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Review

Paneth Cells and Lgr5+ Intestinal Stem Cells in Radiation Enteritis

by
Thifhelimbilu Luvhengo
*,
Uzayr Khan
and
Thomas Kekgatleope Marumo
Department of Surgery, University of the Witwatersrand, Johannesburg 2193, South Africa
*
Author to whom correspondence should be addressed.
Appl. Sci. 2023, 13(5), 2758; https://doi.org/10.3390/app13052758
Submission received: 28 December 2022 / Revised: 15 February 2023 / Accepted: 17 February 2023 / Published: 21 February 2023
(This article belongs to the Special Issue Histopathological Diagnosis in Applied Sciences)
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Abstract

:
Cancer is the leading cause of death in adults and majority of cancers involve abdominal and pelvic organs. Radiotherapy is used in the management of around half of patients who have abdominal and pelvic malignancies and 70% of the treated patients will develop radiation enteritis. The onset of radiation enteritis may delay the completion of treatment or lead to life-threatening conditions such as bowel perforation or obstruction. High-dose ionizing radiation can affect all the layers of the small intestine leading to weakening of its structural integrity, dysbiosis, malabsorption, and derangement of the innate immunity. Advances in the management of cancer has not led to an improvement in the treatment of radiation enteritis as the available preventative or treatment options are still ineffective. Severe acute and chronic radiation enteritis result from the damage to the crypt-based intestinal stem cells and their derivatives, which include the Paneth cells. Paneth cells regulate the proliferation and differentiation of the intestinal stem cells. The other roles of the Paneth cells are protection and nourishment of the intestinal stem cells, and control of the gut microbiota. Paneth cells can also de-differentiate and replace irreversibly damaged intestinal stem cells. This article reviews the anatomy of the epithelium of the small intestine and the intestinal epithelial cells including the Paneth cells. The effect of ionizing radiation on the intestinal stem cells and its derivatives, and the knowledge can be used to develop effective treatment of radiation enteritis is discussed.

1. Introduction

Cancer is the leading cause of death in adults, and as a group, cancer of the cervix, stomach, liver, esophagus, ovary, prostate, rectum, and uterus are among the commonly occurring malignant tumors globally [1]. Radiotherapy is used for curative or palliative treatment in the majority of abdominal or pelvic malignancies [2,3,4]. The small intestine, rectum, and the urinary bladder are sensitive to ionizing radiation and are frequently damaged following radiotherapy for cancer of the cervix, prostate, and rectum [5,6]. The small intestine is more sensitive to ionizing radiation as it contains the stem cells which are among most rapidly dividing cells in adults [7,8]. The physiological status of a patient, the dose (fractionated and overall), and the time of the day during which the radiotherapy was delivered also influence the likelihood of radiation injury [9].
The intestinal stem cells (ISCs) are arranged in tiers with the most actively cycling ISCs and therefore the most sensitive to ionizing radiation being found at the base of the crypt of Lieberkühn (intestinal crypt). The ISCs which are found at the base of the intestinal crypt are known as the leucine-rich repeat-containing G-protein-coupled receptor 5 ISCs (Lgr5+ ISCs). The Lgr5+ ISCs in a normal small intestine are found intermingled with the Paneth cells in a 1:1 ratio [10,11,12,13,14,15,16,17,18]. The other ISCs are found higher up starting from around position 4 (reserve ISCs) along the crypt-villous axis [15,19]. Compared to Lgr5+ ISCs, the reserve ISCs are usually quiescent and thus more resistant to damage due to ionizing radiation [8,20]. The reserve ISCs, Paneth cells, enterocytes, goblet cells, and enteroendocrine can de-differentiate to replace Lgr5+ ISCs if they are irreversibly damaged, for instance following ionizing radiation [11,21,22]. The process of de-differentiation and replacement of the Lgr5+ ISCs is normally led by the reserve ISCs and Paneth cells, and the other intestinal epithelial cells (IECs) only get activated by the Paneth cells that have also been irreversibly damaged [11]. The other roles of the Paneth cells in the small intestine are to protect, nourish, and regulate proliferation and differentiation of the Lgr5+ ISCs [14,23,24,25,26]. The Lgr5+ ISCs use lactate which is produced in the adjacent Paneth cells for their energy production. Additionally, Paneth cells monitor and regulate the microbiota in the lumen of the small intestine [27,28,29,30,31]. Paneth cells provide the link between the innate immunity and adaptive immunity of the in the gut, and ultimately of the entire body [11,27,28,29,30,31].
The most common side effects of radiotherapy to abdominal or pelvic organs is radiation enteropathy/radiation enteritis (RE) [32]. The risk factors of RE include age above 60 years, smoking, diabetes mellitus, hypertension, connective tissue disorders, HIV status, previous abdominal surgery, hypo-albuminemia and concurrent administration of chemotherapy with radiotherapy [9,32]. Radiation enteritis can occur within days or many years following treatment. Acute RE usually manifest within 10 days and its pathological features include oedema of the bowel wall, mucositis, ulceration, perforation, necrosis of small bowel, or death within days. Chronic RE presents after 6 months following radiotherapy and is due to vasculitis and chronic fibrosis. The ongoing fibrosis in chronic RE may lead to stricture formation and mechanical small bowel obstruction [33,34]. The other complications of chronic RE are internal fistulae, dysbiosis, and malabsorption syndromes [35]. The occurrence of either acute and chronic RE may lead to a delay in the completion of treatment or affects the quality of life of a patient even in cases where the cancer is cured.
The prevention, amelioration, and management of RE have remained a challenge ever since the discovery and use of radiotherapy in the treatment of cancer in 1897. Surgical management of RE remain a challenge as postoperative complications such as iatrogenic enterocutaneous fistulae and intestinal failure are common [35,36,37,38]. Steroids, anti-oxidants, vitamins, statins, hyperbaric oxygen, fecal transplant, recombinant Lgr5+ ISCs niche or growth factors, and implantation of mesenchymal stem cells are experimental and their effectiveness in the prevention or management of RE is questionable [36,37].
Current strategies in the management of RE appear to be based on a limited understanding of the collaborative roles which the ISCs and their derivatives together with the gut microbiota and cells in mesenchyme in the peri-crypt environment of the lamina propria play in the maintenance of the integrity and function in the small intestine [14,26,29,36,39,40,41,42,43,44,45,46,47]. A greater understanding of the roles and interactions of the Paneth cells, ISCs, other IECs, gut microbiota and cells in the mesenchyme of the lamina propria of the small intestine play in the maintenance of normal structure and function of the small intestine may lead to the discovery of more effective strategies to prevent, ameliorate, or treat RE. The effective strategies to prevent and manage RE are most likely to be developed from treatment modalities which enhance the collaborative functions of the Lgr5+ ISCs, Paneth cells, other IECs and mesenchymal cells. The section and subsections which follow discuss normal anatomy, the roles which the ISCs, Paneth cells, and other derivatives of the Lgr5+ ISCs play in the maintenance of gut integrity and repair following injury. How each group of the IECs is affected and responds to ionizing radiation are also discussed.

2. The Structure and Functions of the Small Intestine

The small intestine is made up of the duodenum, jejunum, and the ileum. It is the longest segment of the gastrointestinal tract and thus the area of the body which is the most exposed to harm from the external environment. The epithelium of the small intestine has villi and microvilli, and crypts to increase its surface area for the efficient absorption of nutrients.

2.1. The Lgr5 Intestinal Stem Cells

The derivatives of the Lgr5+ ISCs are divided into absorptive and secretory cells, and more than 80% of IECs are absorptive enterocytes [31,46]. The majority of the remaining IECs is made up of goblet cells and Paneth cells, which are secretory [10,12,17]. The other secretory IECs are the enteroendocrine cells and the tuft cells [10,15,40,48,49] (Figure 1).
Whereas all the other derivatives of the Lgr5+ ISCs are found throughout the entire small intestine from the duodenum to the terminal ileum, the M-cells are specialized enterocytes which are found only in regions where there are lymphoid follicles such as the Peyer’s patches in the terminal ileum [50]. Although the enterocytes are primarily responsible for digestion and absorption of nutrients they also, like the other IECs, play a role in the maintenance of the structural integrity and innate immunity in the small intestine [31]. The robust innate immunity in the small intestine is dependent on the maintenance of the physical integrity of surface epithelial cells, quality of the junctional proteins, active surveillance of the gut microbiota, secretion of antimicrobial peptides predominately by the Paneth cells, good quality of mucins which are secreted by the goblet cells, and an adequate supply of nutrients [51]. High-dose ionizing radiation affects the structure, physiology, and immunological function of the entire wall of the small intestine.
All the IECs, bar the M-cells, possess pathogen recognition receptors that include the Toll-like receptors (TLRs) which they use for sampling of luminal contents in the small intestine [52]. Sampling of the intestinal contents by the IECs is continuous to prevent dysbiosis, increased intestinal permeability, and gut inflammation [28,53,54,55]. Dysbiosis, increased intestinal permeability, and gut inflammation are the initiating events in several gastrointestinal and extra-gastrointestinal such as inflammatory bowel disease, type 2 diabetes mellitus, obesity, cancer, and radiation enteritis [44,56,57,58]. The dysbiosis which is seen in chronic RE is superimposed on the damage from the direct and indirect effects of ionizing radiation on the Lgr5+ ISCs, Paneth cells, other IECs, junctional proteins, and mesenchymal cells in the lamina propria. The Lgr5+ ISCs are rapidly dividing cells and therefore highly sensitive to genotoxins and ionizing radiation [19]. The response of the Paneth cells and the other IECs may include de-differentiation and acquisition of stemness to replace the Lgr5+ ISCs if they have been irreversibly damaged following ionizing radiation [21,22,37,45,58,59,60,61,62].
There are several tiers of the ISCs which are distributed along the crypt-villous axis. The Lgr5+ ISCs are the most rapidly dividing and therefore the most sensitive to ionizing radiation. The Lgr5+ ISCs are found intermingled with Paneth cells at the base of the intestinal crypt [47,63]. The reserve ISCs are quiescent and get activated if the Lgr5+ ISCs have been destroyed as is seen in RE [19,47]. The high sensitivity of the Lgr5+ ISCs is necessary to prevent an accumulation of radiation-induced non-fatal DNA damage which would later increase the risk of cancer. The Lgr5+ ISCs are intermingled with the Paneth cells and are heavily reliant on the Paneth cells which secrete antimicrobial peptides such as human α-defensin 5 to sterilize the stem cell zone, provisioning of lactate for their aerobic respiration and regulation of their proliferation and differentiation through elaboration or secretion of niche factors and ligands. The Lgr5+ ISCs normally undergo symmetrical or asymmetrical divisions daily [43]. The symmetrical division of Lgr5+ ISCs ensures clonal expansion whereas asymmetrical division leads to the production of progenies which differentiate to become enterocytes, goblet cells, enteroendocrine cells, Tuft cells, M-cells, cup cells, and Paneth cells [15,47,64].

2.2. Enterocytes

Absorptive enterocytes constitute around 80% of cells in the epithelium of the small intestine [9,15,17,40,46]. Following their production from differentiating Lgr5+ ISCs, the enterocytes migrate outwards along the crypt-villous axis to reach the outer surface of the epithelium of the small intestine. Enterocytes have villi and microvilli on their luminal surface to enhance the capacity for absorption of nutrients. The function of enterocytes is not limited to digestion and absorption of food as they also participate in innate immunity in the gut [40]. The enterocytes undergo apoptosis and get exfoliated after 3–5 days following their generation from the Lgr5+ ISCs [63]. Ionizing radiation leads to a much more rapid turn-over and exfoliation of enterocytes and other IECs.
Despite the lining of the small intestine being made of a single layer of columnar-shaped enterocytes, it can perform the dual function of absorption of nutrients and prevention of passage of harmful pathogens. Together with junctional proteins, enterocytes and other epithelial cells make the luminal epithelium of the small intestine selectively impermeable [40]. The other roles of the enterocytes include sampling of nutrients and the gut microbiota to enhance transcription and synthesis of specific enzymes which are needed for digestion and absorption. Enterocytes use pathogen recognition receptors (PRRs) to sample the gut microbiota [40]. Enterocytes can de-differentiate and become stem cells and replace the Lgr5+ ISCs, if the reserve stem cells and Paneth cells have been fatally damaged by high-dose ionizing radiation [58].
The damage to enterocytes following ionizing radiation accounts for, among others, the malabsorption of nutrients which is seen in patients who have acute and chronic RE. Acute radiation injury leads to swelling, premature aging, and apoptosis of the enterocytes. An increase in the rate of apoptosis leads to an imbalance between replacement and loss, which explains the villous atrophy, shortening of the villi, and the loss of microvilli which are features of RE [65]. Concurrently, damage due to ionizing radiation to the small intestine leads to a reduction in the rate of synthesis of junctional proteins [66]. A consequence of a net loss of enterocytes and the impaired synthesis of junctional proteins is the creation of gaps on the luminal surface of the epithelium that increases permeability of the intestinal epithelium to bacteria and their endotoxins leading to their translocation [67]. The increase in the permeability of the epithelium results in local inflammation which may become systemic due to a spill-over of endotoxins and pro-inflammatory into the systemic circulation that may cause multiple organ dysfunction and death [67]. A reduction in the ability of enterocytes to collaborate with the Paneth cells and tuft cells to monitor and control the luminal organisms may also contribute to the dysbiosis, that is commonly seen in patients who have acute or chronic RE [3].

2.3. Goblet Cells

Goblet cells are the second most populous IECs that are derived from the Lgr5+ ISCs. Majority of goblet cells are found toward the villous surface of the intestinal crypts [15,40]. The number of goblet cells increase progressively along the small intestine and the largest number per surface area of zones in the GIT are found in the distal parts of the ileum and the colon. The life-span of goblet cells is normally less than 7 days [17]. The main function of goblet cell in the small intestine is to secrete mucus and the constituents of mucus which is secreted by the goblet cells includes subtypes of mucin (MUC) and trefoil factors (TFTs) [40,68,69]. The two main components of mucus which are secreted by goblet cells in the small intestine are secretory MUC2 and membrane-bound MUC3 [40,68,69]. The MUC2 forms a carpet on the luminal surface of the epithelium which is permeable to nutrients but impermeable to pathogens. The carpet of mucus which is predominately made up of MUC2 helps to maintain a higher concentration of antimicrobial peptides, which have been secreted by, among others, the Paneth cells in the area adjacent to the surface epithelial cells [40,41]. The goblet cells are also involved in the sampling of nutrients and the microbiota in the lumen of the small intestine. The mucus which is secreted by the goblet also serves as a nutrient for commensal organisms in some of the niches along the GIT.
High dose of ionizing radiation can reduce the number and function of goblet cells and lead to a reduction in the quality and amount of MUC2, MUC3, and TFTs that is produced [7]. The poor quality of mucus produced is ultimately not able to ensure the microbiocidal concentration of antimicrobial peptides and protein produced by the Paneth cells on the luminal surface of the epithelial cells. The lowering of antimicrobial activities and poor quality of mucus result in dysbiosis, an increase in gut permeability, translocation of bacteria, gut inflammation, and systemic inflammation [68]. The trefoil factor normally enhances the growth and development of intestinal epithelium and is especially needed during the repair and regeneration of the intestinal epithelium following radiation-induced damage to the epithelium of the small intestine [70,71,72,73]. Furthermore, goblet cells can de-differentiate and assume stemness if both the Lgr5+ ISCs, reserve ISCs and Paneth cells have been damaged by ionizing radiation [8,22,58]

2.4. Paneth Cells

Paneth cells make up around 5% of the IECs and are found throughout the small intestine from the duodenum to the terminal ileum. Paneth cells start appearing in the small intestine and colon of a human fetus at 12 weeks gestational age [12]. Matured Paneth cells are found at the base of the intestinal crypts where they are in direct contact with the Lgr5+ ISCs [15,62,70]. The life span of the Paneth cells is 3–7 weeks which is 3–4 times longer than that of the other IECs [12,17,40,74,75]. Paneth cells influence the proliferation and differentiation of the Lgr5+ ISCs through the release of niche factors or their ligands such as Wnt and Notch, cytokines, and growth-enhancing factors in collaboration with mesenchymal and immune active cells which reside in the lamina around the base of the intestinal crypts [17,24,60]. The other role of the Paneth cells is to regulate the microbiota in the lumen of small intestine. Paneth cells are the main producers of the antimicrobial peptides and proteins which sterilize the area around the Lgr5+ ISCs and the luminal surface of the IECs [29,62,75,76,77,78]. The main antimicrobial peptides which are secreted by the Paneth cells are human α-defensin 5, human α-defensin 6, and lysosome [12,75,78,79]. Human α-defensin 5 can kill bacteria, parasites, fungi, and most pathogenic viruses [14,29,30,54,77,78].
Paneth cells together with cells which located in the lamina propria are critical for the maintenance of the structural, physiological, and immunological integrity of the small intestine and are activated following a damage to the gut mucosa or emergence of dysbiosis [12,62,74,77,79,80]. Paneth cells are involved in the initiation of the repair process after bowel injury such as following radiation injury. Like the other IECs, Paneth cells can de-differentiate into Lgr5+ ISCs if they themselves are not fatally damaged. Paneth cells and the reserve ISCs lead the process of de-differentiation if they themselves are still viable. Dysbiosis is a common feature of radiation that is also linked to the dysfunction of Paneth cells [39]. Failure of the Paneth cells to regulate the microbiota leads to dysbiosis, increased permeability of the intestinal epithelium, translocation of bacteria and their products, and local inflammation. The inflammation in the wall of the small intestine may spill over and become systemic. Dysbiosis and systemic inflammation are the main drivers of some of the complications associated with acute and chronic RE [33]. The other important functions of the Paneth cells which may be disrupted following ionizing radiation are nourishment of the Lgr5+ ISCs, sampling of nutrients and phagocytosis of the other IECs if they have been damaged or are apoptotic IECs [81].
The quality of Paneth cells and their potency is assessed by studying their morphological appearance, position along the crypt-villous axis, and their overall number per crypt [82]. More objective analysis of their capabilities includes checking the position, size, and the intensity of staining of their apical cytoplasmic granules on immunohistochemistry [70,75,83]. Matured Paneth cells are found at the base of the intestinal crypts where the most radio-sensitive Lgr5+ ISCs which need the most protection are found. Paneth cells have intense and uniform staining of apical cytoplasmic granules. Genomics, transcriptomics, or metabolomics-based studies can determine the level of expression of genes or concentration of protein which are synthesized by the Paneth cells [23,64].

2.5. Other Derivatives of the ISCs

The other IECs constitute less than 1% of the population of cells in the epithelium of the small intestine. These cells include enteroendocrine cells, tuft cells, M-cells, and cup cells [10,17,18,46,48,84,85]. Common to all the other cells except for the cup cells is that they are found closer to the villous side of the intestinal crypt where they can sample nutrients and gut microbiota and can de-differentiate and replace Lgr5+ ISCs. The average lifespan of all the other IECs is around 5 days but may be shortened following injury [48,75]. Both the M-cells and tuft cells actively participate in innate defense in the gut [86]. The tuft cells have pathogen recognition receptors whereas the M-cells selectively allow bacteria and allogenic particles to pass through them unprocessed (transcytosis) to underlying elements of the adaptive immunity [15,49,64]. Table 1 summarizes the estimated population density and some of the functions of the derivatives of the Lgr5+ ISCs.
The proliferation and differentiation of the Lgr5+ ISCs is regulated by niche factors which are jointly produced by Paneth cells, other IECs, the cells that reside in the lamina propria adjacent to the base of the intestinal crypt, gut microbiota, and the enteric nervous system [11,16,42,45,58,80]. The cells in the lamina propria which secrete the niche factors include macrophages, dendritic cells, lymphocytes, endothelial cells, fibroblasts, telocytes, and myofibroblasts [7,49,80,87]. The niche factors determine the type of division which the Lgr5+ ISCs need to undergo, i.e., symmetrical versus asymmetrical based on the physiological status and the stress level. Similarly, differentiation of the Lgr5+ ISCs onto either the absorptive or secretory lineages depends on the strengths of among others Wnt and Notch ligand.

3. Radiation Enteritis

3.1. Pathogenesis and Complications of Radiation Enteritis

Although ionizing radiation mostly affect the labile cells such as the Lgr5+ ISCs, a higher dose can affect stable and permanent cells. Permanent cells such as nerve cells, vascular endothelial cells and muscle cells are usually radio-resistant but get affected if a higher dose is administered. The cells are most at risk during the synthetic or DNA replication phase of the cell cycle [88]. Ionizing radiation causes DNA damage which may be irreversible, leading to early senescence and apoptosis of the surface epithelial cells which would normally take 3–5 days [7]. The increase in the exfoliation of surface epithelial cells creates an imbalance between cell loss and replacement leading to the appearance of defects in the epithelium and increased gut permeability [89]. The other consequence of ionizing radiation to the small intestine is an increase in the production of reactive oxygen, hydrogen, or nitrogen species, which overwhelms the body antioxidant mechanisms and aggravate the damage [7,33].
Features of acute radiation injury include oedema, ulceration, or perforation [4,90]. Microscopic signs of acute RE may include sloughing-off of the epithelial cells and/or their villi [89]. Life-threatening complications of acute RE include bleeding and perforation [4]. Damage to the epithelium of the small intestine may also lead to dysbiosis [39,91,92]. Radiation enteritis is associated with a reduction in microbial diversity and an increase in the number of pathogenic organisms. Ionizing radiation may lead to an increase in the Bacteroides, Lactobacillus, Citrobacter, and Pasteurellaceae species [92]. Dysbiosis which occurs in patients who have RE causes gut and systemic inflammation, similar to what is seen in patients who have inflammatory bowel disease, type 2 diabetes mellitus, and cancer. The change in the microbiota also increase the oxidant stress on the epithelium of the small intestine [93]. Chronic radiation injury can extend beyond the epithelium of the small intestine and include injury to the vascular endothelial cells, fibroblasts, myofibroblasts, telocytes, endothelial cells, neural cells and macrophages, and dysbiosis [17,39,75]. Ionizing radiation of the small intestine also leads to dysbiosis [3,27,39,56]. Table 2 presents a list of some of the acute and chronic effects of ionizing radiation on the small intestine.

3.2. Presentation of Radiation Enteritis

Symptoms of RE are influenced by the acuity and severity of the injury. Manifestations of acute RE may include bloating, abdominal pain, nausea, vomiting and abdominal pains [2,3]. Severe acute radiation enteritis may lead to ulceration, bleeding, ischemia, or perforation of the small intestine [2,5,90]. Long-term complications of radiation injury to the small intestine include fibrosis with the formation of strictures, dysbiosis, steatorrhea, malabsorption syndrome, internal fistulae, and intestinal failure [2,3,34]. Strictures of the small intestine caused by radiation are difficult to treat as the rate of anastomotic leak is high if primary anastomosis is performed after resection of a stenotic segment [90]. A rare but plausible late complication of radiotherapy is the development of secondary malignancies [72,99,100].

3.3. Management of Radiation Enteritis

Management of RE starts with measures to prevent its occurrence by ensuring the patients is fit for radiotherapy [9,92]. Other preventative strategies to reduce collateral damage to the small intestine include administration of prophylactic agents, reducing the fractional or overall dose, narrowing the field of exposure, or shielding the structures that are vulnerable to ionizing radiation [101,102]. Avoiding chemotherapy before radiotherapy and laparotomy with resection of intra-abdominal structures can also reduce the risk of RE [4]. Collateral damage during irradiation can also be reduced by positioning the patient, using interstitial-modulated radiation therapy, stereotactic radiotherapy, intra-operative radiotherapy, brachytherapy, conformal radiotherapy, 3-D and artificial intelligence guided planning [4,103]. Anti-oxidants, statins, steroids, vitamins, herbal or traditional medicines, and measures to maintain the normal gut flora can also prevent the development of radiation enteritis [3,104,105,106,107,108,109].
The treatment of acute RE is mainly supportive and, analgesics, dietary modification and anti-diarrheal drugs are used for control of symptoms [2]. Total parenteral nutrition may be necessary in patients suffering from severe acute or chronic RE [2]. Bleeding and small bowel obstruction are the two most common complications seen during chronic RE [32]. The underlying cause of small bowel obstruction following radiotherapy of pelvic and abdominal malignancies may be strictures, adhesions, or recurrent tumor [5,99,110]. The strictures in the small intestine in patients who have chronic RE are often at multiple sites and are associated with dense fibrosis and obliterative vasculitis which increases the risk of postoperative complications.
The options for the treatment of small bowel strictures due to RE include resection and anastomosis, creation of bypass or bringing out of stoma which may be performed laparoscopically or through open surgical approach [2,99,110]. Bleeding due to RE in the acute or chronic setting may be treated conservatively, endoscopically, or surgically. Endoscopic options for the management of bleeding in RE include argon beam plasma coagulation and radiofrequency ablation [111]. Other treatment modalities such as the use of steroids, glutamine, arginine, statins, angiotensin converting enzyme inhibitors, antioxidants, hyperbaric oxygen, and herbal medications remain experimental [4,57,67,104,106,112,113,114,115]. Additional but still experimental management strategies for RE are mesenchymal stem cells and recombinant niche factors for the Lgr5+ ISCs [36]. Among the recombinant niche factors which have been trialed for prevention, amelioration, or treatment of RE are Wnt ligands, trefoil factor 3, and epidermal growth factors [71]. Table 3 presents a list of treatment modalities which have been used for management of radiation enteritis.

3.4. Outcome following Treatment of Radiation Enteritis

Although most patients who have acute radiation enteritis recover with just supportive treatment, the development of acute radiation enteritis if mild, leads to the deferral of subsequent treatment. The key challenges in the management of radiation enteritis especially its chronic complications are centered on the control of dysbiosis, increased gut permeability, malabsorption, bowel obstruction, fistulation, and intestinal failure [38]. Surgical intervention in patients who have radiation enteritis is associated with high rates of postoperative complications including anastomotic breakdown, iatrogenic small bowel fistula, dehiscence of abdominal wound, and recurrence of adhesions and strictures [2,38].

4. Limitations

Radiation enteritis is a complex disease and many treatment strategies have been described. It is therefore unlikely that this manuscript would have cover all the treatments which have been described. The author has avoided being specific and listing all the niche factors, ligands, and cytokines which are involved in the regulation of the proliferation and differentiation of the Lgr5+ ISCs. Furthermore, not all secretory products of the Paneth cells and other IECs have been mentioned.

5. Conclusions

The number of patients who require radiotherapy is expected to increase due to rise in the rate of occurrence of cancer globally. Similarly, the number of individuals who will potentially be cured of their cancer but develop debilitating acute or chronic complications such as RE will also increase. The available options for radioprotection, amelioration, and treatment of RE are ineffective. An intervention that can simultaneously prevent or reverse the dysbiosis, restore intestinal permeability, booster the innate immunity, and cure the endothelial dysfunction will most likely be effective in the management of RE. As Paneth cells control the microbiota in the gut, regulate proliferation and differentiation of the Lgr5+ ISCs, can acquire stemness, collaborate with cells in the lamina propria, and link innate and adaptive immunity in the small intestine, it is likely that a management strategy that focuses on measures to restore their function would be more effective in the management of RE. The future is likely to see an increase in the use of glutamine to enrich the Paneth cells and the use of intestinal organoids, recombinant niche factors or their ligands, and mesenchymal stem cells in the management of RE. Furthermore, more clinicians are likely to embrace the use of artificial intelligence in decision-making and preparing individualized radiation treatment plan.

Author Contributions

Conceptualization, T.L.; writing original draft, T.L.; review and revision of the draft U.K. and T.K.M.; response to the reviewers, T.L., U.K. and T.K.M. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

This is a review article which did not use patients’ records.

Informed Consent Statement

Getting informed consent was not applicable as it is a review article.

Data Availability Statement

It not applicable as the manuscript is a review article and did not use patients’ data.

Conflicts of Interest

The authors declare no conflict of interest.

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Applsci 13 02758 g001 550
Figure 1. Schematic illustration of the structure of the intestinal crypt showing Lgr5+ ISCs in intimate contact with the Paneth cells at the base of the crypt, enterocytes with microvilli, goblet cells, and enteroendocrine cells. The sketch also shows some of the cells which are critical for the maintenance of normal structure and function of the small intestine that include dendritic cells, endothelial cells, nerve cells, and smooth muscle cells (The illustration was created using BioRender.com).
Figure 1. Schematic illustration of the structure of the intestinal crypt showing Lgr5+ ISCs in intimate contact with the Paneth cells at the base of the crypt, enterocytes with microvilli, goblet cells, and enteroendocrine cells. The sketch also shows some of the cells which are critical for the maintenance of normal structure and function of the small intestine that include dendritic cells, endothelial cells, nerve cells, and smooth muscle cells (The illustration was created using BioRender.com).
Applsci 13 02758 g001
Table
Table 1. Estimate proportional representation of the intestinal epithelial cells of the absorptive and secretory lineages and the roles each cell type plays to support the Lgr5 ISC during a healthy a healthy state and following ionizing radiation.
Table 1. Estimate proportional representation of the intestinal epithelial cells of the absorptive and secretory lineages and the roles each cell type plays to support the Lgr5 ISC during a healthy a healthy state and following ionizing radiation.
Cell TypeCategoryEstimated Percentage of Population of IECs FunctionsLife Span
Enterocytes [9,15,17,40,46,58,63]Non-secretory±80%Sampling of nutrients.
Digestion of nutrients.
Absorption of nutrients.
Maintenance of structural integrity.
Surveillance and control gut microbiota.
Replacement of damaged Lgr5+ ISCs.		3–5 days
Goblet cells [8,15,17,22,40,41,68,69]Secretory±10%Sampling of gut microbiota.
Sampling of nutrients.
Secretion of mucus.
Pooling of antimicrobial peptides.
Secretion of trefoil factor.
Regeneration and repair of epithelium.
Replacement of damaged Lgr5+ ISCs.		3–5 days
Paneth cells [12,14,17,29,30,40,54,75,76,77,78,79,80]Secretory ±5%Control of gut microbiota.
Sampling of nutrients.
Protection of Lgr5+ ISCs.
Nourishment of Lgr5+ ISCs.
Regulation of proliferation and differentiation of Lgr5+ ISCs.
Replacement of damaged Lgr5+ ISCs.		3–7 weeks
Enteroendocrine cell [40,48]Secretory ±1%Sampling of nutrients.
Secretion of gut hormones.		3–5 days
Tuft cells [64]Non-secretory <1%Sampling of nutrients.
Sampling of gut microbiota.
Regulation of gut microbiota.
Production of cytokines.
Replacement of damaged Lgr5+ ISCs.		3–5 days
M-cells [40,48]Non-secretory<1%Sampling of gut microbiota.
Transcytosis of bacteria, viruses and particles.		3–5 days.
Cup cells [48,86]Unknown<1%Unknown.-
Table
Table 2. List of acute and chronic effects of ionizing radiation of the small intestine.
Table 2. List of acute and chronic effects of ionizing radiation of the small intestine.
AcuityPathological Changes
Acute radiation enteritis [94,95]Oedema
Mucositis
Ulceration
Bleeding
Dysbiosis
Increased intestinal permeability
Systemic inflammation
Multiple organ dysfunction
Chronic radiation enteritis [96,97,98]Ulceration
Bleeding
Steatorrhea
Short bowel syndrome
Malabsorption syndrome
Bowel obstruction
Internal and external fistulae
Hepatic dysfunction
Development of secondary malignancies
Table
Table 3. Surgical intervention in patients who have radiation enteritis is associated with high rates of postoperative complications including anastomotic breakdown, iatrogenic small bowel fistula, dehiscence of abdominal wound, and recurrence of adhesions and strictures [2,38].
Table 3. Surgical intervention in patients who have radiation enteritis is associated with high rates of postoperative complications including anastomotic breakdown, iatrogenic small bowel fistula, dehiscence of abdominal wound, and recurrence of adhesions and strictures [2,38].
Pathological DerangementTreatment
PainSteroids [105]
Glutamine [116]
Statins [117]
Metformin [87]
Hyperbaric oxygen [114]
DiarrheaOctreotide [118]
Sucralfate [113]
Probiotics [119]
Glutamine [116,120]
Feces transplant [67,121]
Recombinant growth factors [122]
BleedingGlutamine [116]
Steroids [105]
Hyperbaric oxygen [114]
Herbal medication [107,117]
Traditional medicine [106]
Radiofrequency ablation [111]
Stem cell therapy [36]
DysbiosisProbiotics [119]
Glutamine [116,120]
Feces transplant [121]
Anti-oxidants [93,104,108,122,123,124]
Recombinant TLR ligand [57]
MalabsorptionVitamin B12
Feces transplant [93,121]
Recombinant trefoil factor (TFT) 3 [71]
Recombinant thrombomodulin [117]
Recombinant growth factors [122]
Anti-oxidantsGlutamine [116]
Hyperbaric oxygen [114]
Metformin [87]
Selenium [115]
Statins [65,117]
Vitamin E [115]
FistulaeSurgery [6,99,102]
Obstruction (incomplete versus complete)Surgery [125]
Mesenchymal stem cells therapy [36]
OtherAce inhibitors [126]
Loperamide [127].
Sulfasalazine [127]
Total parenteral nutrition [127,128]
Vitamin B12 [129]
Low fat diet [130]
Elemental diet [130,131]
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Luvhengo, T.; Khan, U.; Marumo, T.K. Paneth Cells and Lgr5+ Intestinal Stem Cells in Radiation Enteritis. Appl. Sci. 2023, 13, 2758. https://doi.org/10.3390/app13052758

AMA Style

Luvhengo T, Khan U, Marumo TK. Paneth Cells and Lgr5+ Intestinal Stem Cells in Radiation Enteritis. Applied Sciences. 2023; 13(5):2758. https://doi.org/10.3390/app13052758

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Luvhengo, Thifhelimbilu, Uzayr Khan, and Thomas Kekgatleope Marumo. 2023. "Paneth Cells and Lgr5+ Intestinal Stem Cells in Radiation Enteritis" Applied Sciences 13, no. 5: 2758. https://doi.org/10.3390/app13052758

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