Inflammatory Bowel Diseases, 2022, 28, 639–648

https://doi.org/10.1093/ibd/izab277
Advance access publication 6 December 2021
Review Article - Basic Science

Excessive Apoptosis in Ulcerative Colitis: Crosstalk

Between Apoptosis, ROS, ER Stress, and Intestinal
Homeostasis
Yue Wan, MBBS, Lei Yang, MBBS, Shu Jiang, PhD, , Dawei Qian, MBBS, and Jinao Duan, PhD#
From the Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine,

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138 Xianlin Road, Nanjing 210023, PR China
#
Co-author.
Address correspondence to: Dr. Shu Jiang, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of
Chinese Medicine, 138 Xianlin Road, Nanjing 210023, PR China (jiangshu2020@126.com).

Ulcerative colitis (UC), an etiologically complicated and relapsing gastrointestinal disease, is characterized by the damage of mucosal epithelium
and destruction of the intestinal homeostasis, which has caused a huge social and economic burden on the health system all over the world.
Its pathogenesis is multifactorial, including environmental factors, genetic susceptibility, epithelial barrier defect, symbiotic flora imbalance, and
dysregulated immune response. Thus far, although immune cells have become the focus of most research, it is increasingly clear that intestinal
epithelial cells play an important role in the pathogenesis and progression of UC. Notably, apoptosis is a vital catabolic process in cells, which
is crucial to maintain the stability of intestinal environment and regulate intestinal ecology. In this review, the mechanism of apoptosis induced
by reactive oxygen species and endoplasmic reticulum stress, as well as excessive apoptosis in intestinal epithelial dysfunction and gut micro-
biology imbalance are systematically and comprehensively summarized. Further understanding the role of apoptosis in the pathogenesis of UC
may provide a novel strategy for its therapy in clinical practices and the development of new drugs.

Lay Summary
Recently, the prevalence of ulcerative colitis (UC) has increased, but the pathogenesis of UC remains poorly understood. A better understanding
of the role of apoptosis in the pathogenesis of UC may provide a promising prospect for UC treatment.
Key Words: apoptosis, ulcerative colitis, intestinal homeostasis, endoplasmic reticulum stress, reactive oxygen species

Introduction translocation, leading to chronic gastrointestinal disorders.5

Ulcerative colitis (UC), a complex inflammatory disorder of Data from various studies demonstrate that the structure and
the gastrointestinal tract with a chronic relapsing course that function of colonic epithelium are abnormal and apoptosis of
generally involving the ileum, rectum, and colon, is charac- IECs in colon tissue is overactivated in UC patients.6 Thus, it
terized by aggravating uncontrolled intestinal inflammation can be speculated that the disorder of apoptosis plays an in-
that leads to the deterioration of the life quality of patients dispensable role in the onset and progression of UC. Beyond
and requires long-term medical and/or surgical intervention.1 apoptosis, the other programmed and nonprogrammed cell
Ulcerative colitis is one of the main forms of inflammatory death mechanisms, including anoikis, pyroptosis, necroptosis,
bowel disease (IBD), with increasing incidence and prevalence ferroptosis, and necrosis, also play a key role in the pathogen-
worldwide. However, the molecular basis and pathogenesis esis of acute and chronic intestinal injury.7 However, because
of UC have not been fully clarified, but they are considered the role of these different cell death pathways in UC requires
to be as the result of complicated interactions between en- further investigation, they will not be discussed here in detail.
vironmental factors, genetic predisposition, epithelial barrier In the following sections, the latest important findings on the
defect, commensal microflora dysbiosis, and dysregulated im- relationship between apoptosis and UC are reviewed.
mune response.2 It is highlighted that the intestinal barrier
dysfunction may be a crucial player in the development of
UC.3 Indeed, the intestinal epithelial barrier defines a physical Apoptosis
boundary between the inside of body and environment. The The term apoptosis, a type of programmed cell death
maintenance of this boundary depends on the fine-tuned regu- regulated by a kind of complex signaling pathways, was
lation of epithelial cell proliferation and death.4 The growing introduced by Kerr in 1972.8 Thus far, a series of the dis-
evidence shows that increased intestinal permeability is highly tinct morphological changes of apoptosis are described,
correlated with the death of dysregulated intestinal epithe- including chromatin condensation, shrinkage of cells, mem-
lial cells (IECs). The inappropriate apoptosis promotes in- brane surface blebbing, oligonucleosomal DNA fragmen-
testinal damage, intestinal barrier dysfunction, and bacterial tation, and ultimately the breakdown of cells into a list of

Received for publication: August 28, 2021. Editorial Decision: September 14, 2021
© The Author(s) 2021. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For permissions, please e-mail:
journals.permissions@oup.com
640 Wan et al

membrane-bound fragments (called apoptotic bodies).8,9 cytochrome c (Cyt-C) and subsequently binds to the cyto-
The apoptotic bodies are phagocytosed by the neighboring solic protein apoptotic protease-activating factor 1 (APAF1).
phagocytic cells through efferocytosis and therefore do not Then, APAF1 and caspase-9 can form a multiprotein complex
cause surrounding inflammatory responses. Hence, apoptosis (called apoptosome), which further activates caspase-9.12,13
is generally considered as an immunologically silent form of Thus, the downstream apoptosis executing molecules such
cell death.10 However, the latest research has shown that as caspase-3, -6, and -7 are activated to induce apoptosis.
apoptotic cells undergo secondary necrosis when the amount The hyperpermeability of the mitochondrial outer mem-
of apoptotic cells exceeds the capacity of macrophages, brane caused by pro-apoptotic Bcl-2-related proteins is a
thereby spilling intracellular contents into the surrounding main factor in this process. Additionally, the death receptor
tissue.11 It may activate macrophages to produce a large pathway requires activation of death receptors (such as
number of inflammatory cytokines such as tumor necrosis APO3, Fas, TNFR, and DR4/DR5), which are triggered by
factor-α (TNF-α) and interferon-α (IFN-α), which promote APO3L, FasL, TNF-α and TNF-related apoptosis-inducing
autoimmune diseases (Figure 1A). ligand.14 The ligand-receptor interaction in which receptor
There are 3 main regulatory processes of apoptosis: the interacting protein kinase 1 (RIPK1) acts as a scaffold protein

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mitochondria-driven pathway, the death receptor pathway, can regulate destruction complex through the recruitment
and the endoplasmic reticulum (ER) stress pathway (Figure of intracellular adaptation proteins known as Fas associ-
2). The mitochondria-driven pathway of apoptosis requires ated with death domain (FADD) and/or TNF-α receptor-
the induction of mitochondrial outer membrane permeabil- associated death domain (TRADD). Then, the destruction
ization, which mediates the discharge of pro-apoptotic factor complex initiates the catalytic activity of caspase-8 and -10

Figure 1. Excessive apoptosis caused by reactive oxygen species and endoplasmic reticulum stress. A, The morphological changes in the progression
of normal cells to apoptosis cells include cell blebbing and shrinkage, nuclear fragmentation, and formation of small vesicles known as apoptotic
bodies. These apoptotic bodies are then engulfed by phagocytes (such as neutrophils, macrophages and dendritic cells), for final degradation. When
the amount of apoptotic cells exceeds the capacity of macrophages, apoptotic cells undergo secondary necrosis, which may lead to inflammation.
B, O2 is reduced to O2•−, which can be either reduced to H2O2 by superoxide dismutase (SOD) or converted to potent oxidant ONOO− by NO•. H2O2
can undergo the Fenton reaction and convert to HO•. Also, H2O2 is reduced to H2O by CAT and GSH-Px system. In the presence of Cl−, H2O2 can be
converted to HOCl and advanced oxidation protein products (AOPPs) by MPO. The increase of ROS induces the opening of mitochondrial permeability
transition pore (PTP), resulting in apoptosis. C, PERK can stimulate the translation of ATF4 by phosphorylating eukaryotic initiation factor 2α (eIF2α).
ATF4 then promotes the transcription of CHOP to upregulate the pro-apoptotic proteins Bim and downregulate the anti-apoptotic protein Bcl-2, leading
to apoptosis. Another apoptosis pathway is the IRE1α-TRAF2-ASK1 complex, which can be activated by ROS, and then phosphorylates JNK to provoke
the apoptosis signaling pathway.
Excessive Apoptosis in Ulcerative Colitis 641

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Figure 2. The intrinsic and extrinsic pathways of apoptosis. The extrinsic pathway is initiated at the cell membrane when there is engagement of
death receptors with their cognate ligands. The intrinsic pathways (including changes in mitochondrial outer membrane permeability and endoplasmic
reticulum stress) are related to the activation of Bcl-2 family proteins. The previously mentioned pathways can cause the activation of the caspase
cascade and then induces apoptosis.

(known as the pivotal protease mediators of extrinsic apop- the densities and distribution of apoptotic cells, and the re-
totic signaling pathway), which can activate caspase-3, -6 sults reported that the ratio of FasL-expressing cells in the
and -7 to promote apoptosis.15 Finally, apoptosis can also colonic lamina propria was higher than that in controls,
be triggered via ER stress pathway. Endoplasmic reticulum which might indicate that apoptosis mediated by the death
stress causes the perturbations of Ca2+ homeostasis, which receptor pathway was overactivated in UC patients.20 The
leads to the activation of caspase-12 and promotes apoptosis latest studies suggest that the mice with IEC-specific FADD
by further activating caspase-9; however, it can promote the or caspase-8 deficiency are more susceptible to colitis.21 Based
expression of pro-apoptotic Bcl-2 family proteins (including on these previously mentioned evidences, it can be speculated
Bax and Bak) to induce apoptosis.16 Crosstalk between 3 that the death-receptor-induced apoptosis is closely related to
pathways exists, where caspase-8, Jun-N-terminal kinase the occurrence of UC. Remarkably, RIPK1, called “receptor
(JNK), and C/EBP homologous protein (CHOP) can acti- interacting protein,” also plays an indispensable role in sup-
vate the Bcl-2 family proteins to trigger mitochondria-driven pressing caspase-8-dependent apoptosis. The mouse model
apoptosis, amplifying the cell death cycle.17 It is observed specifically lacking RIPK1 in IECs can develop severe intes-
that the expressions of apoptotic caspase family members tinal inflammation related to apoptosis, resulting in early
including the initiator caspases (caspase-8, -9, and -10) and postbirth death.22 Further, it is demonstrated that the function
the effector caspases (caspase-3, -6, and -7) are significantly of mitochondria in IECs of UC patients and mice with colitis
increased compared with the normal group in the colon is markedly changed.23 Indeed, mitochondria are recognized
tissues of the experimental colitis mice and UC patients.18 as a major role in apoptosis, adenosine triphosphat (ATP)
This indicates that apoptosis is overactivated in the devel- production, and reactive oxygen species (ROS) generation.
opment of UC. However, when the caspase family members Mitochondrial dysfunction directly induces the dysfunctional
are inhibited, UC can be greatly ameliorated. Artesunate, one apoptosis of ICEs, which leads to the disrupted intestinal epi-
water-soluble semisynthetic derivative of artemisinin, has a thelial function and ultimately exacerbates the severity of UC
significantly protective effect on UC through inhibiting the symptoms.24 Nonetheless, mitochondrial damage is often ac-
expression of cleaved-caspase-3 in colon tissue, which can companied by ER stress, and the latter can promote apoptosis
suppress overactive apoptosis and improve the integrity of again, triggering repeated episodes of intestinal inflamma-
intestinal barrier.19 tion.25 Recently, it is reported that apoptosis of the colon
As early as 2005, colon specimens from inflamed and tissue of UC patients is raised, and a lot of interleukin-8 (IL-
noninflamed mucosa of UC patients were used to analyze 8) and TNF-α are released, probably due to the dysregulated
642 Wan et al

ER stress pathway.26 In the following contents, the crosstalk kinase and p38 further activate and/or repress their down-
between apoptosis, mitochondrial dysfunction and ER stress stream pro- and/or anti-apoptotic molecules, thus inducing
in the development of UC will be further described and dis- apoptosis (Figure 1B).38 In turn, apoptosis-related genes
cussed in details. such as bcl-2 and p53 also effect the level of ROS through
the mitochondrial respiratory chain, which may exaggerate
OS, forming a vicious cycle.39,40 It is indicated in modern
Relationship of Apoptosis With ROS and ER studies that NF-κB and ASK1/JNK/p38 signaling pathways
Stress are strongly activated in the experimental colitis models.41
Interaction of mitochondrial dysfunction, ROS, and apop-
Apoptosis and ROS
tosis affects the development of UC.
Mitochondria, as the main organelle of the intrinsic apop- Reactive oxygen species has been commonly known as the
totic pathway, are also the primary regulators of cellular me- pathogenesis of UC. At present, antioxidants and some nat-
tabolism and redox balance, which play a vital role in the ural products are utilized to treat UC. For example, a polysac-
pathogenesis and progression of diseases.27 Mitochondrial charide (called EP-1) from the cultured mycelium of Hericium
dysfunction caused by structural and metabolic damage is

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erinaceus could relieve UC by improving mitochondrial func-
particularly prominent in the oxidative stress (OS)-related tion, counteracting the overactivation of ROS, and reducing
diseases, especially in UC.28 The increased OS can impair the apoptosis.42 An in-depth understanding of the interrelation-
mitochondrial function and homeostasis, leading to the ex- ships among mitochondrial dysfunction, apoptosis, and ROS
cessive generation of mitochondrial ROS.29 When cells are ex- can provide preclinical evidences and molecular basis for
posed to ROS, apoptosis seems to be the major mode of cell developing new therapies in UC.
death. Clearly, mitochondrial dysfunction, ROS, and apop-
tosis are the interrelated events.
Under physiological conditions, ROS are the by-products Apoptosis and ER Stress
of normal cell metabolism, such as superoxide anions (O2•−), Apoptosis, unfolded protein response (UPR), and ER stress are
hydrogen peroxides (H2O2), hypochlorous acid (HOCl), and interconnected at multiple levels. The endoplasmic reticulum
hydroxyl free radicals (OH•); whereas superoxide dismutase is the main site for folding, post-translational modifications,
(SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) and transportation of secreted and membrane proteins; thus
are the major antioxidant enzymes. Superoxide anions can it is responsible for maintaining protein homeostasis in all
be converted to more stable and diffusible H2O2 by SOD- eukaryotic cells.43 When the homeostasis balance is disrupted
mediated catalysis or can quickly react with NO to form by environmental factors (smoking), genetic factors (gene mu-
the highly reactive peroxynitrite (ONOO−). In addition, tations), and a variety of pathological factors (such as calcium
H2O2 is decomposed to water and oxygen or can be trans- depletion, acidosis, lipid overload hyperglycemia, or infec-
formed into HOCl (100 times more toxic than H2O2) by the tion), ER stress can be induced in the ER with a large number
antioxidant enzyme.30 Hydrogen peroxides can also react of unfolded and misfolded proteins being formed, leading to
nonenzymatically with O2•− to produce OH• which is the the activation of UPR.44 Specifically, triggers of the signaling
so-called Fenton reaction in the presence of Fe2+ (Figure 1B). response to activate UPR include cells with highly secretory
These compounds induce cell differentiation and apoptosis, activity (such as Paneth or goblet cells), and hormones (such
thus contributing to the natural aging process.31 In the OS as epidermal growth factors and vascular endothelial growth
status, accumulated ROS can trigger protein dysfunction, factors).45 Likewise, cytokines can aggravate or reduce ER
lipid peroxidation, and DNA damage, resulting in excessive stress and protein generation in the secretory cells. For in-
apoptosis.32 The histological feature of UC is severe infil- stance, the stimulation of the inflammatory triad (IL-6, IL-1β,
tration in the mucosa. Multiple experimental studies dem- and TNF-α) provokes a phase of elevated ER stress; con-
onstrated that the inflamed colon cells of UC patients and versely, IL-10 can directly act on goblet cells in the intestine to
mice with colitis produced more ROS than the controls, suppress protein misfolding and ER stress, which restore the
including SOD, H2O2, and HOCl.33 Further, a large amount mucosal barrier function.46 STING, an ER resident adaptor
of superoxide is presented by histopathological analysis of protein that binds to cyclic dinucleotides, is the prime inducer
neutrophils and macrophages in the intestinal mucosa of UC of type 1 IFN and specifically participates in antiviral and
patients.34 The formation of these reactive substances is usu- antibacterial immunity. Recently, it has been found that ex-
ally identified in the early stage of the disease process and cessive STING signaling can disrupt calcium homeostasis and
closely related to the severity of UC. And with increased for- render T cells hyperresponsive to ER stress, which may cause
mation of ROS, the levels of endogenous antioxidants (such prolonged activation of UPR and ER stress.47 However, the
as glutathione and Cu/Zn-SOD) in the colonic mucosa of UC long-term activation of UPR is associated with many path-
animals are in decline.35 Remarkably, these products of lipid ologies, including metabolic diseases (eg, type 2 diabetes),
peroxidation can interact with the membrane receptors and autoimmune disease (eg, UC), and cancer. Notably, UPR con-
transcription factors to activate signaling for intrinsic apop- stitutes a highly conserved and intricately regulated group
tosis.36 Importantly, the accumulated ROS can be regarded of pathways which aim to initially rebuild homeostasis by
as chemical messengers to trigger a series of signaling path- stimulating genes involved in protein folding and antioxidant
ways including NF-κB and apoptosis signal-regulating kinase mechanisms.45,48 Over time, activated UPR involves a series
1 (ASK1)/JNK/p38, which affect cell proliferation, differen- of cellular signaling pathways that largely determine the state
tiation, and apoptosis. Reactive oxygen species are the most and fate of cells (like apoptosis).49 The CHOP pathway plays
effective activators of ASK1, which can lead to the activation a major role in apoptosis induced by ER stress. Research
of downstream effector mitogen-activated protein kinases shows that CHOP-deficient cells are resistant to ER stress–in-
(MAPKs) (such as JNK and p38 MAPK).37 Jun-N-terminal duced apoptosis.50 Recently, the upstream and downstream
Excessive Apoptosis in Ulcerative Colitis 643

pathways of apoptosis such as protein kinase RNA-like endo- Interplay Among ROS, ER Stress, and Apoptosis
plasmic reticulum kinase/ activating transcription factor 4/ There is a considerable interaction among ROS, ER stress,
C/EBP homologous protein (PERK/ATF4/CHOP), inositol and apoptosis. Numerous studies in the past decade empha-
requiring protein 1α/ apoptosis signal-regulating kinase 1 / size that ROS and ER stress as closely linked events play a
Jun-N-terminal kinase (IRE1α/ASK1/JNK) caused by CHOP significant role in cell homeostasis and apoptosis. A unique
have attracted more attention of researchers. Specifically, feature of ER is its luminal redox tension. The interior of ER
unfolded proteins in ER stimulate the oligomerization and mimics the relatively oxidized extracellular environment and
autophosphorylation of PERK, and then phosphorylate eu- promotes the cross-linking of sulfhydryl groups to form di-
karyotic translation initiation factor 2α (eIF2α). The phos- sulfides that cannot survive in the reduced cytoplasm.66 The
phorylated eIF2α promotes the transcription of ATF4, formation of disulfide bonds in the ER lumen is more suscep-
which induces the expression of CHOP.51,52 Under prolonged tible to the changes in the redox balance, where exogenous
stress, CHOP initiates the apoptotic response by activating oxidants including peroxides, metal ions, ROS producers,
pro-apoptotic BH3 domain-only proteins such as Bim and and lipid oxidation products can disturb protein folding and
decreasing Bcl-2 anti-apoptotic protein. Additionally, CHOP cause ER stress.67 The main oxidation product of cholesterol,

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is able to mediate apoptosis signaling through caspase-12 7-ketocholesterol, triggers the overproduction of Nox4 and
cascade.53 Unfolded proteins in ER also motivate the oligo- ROS and upregulates gene encoding ER chaperones (including
merization and autophosphorylation of IRE1α. The activated Bip and GRP94) to induce ER stress in HT-29 cells.68 However,
IRE1α forms a complex with TNF receptor-associated factor in the stressed ER, it is confirmed that both ER and mitochon-
2 (TRAF2) to induce the activation of ASK1, which can then dria can cause a rise in ROS levels. The endoplasmic reticulum
phosphorylate JNK. The activation of JNK not only partici- is the site where Ca2+ is stored and regulates the intracellular
pates in the modulation of CHOP but also directly regulates calcium homeostasis. During ER stress, calcium storage is de-
apoptosis-related genes, leading to apoptosis (Figure 1C).54,55 pleted due to the release from the ER. Meanwhile, ER calcium
Mechanistically, it is proved that ER stress and excessive moves to mitochondria, enhances metabolism, and increases
apoptosis induced by ER stress play a significant role in the the generation of mitochondrial ROS signaling, which cycles
occurrence and development of UC. Dextran sulfate sodium back to ER, leading to further release of Ca2+. The release of
(DSS)-induced UC model in mice was used to confirm this con- Ca2+ from ER and production of mitochondrial ROS create
clusion. It is indicated that DSS exposure caused excessive ER a vicious circle, which destroys cellular homeostasis and in-
stress, evidenced by the activation of ER stress sensors PERK, duces apoptosis.69 Besides, the dysregulated formation and
IRE1α, and their respective signaling pathways. Meanwhile, breakage of disulfide bonds may lead to the accumulation
a significantly increased expression of GRP78 and CHOP, fol- of ROS under persistent stress conditions. Notably, the tran-
lowed by the upregulation of caspase-12 and Bim, as well scription factor CHOP also controls the generation of ROS
as the reduction of the Bcl-2/Bax ratio, can induce increased via the promotion of endoplasmic reticulum oxidoreductin
apoptosis and disturbed intestinal homeostasis.56 1α (ERO1α) signaling, which can promote a hyperoxidizing
Genome-wide association studies have identified various environment and lead to apoptosis.70 Thus, the generation of
susceptibility loci for CD and UC in the past few years, the ROS can be upstream and downstream of UPR, suggesting a
latest of which links 241 susceptibility loci to IBD.57 After strong crosstalk between ROS and ER stress. And ROS and
further screening, ER-related genes closely related to the de- ER stress strengthen each other in a positive feed-forward
velopment of UC are identified, including orosmucoid-like 3 loop, which interferes with cell function and activates pro-
(ORMDL3), anterior gradient 2 (AGR2), and X-box binding apoptotic signaling. Overall, it is also the interaction among
protein-1 (XBP1).58–60 Orosmucoid-like 3 can promote UPR by ROS, ER stress, and apoptosis that leads to repeated attacks
altering ER-mediated Ca2+ homeostasis, which may be a cause and deterioration of UC.
of UC.58,61 The gene mutation testing is performed on UC pa-
tients, and it has been found that AGR2 is downregulated in
UC patients compared with normal controls.62 Furthermore, Apoptosis and Intestinal Homeostasis
the inducible AGR2-/- mice are possible to develop terminal
colitis, which is triggered by enhanced apoptosis and UPR Apoptosis and Intestinal Barrier Function
activation.63 The transcription factor XBP1, a crucial com- The complicated interaction between the microflora, intes-
ponent of ER stress response, is linked to the activation of tinal epithelial barrier, and host immune system maintains
JNK in ER stress signaling pathways. The specific deletion of intestinal homeostasis. Diverse regulatory mechanisms co-
XBP1 in IECs can lead to increased apoptosis and destroy the operate to protect intestinal health, and the dysregulation
intestinal epithelial barrier, thus enhancing the susceptibility of these pathways can result in chronic inflammatory dis-
to UC.60,64 For these susceptibility loci, numerous potential orders.71 However, the intestinal epithelium can form a
therapeutic agents for UC are continuously being discovered. physical and protective barrier to resist harmful luminal
Lately, it has been reported that HLJ2 (an XBP1 agonist) can microenvironments while providing selective permeability
be a drug candidate for the treatment of UC because of its for the absorption of nutrients. The intestinal epithelium is
ability to inhibit continuous activation of ER stress and pro- covered by a single-cell layer composed of different subtypes
tect the intestinal mucosa.65 of the specialized IECs including enterocytes, enteroendocrine
In brief, prolonged ER stress and impaired UPR signaling cells, goblet cells, Paneth cells, and tuft cells, all of which are
may cause the progression of UC by inducing excessive apop- differentiated from common epithelial stem cells.72 The intes-
tosis of ICEs. By targeting related proteins in the interaction tinal barrier is formed by an endothelial cell network, and the
network of ER stress and apoptosis, novel pharmacological cell-cell interactions between neighboring endothelial cells are
methods can be developed to enhance intestinal homeostasis composed of tight junctions (TJs), adherens junctions (AJs),
and become advanced strategies for the therapy of UC. and gap junctions.73
644 Wan et al

Among these junctions, TJs represent the appositions apoptosis.81 The overexpression of claudin-4 and claudin-15
of so-called “kissing points” between the side membranes can promote apoptosis in vitro.82,83 Recently, it has been re-
of adjacent cells, forming a continuous seal. These TJs are vealed that some natural herbal medicines can attenuate UC
important for maintaining intestinal barrier homeostasis, by regulating the expression of claudins in animal studies
whereas AJs form a stable mechanical connection between and human clinical trials.78,84 Intriguingly, it is implicated
neighboring cells, and gap junctions mainly provide inter- that E-cadherin, a transmembrane glycoprotein and principle
cellular communication.74 Especially TJs, also known as component of AJ, may significantly contribute to functional
zonulae occludentes, are important parts in the construction defects of the gut barrier in the process of UC. According
of a constitutive barrier within epithelial cells. The complex to reports, the expression of E-cadherin in tissue biopsies
TJ protein network is composed of transmembrane proteins, of UC is reduced.85 Additionally, the specific knockout of
including claudins, occludins, junctional adhesion molecule E-cadherin in the murine embryonic intestinal epithelium can
(JAM), and scaffolding proteins that anchor membrane com- cause a serious disruption of intestinal morphogenesis and
ponents to the actin cytoskeleton (ZO isoforms; Figure 3).75 death within 24 hours.86
It is well-known to all that gastrointestinal-specific claudins In a future study, the interaction between apoptosis and

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are considered to be the main tight junction-forming pro- intestinal barrier function and how they affect the occurrence
teins.76 Claudins, a multigene transmembrane protein family of UC should be further investigated, and the understanding
with at least 27 members, are mainly located in the intestinal of their regulatory mechanism could be helpful to design in-
epithelia. Claudins are the vital proteins to ensure the perme- novative treatment strategies.
ability of TJs. Their primary roles in TJs are to regulate the
selective permeation of specific and small ions between indi-
vidual epithelial cells.77 The differential expression of various Balance Between Intestinal Epithelial Proliferation,
members of the claudin family is proved to be the cause of Differentiation, and Apoptosis
the impaired epithelial barrier function of UC. In UC, an in- Generally, the intestinal mucosal epithelium is organized
crease in the expression of claudin-1, -2, and -18 in the in- into millions of crypt-villus units and is characterized by a
testinal epithelium was observed, whereas the expression of high cellular turnover rate, leading to the renewal of entire
claudin-3, -4, -5, -7, and -8 was downregulated.78–80 Previous intestinal epithelium every 3-5 days.87 Inside the crypt, con-
studies indicate that the knockdown of claudin-1 can en- tinuously dividing stem cells generate progenitor cells, which
hance the susceptibility of MCF-7 cell line to TNF-α-induced proliferate rapidly and eventually transform into mature

Figure 3. Components of the intestinal epithelial cell barrier. In the intestinal epithelial cell barrier, we can find different types of cells (enterocytes,
goblet cells, Paneth cells, etc.). Enterocytes form the physical barrier against the harmful luminal microenvironment, while providing selective
permeability for absorption of nutrients; goblet cells secrete mucus to form an additional protective intestinal layer; Paneth cells secrete antimicrobial
peptides (AMPs) to help maintain the gastrointestinal barrier. Tight junctions between epithelial cells prevent harmful molecules from passing through
the intercellular space. The intestinal epithelium is disrupted owing to apoptotic foci and an altered expression of tight junction proteins, thereby
allowing commensal or environmental microbes to invade the tissue, activating immune cells, and cytokines expressed by immune cells (for example,
TNF-α and IFN-γ) could trigger additional epithelial cell apoptosis.
Excessive Apoptosis in Ulcerative Colitis 645

IECs. Then, these cells are pushed out of the crypt through on human HT-29/B6 colon cells, it has been found that oral
the next generation of epithelial cells to reach the top of the and fecal C. concisus strains can damage gut barrier func-
villus, where they finally undergo apoptosis and shed into tion by inducing the apoptosis of IECs.98 Additionally, some
intestinal lumen.88 Under physiological conditions, prolifer- studies confirm that samples from UC patients and healthy
ation is restricted to the cells close to basement membrane, controls contain the same level of sulphate reducing bacteria
whereas apoptosis mainly occurs in superficial cells lining (SRB), but there are significant differences in the structure of
the lumen. But under pathological conditions, the normal SRB community between the 2 groups. The SRB combination
sequence of cell proliferation, differentiation, and apop- which is obtained from biopsy tissues of patients with UC can
tosis signaling along the crypt-villus axis may be disrupted.89 induce the apoptosis of human intestinal epithelial cell lines.99
Modern studies indicate that abnormal apoptosis is one of the Intriguingly, some microorganisms can play a protective role
major causes that accelerates UC. The differentiated colonic in the intestine. Probiotics are proven to improve intestinal
epithelial cells die prematurely through apoptosis, and the mucosa barrier function by regulating the apoptosis and dif-
excessive proliferation of immature crypt cells can damage ferentiation of cells in UC.100 The probiotic Lactobacillus
the intestinal epithelial barrier, which leads to the intestinal rhamnosus GG can prevent TNF-induced apoptosis of ICEs

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hyperpermeability and allows commensal or environmental in human and mice to regulate the intestinal barrier func-
microbes to invade the tissue. The recognization of micro- tion.101 Lactobacillus plantarum JM113 is able to ameliorate
bial pathogen-associated molecular patterns by pattern rec- deoxynivalenol-induced apoptosis and intestinal inflamma-
ognition receptors on immune cells triggers the production tion by adjusting the composition of bacterial community and
of cytokines (eg, TNF-α and IFN-γ), resulting in inflamma- is expected to be used as a potential candidate for the treat-
tion.90,91 Both TNF-α and IFN-γ further induce additional ment of UC.102 Furthermore, numerous biologically active
apoptosis (Figure 3), and this vicious feedback eventually re- substances (such as intestinal short-chain fatty acids, secreted
sults in the clinical signs and symptoms of UC. Furthermore, proteins, and bacteriocins) are released by probiotics and play
other cells such as enteroendocrine cells release various an indispensable role in treating UC-associated inflamma-
humora and paracrine mediators (eg, serotonin, vasoactive tion.103 For example, the efficacy of butyric acid in protecting
intestinal peptide, somatostatin, and ghrelin), which can in- the integrity of intestinal epithelium and reducing intestinal
duce diverse immunomodulatory effects, including cellular inflammation has been verified in studies.104
recruitment, activation, phagocytosis, antigen presentation, Conversely, apoptosis also regulates the homeostasis
and cytokine secretion. Meanwhile, tuft cells play a crucial of intestinal flora. In an article recently published by the
role in the initiation of type 2 immune response, which is usu- Ravichandran lab, it is implicated that the mammalian nu-
ally activated during the protozoa parasite infections after the trients (such as small molecules and metabolites) released
destruction of intestine.3 Recently, it has been confirmed that from apoptotic intestinal epithelial cells boost the growth
G protein-coupled estrogen receptor (GPER) activation pre- of multiple Enterobacteriaceae. Notably, Enterobacteriaceae
vents DSS-induced acute colitis by inhibiting the crypt cell can directly induce cell death and intestinal inflammation.105
apoptosis and protecting proliferation of crypt cells.92 Similar Besides, the mucosal immune system maintains homeostatic
results are also found in another study: knockdown of human balance of the intestinal microflora by producing immune
antigen R (HuR) can alleviate TNBS-induced UC in rats by molecules (like secretory immunoglobulin A), the production
reducing excessive apoptosis of the colon tissues and rebalan- of which is mediated by IECs.106 Excessive apoptosis of IECs
cing the proliferation and apoptosis of ICEs.93 causes the disruption of mucosal immune system, which in
turn triggers intestinal dysbacteriosis, allowing commensal
or environmental microbes to invade the tissues and produce
Apoptosis and Intestinal Microbiota
persistent inflammation.107 In the latest study, it is reported
Currently, there is increasing appreciation that the intestinal that palmatine can assist UC management by reducing endo-
microbiome, a complex ecosystem composed of bacterial thelial cell apoptosis, improving mucosal integrity and rebal-
species living in the intestinal lumen, plays a vital role not ancing the microbiota community.108 Thus, the regulation of
only in maintaining general health but also in mediating the apoptosis and intestinal flora can ameliorate the pathological
pathogenesis of critical diseases.94 The intestinal microflora symptoms of UC.
is an environmental factor that determines the renewal and
remodeling of intestinal epithelium. Its change may cause the
dysfunction of apoptosis, thereby destroying the integrity of
the intestinal barrier and promoting the transport of harmful
Conclusion and Future Perspectives
metabolites that can induce the inflammatory response and In the past decade, research on the cell death in the intes-
lead to the progression of UC.95 Conversely, apoptosis also tine has substantially enhanced our understanding of the
plays a considerable role in regulating the composition of pathogenesis of UC. Here, we focus on the relationship of
intestinal flora, and dysfunctional apoptosis may affect gut dysfunctional apoptosis with ROS release, ER homeostasis,
dysbiosis. intestinal homeostasis, and the composition of gut microbiota.
The role of bacteria in the progression of UC has been Remarkably, it is noted that the regulation of dysfunctional
proven by quite a few clinical studies. Campylobacter apoptosis can effectively ameliorate UC. However, most of
concisus (C. concisus), firstly isolated from human oral cavity, our present understandings on apoptosis of IECs in UC come
is defined as an emerging human intestinal pathogen.96 It is from animal models, and future investigations should be de-
elucidated that C. concisus infection of the gastrointestinal voted to translating the experimental findings into human
tract can be closely associated with prolonged diarrhea and models. Therefore, strategies should be explored to regulate
UC.97 By investigating the pathophysiology of C. concisus specific apoptosis with no toxic effects to establish a safe and
and the effects of C. concisus strains from different sources effective therapy for UC treatment. Recently, several studies
646 Wan et al

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Funding tered expression of FasL and perforin cytotoxic pathways. Int J

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Innovation Center of Chinese Medicinal Resources
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