Autophagy in intestinal injury caused by severe acute pancreatitis
Hong-Yao Li, Yu-Jie Lin, Ling Zhang, Jing Zhao, Dan-Yang Xiao, Pei-Wu Li
Department of Emergency, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, Gansu 730030, China.
Severe acute pancreatitis (SAP) is a potentially lethal
disease with considerable morbidity and mortality. It is
often accompanied by systemic inﬂammatory response
syndrome, sepsis, and organ dysfunction.
It is generally
believed that intestinal barrier dysfunction and bacterial
translocation (BT) are the primary causes of systemic
inﬂammation and sepsis complications in patients with
Recently, increasing evidence has shown that
autophagy plays an important role in intestinal homeosta-
sis. Autophagy can protect the intestinal mucosal barrier
during SAP by degrading and recovering the cytoplasmic
content of intestinal epithelial cells and damaged organelles,
removing invading microorganisms, and participating in
antigen presentation and lymphocyte development.
Therefore, regulating autophagy as a form of treatment
for SAP may bring beneﬁcial results.
Autophagy is deﬁned as a catabolic process that is conserved
among all eukaryotic organisms. Its main functions are to
degrade cytoplasmic content and recover damaged organs
andproteinstomaintainintracellular homeostasis when cells
face stress factors such as starvation. Apart from starvation,
autophagy is critical in responding to a diverse range of
stressors namely hypoxia, infection, endoplasmic reticulum
stress, tissue remodeling, cellular debris breakdown, turnover
of damaged organelles, tumor suppression, immune response,
and cell death.
Our current knowledge on autophagy
broadly differentiates it into three types: macroautophagy,
microautophagy, and chaperone-mediated autophagy
(CMA). Among them, CMA is highly speciﬁc and has only
been described in mammals so far.
The activation and
execution of autophagy can be divided into two stages: (1)
signal transmission with molecular switches that induce or
turn off autophagy (protein kinase A, mitogen-activated
protein kinase, and mammalian target of rapamycin [mTOR])
and (2) the morphologically detectable execution stage: initial
(dependent on the Unc-51 like autophagy activating kinase 1
complex), nucleation (dependent on BECLIN1-PtdIns3KC3-
ATG14L complex), extension and closure (dependent on
Autophagy protein 12 [Atg12]-Atg5 and light chain 3 [LC3]-
phosphatidylethanolamine conjugate system), and cycling
(dependent on Atg9).
An intact gut mucosa serves as an effective barrier between
the luminal bacterial microbiome as well as stool contents
and the systemic circulation.
The intestinal mucosal
barrier is mainly divided into biological barriers (intestinal
microorganisms), immune barriers, and mechanical barriers
(intestinal epithelial cells, gap junctions [GJs], and tight
These barriers maintain host health in
different ways, such as promoting the development and
maturity of the immune system, limiting the direct contact of
microorganisms with the intestinal mucosa, and reducing
the possibility of freeing them from the intestinal lumen. In
addition, adaptive immunity occurs through dendritic cells
(DCs) that continuously sample the bacteria in the lumen to
minimize the exposure of resident bacteria to systemic
immunity and to keep the immunity of the intestinal mucosa
“ignorant”to the microﬂora.
TJs between cells are gates
or barriers that prevent hydrophilic molecules between
adjacent cells from penetrating to the next cell. GJs channels
provide direct communication between cells and promote
physical adhesion between cells.
Intestine is one of the remote organs that are damaged in the
SAP process. It is not only a “victim”of SAP but also further
promotes the deterioration of the disease. Intestinal BT is
considered to be a central mechanism for the development of
Microcirculation disorders, ﬂuid loss in the third
space, hypovolemia, visceral vasoconstriction, and ische-
mia-reperfusion injury can occur in SAP, which can cause
intestinal reactive oxygen species (ROS). ROS in the
intestine and the storm of inﬂammatory factors are the
main reasons for the damage or obstacles to the mucosal
function of the intestinal mucosal barrier. Impaired
intestinal barrier function allows a large number of
intestinal bacteria and endotoxins to enter the blood and
lymph circulation and ﬁnally enter the entire internal
organs, triggering a “second attack,”and causing secondary
Correspondence to: Dr. Pei-Wu Li, Department of Emergency, Lanzhou University
Second Hospital, Lanzhou University, Lanzhou, Gansu 730030, China
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Chinese Medical Journal 2021;134(21)
Received: 09-11-2020 Edited by: Jing Ni
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pancreatic infection and sepsis.
Thus, it is very
meaningful to protect the intestinal damage during SAP.
Autophagy acts as a double-edged sword in the gut. The
various roles of autophagy in regulating homeostasis and
inﬂammation are extremely signiﬁcant in the context of the
intestinal mucosa, where most of the stressors are likely to
According to current researches, autophagy is
controlled by almost all types of pattern recognition
receptors and is also regulated by cytokines and receptors
of innate immunity and adaptive immunity. This means
that autophagy actively or passively participates in several
regulatory pathways, whether in chronic inﬂammation
of the intestine or SAP, which is why researchers are
particularly interested in its role in the intestinal muco-
At present, the main functions of autophagy in
intestinal mucosal homeostasis are as follows. (1) Elimi-
nate invading microorganisms and toxins. Autophagy can
be initiated during the process of host cells taking up
bacteria or macrophages actively engulﬁng bacteria. Other
studies reported that Atg5 contributed to antibiosis,
especially by increasing susceptibility to infection and
controlling dissemination of Listeria monocytogenes,
Mycobacterium tuberculosis, and Salmonella.
over, autophagy facilitates the binding of endogenous
antigens with major histocompatibility complex-II mole-
cules that are recognized by a cluster of differentiation 4
Autophagy can also sense viral RNA and DNA in
the cytoplasm through retinoic acid inducible gene I and
cyclic guanosine monophosphate-anti-microbial peptide
synthetase, thereby inhibiting the production of type I
interferon (IFN-I). The effect is to enhance the resistance of
the intestine to the virus.
(2) Protect the TJs and GJs
vesicle turnover of the intestine. Change in paracellular TJs
proteins is the main factor that increases intestinal
permeability in SAP.
Studies have shown that autophagy
can increase the TJs barrier function in Caco-2 intestinal
stem cells (IECs) by enhancing Claudin-2 (a cation-
selective pore-forming protein that plays an important
role in TJs and the intestinal barrier) protein’s lysosomal
Autophagy can also degrade other abnor-
mal TJ proteins to prevent the release of intestinal toxins
and pro-inﬂammatory cytokines.
It was recently shown
that defects in mitochondria and ER functions induce
intestinal permeability, promoting Escherichia coli inter-
nalization and transcytosis across the epithelium, and these
are counteracted by selective autophagy-mediated elimi-
nation of intracellular bacteria, which is so-called
However, uncontrolled autophagy can
destroy the structure of TJs proteins because of excessive
degradation, ultimately leading to apoptosis.
tain the secretion of Paneth cells (PC) and goblet cells. A
study showed that autophagy can maintain the secretory
function of PC.
Many autophagy-related genes, includ-
ing nucleotide-binding oligomerization domain 2, autoph-
agy-related protein16L1 (ATG16L1), leucine-rich repeat
kinase 2, and X-box binding protein 1, exert various effects
Moreover, autophagy controls the development
and function of goblet cells, and the ATG16L1
polymorphism alters goblet cell morphology.
agy deﬁciency (eg, Atg5,Atg7, and LC3) in goblet cells
reduced mucin production by affecting ROS generation
and calcium release from the ER.
(4) Balance the immune
response of the intestine. Macrophages, DCs, T cells, B
cells, and natural killer cells are the important components
of the intestinal mucosal immune system. A growing body
of evidence has emerged supporting the view that
autophagy mediates the crucial functions of triggering
and modulating innate and adaptive immune responses
such as antigen presentation, cytokines secretion, and
antimicrobial peptide production.
Autophagy can affect
the cytoskeleton or organization of DCs and can also
indirectly affect the activation of T cells. The reduction in
autophagy levels leads to reduced antigen sampling and
interleukin-10 (IL-10) secretion, increased DCs matura-
tion, and increased T-cell proliferation and production of
pro-inﬂammatory type of DCs, which will cause the
overgrowth of intestinal bacteria and increase the risk of
bacteria being freed from the intestinal cavity.
Regulate ROS and inﬂammation. Autophagy, especially
mitophagy, by eliminating damaged or superﬂuous
mitochondria, plays a major role in limiting ROS
accumulation. Mutations in the autophagy-related genes
or autophagy deﬁciency have an impact on ROS levels via
the impaired elimination of dysfunctional mitochondria in
several cell types.
Understanding the role of autophagy
and oxidative stress in SAP-induced intestinal mucosal
injury is critical for the development of new therapeutic
Excessive inﬂammation is also a key factor in
intestinal damage. High-mobility group box-1 (HMGB1),
the key inﬂammatory mediator, has a conﬁrmed associa-
tion with SAP. Studies observed that HMGB1 inhibition
ameliorated the disruption of TJs and autophagy exhibited
in SAP and adjusted oxidative stress to maintain the
Kim et al
ATG16L1-deﬁcient macrophages exhibited Toll/IL-1 re-
ceptor domain-containing adaptor or inducing IFN-b
dependent activation of the inﬂammasome, resulting in the
production of high amounts of the inﬂammatory cytokines
such as IL-1band IL-18. Thus, it has been demonstrated
that autophagy can modulate cytokine-induced pro-
grammed cell death in intestinal epithelium, limiting
(6) Produce antiﬁbrosis effects.
Autophagy mainly promotes the degradation of ﬁbroblast
collagen to exert antiﬁbrotic effects. When autophagy is
inhibited, it will aggravate ﬁbrosis. But the degree of
ﬁbrosis is related to the level of autophagy in different
organ environments. Other studies observed that autoph-
agy seems to inhibit intestinal ﬁbrosis by modulating the
function of the innate immune system and the mesenchy-
(7) Balance intestinal epithelial cells
(ISCs) regeneration. The critical role of autophagy in
maintaining ISC functions under different physiological
conditions has been discovered only in recent years. Recent
work has suggested that deletion of the Atg5 gene in
intestinal epithelial cells results in accumulation of
mitochondria and ROS in leucine-rich repeat-containing
G protein-coupled receptor 5 (Lgr5) ISCs and impaired
their capacity to induce intestinal regeneration following
irradiation. Subsequently, researchers show that loss of
Atg7 induces the p53-mediated apoptosis of Lgr5
Wu et al
also pointed out that intrinsic
autophagy supported ISCs maintenance and promoted
the recovery of IECs after radiation-induced injuries. It is
suggested that autophagy may play an important role in
inducing the self-renewal of ISCs in intestines.
Chinese Medical Journal 2021;134(21) www.cmj.org
In view of the importance of autophagy in various diseases,
researchers have great interest in developing potential
treatments to regulate this pathway. The disaccharide
trehalose, which increases the efﬁciency of autophagy,
reduces pancreatic injury and AP severity in animal models
and holds promise as a potential therapeutic agent in AP.
Chloroquine (CQ) and its derivatives have been widely
used to inhibit autophagy in vitro with the beneﬁtof
relatively low toxicity. In the dextran sulfate sodium-
induced murine colitis model, CQ administration signiﬁ-
cantly retarded colon length shortening, inﬂammatory cell
inﬁltration, tissue damage, and body weight loss.
Similarly, it was reported that glutamine enhances
autophagy in IECs both under basal and stress-induced
conditions by regulating mTOR and mitogen-activated
protein kinase/p38 pathways, thus limiting stress-induced
In addition, recent studies suggested
that bone marrow-derived mesenchymal stem cells sup-
pressed autophagy in multiple organs (including the
pancreas, small intestine, and lungs) to protect against
SAP-induced multiple-organ injury.
In the future, with
the deepening of related research, we believe that more
targeted drugs will be developed.
Patients who survive the SAP process often have some
sequelae, such as diabetes, pancreatic exocrine insufﬁcien-
cy, and chronic pancreatitis. At the same time, the high
incidence of AP also highlights the urgent need for new
treatment methods. The role of autophagy in various
diseases has shown exciting results and has become a new
research ﬁeld. However, the mechanism of autophagy in
intestinal homeostasis and the potential effects during SAP
still require more researches. We hope this review provide a
comprehensive perspective revealing the role of autophagy
modulators in diseases and opening up a new world for the
treatment of SAP.
This work is supported by a grant from the Lanzhou Talent
Innovation and Entrepreneurship Project (No. 2016-RC-52).
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How to cite this article: Li HY, Lin YJ, Zhang L, Zhao J, Xiao DY, Li PW.
Autophagy in intestinal injury caused by severe acute pancreatitis. Chin
Med J 2021;134:2547–2549. doi: 10.1097/CM9.0000000000001594
Chinese Medical Journal 2021;134(21) www.cmj.org