DISCUSSION
In this study, constipated patients had a 2.11-fold higher risk for AD
than non-constipated patients, regardless of age, gender, or
comorbidities. Best of our knowledge, this is the first and largest
epidemiological research to utilize the nationwide population-based
dataset to clarify the relationship between constipation and AD. This
association could be of clinical and pathophysiological importance. Our
findings highlight the considerably higher risk of AD in people with
constipation. Constipation thus seems to be influential in the
development of AD. Clinicians should be alert to the possibility of AD
in patients with constipation. Similarly, constipated patients should be
informed of the possible risk of AD and be provided with appropriate
management for AD as required. Our findings further underline the
importance of maintaining good bowel habits so as to avoid constipation,
which would in turn mitigate risk of AD.
Our findings are in line with an epidemiological study conducted in
Japan, which analyzed the risk factors for allergic disease in 21802
students, aged 15-18 years old, living in the same prefecture between
2012 and 2013.22 The results of the study indicated
that constipated students had a 1.17-fold risk for developing AD, which
was comparable to the 2.34-fold elevated risk found among teenagers in
our study (95% C.I. 1.84-2.98 p<0.001). Moreover, we observed
a significantly higher risk of AD not in only childhood, but also in
adulthood.
We also noticed that the risk of AD disclosed significantly higher in
patients with hypertension, chronic liver disease, COPD, or diabetes,.
Most of these comorbidities, such as diabetes and COPD, were associated
with chronic inflammatory status, which might lead to release of serum
cytokines and T-cell activation. We also speculate that constipation
might worsen pre-existing dysbiosis in vulnerable patients with
diabetics who may therefore have an increased risk of AD. Intriguingly,
a general population study conducted in Copenhagen, suggested that null
mutations in the filaggrin gene in patients with diabetes were connected
with a higher prevalence of atopic dermatitis. This result implies that
poor protection of skin barrier in diabetes patients may lead greater to
exposure allergens and increased epidermal water
loss.23
The pathophysiological mechanisms underlying the relationship between
constipation and atopic dermatitis remain unclear. In recent years,
there has been considerable research conducted on the gut microbiota and
a number of investigations have indicated that alterations in the gut
microbiota might contribute to constipation and constipation-related
symptoms.9,18 Compare to the healthy people,
constipated individuals had relatively lower amount of obligate bacteria
(e.g. Bifidobacterium, Lactobacillus, and Bacteroides spp.) and
relatively higher amount of potentially pathogenic microbes, such as
Pseudomonas aeruginosa. These changes in the intestinal environment
could influence bowel motility by the active
substances.24. Similar changes in gut microbiota were
reported in patients with AD. For instance, a study in Japan indicated
that lower Bifidobacterium counts were found in patients with AD
compared with those of healthy people in the fecal
microflora.25 In addition, other studies observed that
there were low numbers of Bifidobacterium and Bacteroides spp. as well
as a lack of intestinal microbiota variation in AD
patients.26,27 Some studies demonstrated that
microbial-derived metabolic products, specifically SCFAs, functioned as
important drivers of T-cell subset proliferation and
activity.28,29 Morevoer, it has been shown that
production of intestinal microbial SCFAs might down-regulate
proinflammatory reactions at the allergen-insult
site.13,30,31 In contrast, immune homeostasis might be
destroyed by typical ”Westernized” dietary intake, which can be
characterized as being high proportion in fat and less proportion in
fiber, altering the gut microflora, and resulting in reduced production
of SCFAs.10,13,32–34 Furthermore, SCFAs might affect
bowel motility via stimulating the contraction of colonic muscles,
thereby helping to relieve or prevent
constipation.35,36 Therefore, low fiber intake in
constipated subjects might also have a key role in the development of
atopy. Taken together the currently available evidence indicates that
the gut microbiota might play a pivotal mechanistic role linking
constipation and atopic dermatitis. It is not known how constipation
changes the composition of the intestinal microbiome and how relevant
this is to AD. Further comprehensive metagenomic and metabolomic
analyses of the intestinal microbiota in constipated people are
warranted to elucidate the mechanisms underlying these associations.
The major advantages of this study were the relatively long follow-up
period and large sample size. A complete past history of utilized
medical services was available for all cases. Thus, there was minimal
selection, information, and recall bias. As such, it was possible to
properly test our hypothesis. There were some potential limitations in
our study. First, the diagnoses of constipation and AD were entirely
dependent on the ICD-9 codes in the administrative dataset. We did not
perform a review of the patients’ medical records so it was not possible
to verify the accuracy of diagnoses, and therefore there may have been
some misclassification. It is worth noting, however, that any
misclassifications were more likely to be random, and associations are
often underestimated rather than overestimated. In addition, clinical
judgment might have varied among clinicians, and so diagnoses may not
have been consistent, which might have influenced their validity.
However, Taiwan’s NHI administration monitors the accuracy of the claims
data to prevent violations. Second, the NHIRD does not contain data on
covariates, such as social adversity, personal lifestyle, family
history, laboratory data and environmental factors. Although we adjusted
for various comorbidities and matched propensity scores, these
unmeasured confounding factors could have affected our results. Third,
it remains unclear as to whether the findings of our study may be
extrapolated to other ethnic groups, as the majority of our patients
were Taiwanese. Further clinical studies should include other
ethnicities and nationalities to determine the generalizability of the
associations observed herein.