Received August 28, 2017
Accepted for publication November 13, 2017
The functions of various tissues and organs are degraded in
the course of aging, including intestinal barrier dysfunction.
Changes in the intestinal mucosal barrier function, nutritional
absorption, mucosal immunity, and intestinal microorganism
patterns are more commonly seen in geriatric patients (1).
Impaired blood flow, ischemic changes, chronic psychological
stress and increased use of NSAIDs naturally contribute to
an impaired epithelial barrier in elderly patients (2). Integrity
of intestinal epithelial cells serves as the largest mucosal
barrier between the internal host and external environment.
Intestinal permeability indicates the mucosal barrier integrity
and describes the paracellular leakiness of the intestinal lining.
Increased intestinal permeability is one of the important signs
of impaired intestinal barrier function. Previous studies have
reported that intestinal permeability increases with age in
rodents and old baboons, suggesting an age-related declination
of the intestinal barrier function (3-5).
Ageing is accompanied by a chronic state of low-grade
inflammatory status. The intestinal environment is substantially
changed with ageing, which in turn contributes to the
disturbances in the inflammatory status of the elderly .
Disturbances of the gut barrier have long been associated with
local as well as systemic diseases (7). Age-related intestinal
barrier dysfunction and differences in the gut microbiota
composition are related to the progression of inflammatory
aging and age-related diseases (8). It is generally perceived that
the intestinal mucosal barrier becomes leaky in the elderly and
contributes to the occurrence of age-related diseases, such as
Parkinson’s disease, Alzheimer’s disease, atherosclerosis, and
diabetes (9, 10). Current understanding regarding the effects
of aging on the physical and immunological properties of this
important epithelial barrier is limited. Our previous studies
have showed that age-related intestinal barrier dysfunction
may be associated with mucosal atrophy, damages to tight
junction (TJ) structure, and remodeling of intestinal epithelial
tight junction proteins (11). Studies on the mechanism and
protective measures of intestinal barrier dysfunction may
provide information to future clinical treatments to improve the
quality of life of geriatric patients.
Glucagon-like peptide-2 (GLP-2), a gut hormone that
promotes growth and function of the intestinal epithelium,
is derived from the L cells of the distal ileum and colon in
response to proximal enteric neuronal signaling and luminal
nutrients. The intestinal growth-promoting effects of GLP-2
result in significant enhancements in both small intestinal
weight and crypt-villus height in mice (12). Extensive studies
have demonstrated that GLP-2 played a major role in the
repair of impaired intestinal mucosa by promoting intestinal
growth, attenuating apoptosis in the intestinal mucosal
epithelial cells, and reducing intestinal permeability (13-15).
GLUCAGON-LIKE PEPTIDE-2 IMPROVE INTESTINAL MUCOSAL BARRIER
FUNCTION IN AGED RATS
, J. WU
, L. LI
, Y. LU
, Y. SHAO
, Y. QI
, B. XU
, Y. HE
, Y. HU
1. Department of Geriatrics, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200030, China; 2. Center for Obesity and Metabolic Surgery, Huashan Hospital, Fudan
University, 12 Middle Wulumuqi Road, Shanghai 200040, China, Weiying Ren , Jiayu Wu and Li Li contributed equally to this work. Corresponding author: Yu Hu, Department of
Geriatrics, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200030, China, E-mail: firstname.lastname@example.org, Tel:+86-021-64041990-3766, Fax:+86-21-64035399
Abstract: Glucagon-like peptide-2 (GLP-2) plays a major role in repairing impaired intestinal mucosa, but its
mechanism in the improvement of intestinal barrier function during the aging process remains unclear. In this
study, 26-month-old male Sprague-Dawley rats were randomized to control group and GLP-2 group treated
with a dose of 250 μg•kg-1•d-1 by intraperitoneal injection. After 14 days of treatment, intestinal mucosal
morphometric changes were observed by light microscopy and transmission electron microscopy (TEM).
Small intestinal permeability was evaluated by fluorescein isothiocyanate (FITC)-labeled dextran. The mRNA
and protein expression of Zonula Occludens-1 (ZO-1), occludin, claudin-1 and the GLP-2 receptor (GLP-2R)
were detected by Real-time PCR and Western blot. Our results showed that GLP-2 administration significantly
improved the age-related atrophy of intestinal mucosa and villi and increased small intestinal permeability. The
mRNA and protein expression of ZO-1and occludin in ileum were up regulated in the GLP-2-treated old rats.
In addition, the serum GLP-2 levels were negatively correlated with small intestinal permeability measured by
FITC-dextran levels (r=-0.610, P<0.01). Taking all these data together, it is concluded that GLP-2 improved
small intestinal epithelial barrier function in aged rats mainly by facilitating intestinal mucosa growth, alleviating
the increased small intestinal permeability and increasing ZO-1 and occludin expression. Our observations
provide evidence for the clinical significance of GLP-2 in preventing the intestinal epithelial barrier dysfunction
Key words: Glucagon-Like Peptide-2, aged rats, intestinal barrier function, tight junction, intestinal permeability.
Abbreviations: GLP-2: glucagon-like peptide-2; GLP-2R: glucagon-like peptide-2 receptor; TJ: tight junction;
TEM: transmission electron microscopy; FITC: fluorescein isothiocyanate; HE: hematoxylin and eosin.
© Serdi and Springer-Verlag International SAS, part of Springer Nature
J Nutr Health Aging. 2018;22(6):731-738
Published online March 19, 2018, http://dx.doi.org/10.1007/s12603-018-1022-8