The Role of The Intestinal Epithelium in The Weep
The Role of The Intestinal Epithelium in The Weep
The Role of The Intestinal Epithelium in The Weep
Review
The Role of the Intestinal Epithelium in the “Weep and Sweep”
Response during Gastro—Intestinal Helminth Infections
Piotr Baska
˛ 1, * and Luke James Norbury 2
Simple Summary: The immune system actively combats intruders such as bacteria, viruses, fungi,
and protozoan and metazoan parasites using leukocytes. During an infection white blood cells
are activated to internalize bacteria or viruses and release a number of molecules to kill pathogens.
Unfortunately, those mechanisms are ineffective against larger intruders like helminths, which are
too large to be killed by a single immune cell. To eliminate gastro-intestinal helminths an integrated
response involving the nervous, endocrine, and immune systems are used to expel the parasites.
This is achieved through increased gut hydration and muscle contractions which detach worms from
the gut and lead to release outside the body in a “weep and sweep” response. Epithelial cells of
the intestine are significant players in this process, being responsible for detecting the presence of
helminths in the gut and participating in the regulation of parasite expulsion. This paper describes
the role of the gut epithelium in detecting and eliminating helminths from the intestine.
Abstract: Helminths are metazoan parasites infecting around 1.5 billion people all over the world.
During coevolution with hosts, worms have developed numerous ways to trick and evade the host
immune response, and because of their size, they cannot be internalized and killed by immune cells
Citation: Baska,
˛ P.; Norbury, L.J. The
in the same way as bacteria or viruses. During infection, a substantial Th2 component to the immune
Role of the Intestinal Epithelium in
response is evoked which helps restrain Th1 -mediated tissue damage. Although an enhanced Th2
the “Weep and Sweep” Response
during Gastro—Intestinal Helminth
response is often not enough to kill the parasite and terminate an infection in itself, when tightly
Infections. Animals 2022, 12, 175. coordinated with the nervous, endocrine, and motor systems it can dislodge parasites from tissues
https://doi.org/10.3390/ and expel them from the gut. A significant role in this “weep and seep” response is attributed to
ani12020175 intestinal epithelial cells (IEC). This review highlights the role of various IEC lineages (enterocytes,
tuft cells, Paneth cells, microfold cells, goblet cells, and intestine stem cells) during the course of
Academic Editor: Natalia Elguezabal
helminth infections and summarizes their roles in regulating gut architecture and permeability, and
Received: 30 November 2021 muscle contractions and interactions with the immune and nervous system.
Accepted: 10 January 2022
Published: 12 January 2022 Keywords: helminths; immune response; IEC; immunomodulation; gut immune response; im-
Publisher’s Note: MDPI stays neutral mune regulation
with regard to jurisdictional claims in
published maps and institutional affil-
iations.
1. Introduction
“Weep and sweep”—this term is used to describe the host response against gastro-
intestinal (GI) helminths. The main features of this phenomenon are an increase in fluid in
Copyright: © 2022 by the authors.
the gut lumen and enhanced smooth muscle contraction; this facilitates expulsion, rather
Licensee MDPI, Basel, Switzerland.
than the killing of the intruder [1]. Although the premise of “weep and sweep” is simple,
This article is an open access article
the mechanisms that regulate this phenomenon are complicated and require the interplay
distributed under the terms and
conditions of the Creative Commons
of the immune, endocrine, and nervous systems, not only through chemical mediators
Attribution (CC BY) license (https://
but through physical interactions. The response needs to be strong enough to efficiently
creativecommons.org/licenses/by/ terminate infection but gentle enough to only cause minor or at least acceptable injuries. A
4.0/).
balance between the three classical Th1 , Th2 , and Threg responses needs to be maintained
to avoid any dysregulation which may lead to immune-mediated injuries.
For the response to be efficient and balanced a number of regulatory mechanisms
have evolved (schematically represented in Figure 1). The first stage in this complicated
host-parasite interplay is host recognition of the parasite, which triggers several effector
mechanisms. However, while it is easy to indicate the first step—recognition, our compre-
hension of the mechanisms underlying this process are still in their infancy. There are a
number of fantastic reviews describing the mediators of immune responses [2], the sys-
tems (neural, immune, endocrine) involved [3–5], or scrutinizing known processes during
helminth infections [6]. However, the purpose of this review is to sequentially describe the
events beginning from helminth recognition through effector mechanisms. Unfortunately, it
can be difficult to describe the chronology of events since the cooperation of numerous host
organs and systems commences and occurs concurrently. Moreover, mediators and effector
cells participate in various components and stages of the weep and sweep phenomenon.
Nevertheless, it is hoped this review will bring attention to little-known facts of, and give a
new insight into, the “weep end sweep” response.
Figure 1. Helminth induced interactions between epithelial, neural, and immune cells. Upon infection
tuft cells (TC) release IL-25 and other intestinal epithelial cells (IEC) secrete TSLP, IL-33, and ATP,
signaling tissue damage. Group 2 innate lymphoid cells (ILC2) stimulated by alarmins release IL-4,
IL-5, IL-9, and IL-13, inducing goblet cell secretion, alternatively activated macrophages (AAM),
and eosinophilia. ILC2 also cooperate with the nervous system, and upon being stimulated by
neuromedin U release amphiregulin which has tissue-protective properties. Enteroendocrine cells in
response to IL-33 release serotonin which induces muscle contraction or epithelium permeability.
Animals 2022, 12, 175 3 of 13
2. Helminths
Helminths are an artificial grouping that is comprised of multicellular parasitic worms.
They inhabit host tissues (GI tract, lungs, muscles, and other organs) and infections may be
long lasting, even up to 20 years. Helminths are a problem of both human and veterinary
medicine. According to the CDC (US centers for disease control and prevention) up to
1.12 billion, 795 million, and 740 million people suffer from Ascaris, whipworm, and
hookworms, respectively [7]. Helminth infections may lead to cognitive impairment [8],
tissue damage [9], pregnancy complications [10], and numerous other symptoms and can
sometimes be fatal [11]. The high prevalence, detrimental effects, and increasing drug
resistance of helminths [12,13] have led to much research on developing vaccines [14–18];
however, despite promising results, there is still much to be done to achieve final success.
Fully eradicating helminth infections may even in some aspects be controversial, since they
may mitigate autoimmune diseases [19–21] and allergies [22,23] by dampening Th1 and
inducing Th2 host immune responses [24,25]. The resulting main effects of this response
typically are the presence of alternatively activated macrophages, tissue repair, eosinophilia,
and the production of IgE [26,27]. This state can be beneficial for both the host and the
parasite since Th2 /Threg responses protect tissue and induce wound healing in the host,
while the parasite can complete its life cycle and achieve reproductive success. There are
a variety of helminth species, each with its own host-parasite interplay which influences
infection progression and outcome; moreover, host genetic background [28] and parasite
strain [29,30] can also impact the immune response.
is the 2nd barrier (behind mucus) to interact with these distinct foreign organisms. It is also
an immune active tissue interacting with myeloid cells, lymphoid cells, and the nervous
system, orchestrating recognition of pathogens and finetuning the effector mechanisms of
responses. Upon stimulation, the intestinal epithelium exhibits altered gene expression [36]
and releases distinct cytokines [37] promoting a shift in the immune response towards
Th2 [38] or Threg phenotypes [37,39]; this is in contrast to the lung epithelium where an
inflammatory response is more desired [40].
Each helminth species is unique and may trigger distinct mechanisms since each occu-
pies its own niche in the GI tract and has different biological characteristics (e.g., feeding,
mating). Most data regarding the role of intestinal epithelial cells (IECs) during helminth
infections comes from research with four nematodes: Trichuris muris, Trichinella spiralis,
Nippostrongylus brasiliensis, and Heligmosomoides polygyrus. T. muris localizes in the caecum
with its anterior part anchored in “syncytial tunnels” formed from modified epithelial
cells [41], whereas T. spiralis, N. brasiliensis and H. polygyrus reside in the small intestine [42].
H. polygyrus attaches to the intestine through coiling around the villi on epithelial cells [43],
N. brasiliensis feeds on host villus tissue [44] and T. spiralis occupies a few epithelial cells
creating a multicellular niche [45]. Despite the different biology and living niches, their
impact on the host immune response shows a number of common features (reviewed
below). Studies over the last 15 years have focused on investigating the immune interplay
between parasites and the host immune system (cytokine profiles, gene expression pat-
terns), whereas other aspects like physical contact between the worm and host epithelium
remained somewhat neglected. It is now clear that both parasite physical interactions with
host tissues as well as the impact of molecules released by parasites on the host are part of
an extremely complicated process and should be investigated in complement with molecu-
lar research. Upon infection GI parasites penetrate through the mucus barrier and provoke
a host reaction; sometimes it is impossible to define whether a particular phenomenon is
an outcome of helminth actions or the host immune response. Nevertheless, despite the
very first interactions remaining elusive, initial events occur in response to IL-25, IL-33, and
TSLP signaling pathways [46]. The hallmark of the anti-GI helminth response are goblet cell
hyperplasia, eosinophilia, enhanced peristalsis, and release of Th2 type cytokines. However,
an exacerbated host response may lead to detrimental effects, and negative feedback loops
are initiated to fine-tune the response.
7. Helminth Recognition
Mammals use pathogen-associated molecular patterns (PAMPs) to adjust immune
responses to a particular foe, and are equipped with Toll-like receptors (TLRs) [66] or NOD-
like receptors (NLRs) [67] that specifically recognize bacterial and virus antigens; however,
the pattern recognition receptors (PPRs) for helminth PAMPs have not yet been fully
defined. The classic pathway of antigen recognition and presentation involves the sampling
of the gut lumen by dendritic cells (DC) followed by internalization and presentation of
antigens via MHCII to T cells. However, there is also a surprisingly significant role for
MHCII expressed on IECs in the gut, which seems to be attributed to ISC Lgr5+ cells
which act as nonconventional antigen-presenting cells and orchestrate epithelium structure
Animals 2022, 12, 175 6 of 13
both during homeostasis and infections [68]. These cells are sensitive to cytokines and
are promoted towards renewal, or differentiation to Paneth cells or TCs upon exposure to
Threg , Th1 , and Th2 (and their cytokines), respectively [69]. MHCII ablation in ISC during
H. polygyrus infection leads to impaired TC expansion, and MHCII ablation in the gut
decreases worm expulsion [69].
MHC II is also expressed on M cells which use the complex to capture luminal anti-
gens [70] and pass it to gut-associated lymphoid tissue (GALT). Despite interest in MHCII
use by M cells to stimulate the immune response, our understanding of this process is
still limited [71]. M cells appear to constantly probe for luminal antigens, which are then
presented to immune cells. M cells are located in FAE (follicle associated tissue) [72] which
contains a decreased number of Paneth and goblet cells, therefore the mucus layer is thinner
and the release of antimicrobial peptides is decreased [73]. M cells play an important role in
antibacterial immunity, associated with Th1 /Th17 , but their efficiency at clearing metazoan
parasitic infections is still to be determined.
More effective sentinels during helminth infections are Dclk1 + TCs [4]. TCs [74]
orchestrate cell homeostasis at the intestinal mucosal barrier through a positive loop
via the constant release of IL-25, enabling low-level synthesis of IL-13 which promotes
their differentiation through binding to IL-4Rα [75]. TCs proliferate upon infection by
N. brasiliensis [75], T. spiralis [76], and H. polygyrus [77], with proliferation dependent on
the Pou2f3 transcription factor [78]. TCs use chemosensing through taste receptors; TAS1R
and TAS2R possess the ability to sense sweet, sour, and umami. However, recent findings
show that evolution has adapted TCs to also identify metazoan invaders in the GI tract [79].
Human TAS1R and TAS2R are classes of G-protein-coupled receptors (GPCRs) [80] and
transduce signals through interaction with G protein—gustducin [81]. It has been shown
that mouse Tas2rs mediates the release of IL-5 upon stimulation with T. spirals or its
secretory antigens; moreover, the infection changes the mRNA expression profile of Tas2r
family members [76] which may imply distinct roles for particular Tas2r in T. spiralis
recognition. The function of other Tas receptors has also been explored, including during
H. polygyrus infection, results indicating that Tas1r3 is engaged in maintaining intestinal
cell homeostasis during health, rather than being involved in directly mounting a response
against nematode infections [82].
Further exploration of the role of taste receptors in helminth recognition should be
undertaken in the context of microbiota colonizing the gut, especially those that release
succinate. Recently Nadjsombati et al. [83] showed that N. brasiliensis also releases succinate
and that dietary supplementation with this chemical decreases the worm burden via the
mounting of a Th2 response. Moreover, GI helminth infections can affect the composition
of gut microbiota [62], and it is possible that these changes can facilitate the recognition
of helminths invaders due to impacts on different receptors while physical injury to the
epithelium caused by the worms may also result in stronger signals and impacts on
immune cells.
Other receptors possibly engaged in helminth recognition are TLRs. T. spiralis directly
interact with TLR2 and TLR4 on DCs [84], and TLRs are also present on IEC [85]. However,
recognition of T. spiralis ES by TLR2 and TLR4 skew DC toward a Threg response [84] and it
is likely to be an intentional immunomodulatory action of parasites [86]. Alternatively, T.
muris ES may directly activate enteroendocrine cells, in a TLR2-dependent manner [87],
which would support a role for TLR2 in helminth recognition. Nevertheless, the particular
epitope (amino acid sequence or sugar moiety) recognized by the TLR remains unknown
and it is also yet to be determined if TLRs play a crucial role or are merely auxiliary receptors
in helminth recognition. Summing up, the proven ability of TLRs to bind parasite antigens
indicates a role in recognizing parasitic infections and justifies further investigation of
this phenomenon.
Animals 2022, 12, 175 7 of 13
but also enhances muscle contractions [102]. Moreover, IL-33 in cooperation with IL-13
amplifies muscle responses to ACh [103]. Nevertheless, during helminth infections, these
responses to the reflexes need to be restrained to prevent diarrhea and dehydration [103].
This balance is maintained by a combination of ACh degradation through the actions
of the hydrolyzing enzyme acetylcholinesterase and through effector mechanisms of the
Th2 response which leads to decreased serotonin—ACh induced epithelial secretion, as
observed during H. polygyrus, N. brasiliensis, and T. spiralis infections [103]. This shows the
elegant cooperation of the nervous and immune systems which when disrupted leads to
abrogation of the Th1 /Th2 balance and impaired worm expulsion [64] and tissue damage.
Serotonin may have one more intriguing role during helminth infection. As it is not a
mammal-specific neuromediator and may also be utilized by the tapeworm Hymenolepis
diminuta [104], it has led to speculation that it may be beneficial for the parasite as a “free”
neuromediator [5]. Alternatively, its role in parasite expulsion is evident, therefore its
precise role during infection requires further exploration.
Another significant epithelium-derived hormone is cholecystokinin (CCK). It is re-
leased by EEC I cells during infection [105] inducing hypophagia, which allows the host
to focus on an immune response rather than on digestion. CCK is also an enhancer of
gut motility [106]. Stimulation of TLR-2, TLR-4, and TLR-9 [107] as well as taste receptors
T1R1—T1R3 [108], likely caused by increased contact of bacteria and amino acids with
EEC, induce CCK release. Consequently, CCK may be involved in parasite expulsion via
interaction with the microbiota as parasites damage mucus and allow increased microbial
access to the epithelium.
10. Conclusions
IECs play a significant role in raising, maintaining, and regulating the immune re-
sponse. They are influential in the response against GI helminths and are an important
component of the complicated interplay of immune, neural and hormone systems. Dys-
regulation of the interactions between these systems can result in immunopathology or
immunosuppression.
IECs, with physical contact with parasites, are crucial during the early stages of
immune response induction, especially through the release of alarmins (IL-25, IL-33, and
TSLP) which prime ILC2 to induce Th2 cells and AAM. However, fully defining the role
IECs have in inducing the response against parasites requires the identification of the
helminth PAMPs that are recognized by IECs and DCs that probe the gut lumen. These
remain elusive, and it is possible that separate receptors for helminth PAMPs may not exist.
GI helminths interact with TLR2 and TLR4 which are thought to be classical receptors for
bacteria, supporting the hypothesis that helminths are not recognized by particular TLR or
NLR, but rather a number of signals raised through tissue damage, gut microbiota, and
helminth antigens activate appropriate signaling pathways which lead to the “weep and
sweep” response.
During the “weep and sweep” response, IECs release mucus which acts as a physical
barrier to intruders, detaches parasites from the intestine through an epithelial escalator, in-
creases water influx to the gut lumen, and induce muscle contraction. All these mechanisms
are tightly associated with immune and hormone mediators that contribute to maintain-
ing an appropriate Th2 /Threg and Th1 balance. This balance results in a response strong
enough to eradicate intruders and gentle enough to prevent excessive host tissue damage.
Summing up, IECs (among other components—immune cells, muscle, hormone-
releasing cells) should be considered as an important node in the complicated interactions
that constitute an effective response to GI helminths.
Author Contributions: Conceptualization, P.B.; methodology, not applicable; software, not applica-
ble; validation, not applicable; formal analysis, not applicable; investigation, not applicable; resources,
not applicable.; data curation, not applicable; writing—original draft preparation, P.B.; writing—
review, L.J.N.; visualization, L.J.N.; project administration, not applicable; funding acquisition, not
applicable. All authors have read and agreed to the published version of the manuscript.
Animals 2022, 12, 175 9 of 13
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