis Sci. 2015;60:3085–3091.
[25] Garg M, Lubel JS, Sparrow MP, et al. Review article: vitamin D
and inflammatory bowel disease–established concepts and future
directions. Aliment Pharmacol Ther. 2012;36:324–344.
[26] Frigstad SO, Høivik M, Jahnsen J, et al. Vitamin D deficiency in
inflammatory bowel disease: prevalence and predictors in a
Norwegian outpatient population. Scand J Gastroenterol.
2017;52:100–106.
[27] Veit LE, Maranda L, Nwosu BU. The nondietary determinants of
vitamin D status in pediatric inflammatory bowel disease.
Nutrition. 2015;31:994–999.
[28] Limketkai BN, Bechtold ML, Nguyen DL. Vitamin D and the
Pathogenesis of Inflammatory Bowel Disease. Curr Gastroenterol
Rep. 2016;18:52.
[29] Becerril-Montekio V, Reyes J, Manuel A. Sistema de Salud de
Chile. Salud Publica Mex. 2011;53:s132–s142.
[30] The SoDa Service. Available from: http://www.soda-pro.com/.
[31] Gonzalez G, Jimenez M, Rosowski J, et al. Is there a geographic
variability in the detection of hypovitaminosis D during winter?
National Multicenter Study in healthy elderly women. Rev Med
Chil. 2004;123:1290–1291.
[32] Einisman H, Reyes ML, Angulo J, et al. Vitamin D levels and vita-
min D receptor gene polymorphisms in asthmatic children: a
case-control study. Pediatr Allergy Immunol. 2015;26:545–550.
[33] Brinkmann K, Le Roy C, Iniguez G, et al. Severe vitamin D defi-
ciency in children from Punta Arenas, Chile: influence of nutri-
tional status on the response to supplementation. Rev Chil
Pediatr. 2015;86:182–188.
[34] Cediel G, Corvalan C, Aguirre C, et al. Serum 25-hydroxyvitamin D
associated with indicators of body fat and insulin resistance in
prepubertal chilean children. Int J Obes (Lond). 2016;40:147–152.
[35] Bases de Datos. Departamento de Estadısticas e Informacio n de
Salud. Available from: http://deis.cl/.
[36] Instituto Nacional de Estadısticas. Available from: http://www.ine.
cl/canales/menu/publicaciones/compendio_estadistico/pdf/2011/
1.2demograficas.pdf.
[37] Comisio n Nacional de Energıa. Irradiancia Solar en Territorios de
la Republica de Chile. 1st ed. Santiago, Chile: Margen Impresores;
2008.
[38] Ministerio de Desarrollo Social DS, Encuesta CASEN 2009. Available
from: http://www.ministeriodesarrollosocial.gob.cl/observatorio/casen/.
[39] Benchimol E, Smeeth L, Guttmann A, et al. The Reporting of stud-
ies Conducted using Observational Routinely-collected health
Data (RECORD) Statement. PLoS Med. 2015;12:e1001885.
[40] Govani SM, Higgins PD, Stidham RW, et al. Increased ultraviolet
light exposure is associated with reduced risk of inpatient surgery
among patients with Crohn's disease. J Crohns Colitis.
2015;9:77–81.
[41] Holmes EA, Xiang F, Lucas RM. Variation in incidence of pediatric
Crohn's disease in relation to latitude and ambient ultraviolet
radiation: a systematic review and analysis. Inflamm Bowel Dis.
2015;21:809–817.
[42] Le Roy C, Reyes M, Gonzalez JM, et al. Vitamin D nutrition in
Chilean pre-school children living in extreme latitudes. Rev Med
Chil. 2013;141:435–441.
[43] Bora S, Cantorna MT. The role of UVR and vitamin D on T cells
and inflammatory bowel disease. Photochem Photobiol Sci.
2017;16:347–353.
[44] Talley NJ, Abreu MT, Achkar JP, et al. An evidence-based system-
atic review on medical therapies for inflammatory bowel disease.
Am J Gastroenterol. 2011;106(Suppl 1):S2–S25; quiz S26.
[45] Aamodt G, Jahnsen J, Bengtson MB, et al. Geographic distribution
and ecological studies of inflammatory bowel disease in southeast-
ern Norway in 1990–1993. Inflamm Bowel Dis. 2008;14:984–991.
[46] Li X, Sundquist J, Sundquist K. Educational level and occupation
as risk factors for inflammatory bowel diseases: a nationwide
study based on hospitalizations in Sweden. Inflamm Bowel Dis.
2009;15:608–615.
[47] Kabbani TA, Koutroubakis IE, Schoen RE, et al. Association of vita-
min D level with clinical status in inflammatory bowel disease: a
5-year longitudinal study. Am J Gastroenterol. 2016;111:712–719.
 SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY 737

[48] Waldschmitt N, Chamaillard M. Time for epithelial sensing of vita- [51]
min D to step into the limelight. Gut. 2015;64:1013–1014.
[49] Wang TT, Dabbas B, Laperriere D, et al. Direct and indirect induc-
tion by 1,25-dihydroxyvitamin D3 of the NOD2/CARD15-defensin [52]
beta2 innate immune pathway defective in Crohn disease. J Biol
Chem. 2010;285:2227–2231.
[50] Nerich V, Monnet E, Weill A, et al. Fine-scale geographic variations of [53]
inflammatory bowel disease in France: correlation with socioeconomic
and house equipment variables. Inflamm Bowel Dis. 2010;16:813–821.
Hewison M. Vitamin D and the immune system: new
perspectives on an old theme. Endocrinol Metab Clin North Am.
2010;39:365–379.
Fawaz L, Mrad MF, Kazan JM, et al. Comparative effect of 25(OH)D3
and 1,25(OH)2D3 on Th17 cell differentiation. Clin Immunol.
2016;166–167:59–71.
Encuesta nacional de consumo alimentario, informe final. 2014.
Available from: http://web.minsal.cl/sites/default/files/ENCA-
INFORME_FINAL.pdf.