Open access peer-reviewed chapter
Abstract
Although its most well-written functions are digestion and absorption of nutrients, the gastrointestinal tract (GIT) is the most significant player in the human immune system. The GIT is home to more than 60% of the active immune cells in the entire body. Notwithstanding, the human gut is continuously exposed to antigens ingested with food and resident microorganisms. The density of microorganisms in the lumen of GIT increases aborad and is much higher in the colon. Despite a relatively low bacterial load in the small intestine, the environment is more precarious because it is nutritious and exposed to digestive enzymes. Its lining is made up of a single layer of epithelial cells covered by a thin and attenuated layer of mucus. Despite the continual exposure to the luminal antigens, the gut’s immune system is kept in a state of relative immunosuppression. The pathogenesis of some of the common non-communicable diseases includes a systemic inflammatory state initiated by dysbiosis in the gut, increased permeability of the intestinal epithelium, translocation of microbiomes or their products, and then a persistent pro-inflammatory state. Paneth cells are the key players in the innate immunity of the gut and are responsible for maintaining its integrity.
Keywords
- Paneth cells
- microbiome
- dysbiosis
- antimicrobial peptides
- defensins
- innate immunity
- systemic inflammation
1. Introduction
The gastrointestinal tract (GIT) is the largest organ in the body and is constantly exposed. At least 60% of active immune cells reside in the tissues of the GIT. An everyday healthy lifestyle requires a structurally intact and normal functioning GIT. The integrity of the GIT is maintained through continuous replacement of surface epithelial cells, which exfoliate and have to be replaced every 4–5 days [1]. Other key factors which are important for the physical integrity of the epithelium throughout the GIT are tight intercellular junctions, fine-tuning of the gut microbiome and active dampening down of the immune response. Dysbiosis followed by an ongoing systemic inflammatory state is involved in the pathogenesis of several gastrointestinal and extra-gastrointestinal conditions [2]. Medical conditions linked with a sustained pro-inflammatory state are inflammatory bowel disease (IBD), obesity, malignancies, arthritis, diabetes mellitus and acute or chronic organ-system dysfunction [1, 2, 3].
Dysbiosis is a prelude in the pathogenesis of inflammatory bowel disease (IBD), obesity, and other diseases associated with the prolonged systemic inflammatory state. It is defined as a change in the number or type of luminal microorganisms. Dysbiosis leads to the appearance of allochthonous organisms at various niches in the GIT, especially in the lumen of the small intestine and or the colon [3]. Dysbiosis leads to translocation of luminal microorganism and their products such as endotoxins, immune activation, and initiation of systemic inflammation. This chronic systemic inflammatory state is resistant to insulin and is obesogenic, diabetogenic, carcinogenic, and thrombogenic [1]. Dysbiosis and systemic inflammation also play a role in the pathophysiology of some of the complications associated with chronic human immunodeficiency virus (HIV) infection before or during treatment with antiretroviral (ARV) drugs [2]. Dysbiosis and chronic stimulation of gut immunity and subsequently systemic inflammation are purported to be among the factors which induce progressive deterioration of systemic immunity and depletion of CD4 T-lymphocytes count, and why HIV is currently not curable.
The integrity of the epithelium throughout the GIT, especially at the small intestine region, has to remain intact to ensure a healthy life. The gut immune system can defend the body from a state of perpetual systemic pro-inflammation because of a robust innate immunity that functions in liaison with elements of adaptive immunity. Every plant and animal species has a built-in mechanism to secrete antimicrobials (defensins) that prevent invasion by pathogenic organisms. Neutrophils are responsible for the secretion of defensins throughout the entire body in mammals, including the skin and parts of the GIT. Human alpha defensins are only produced by Paneth cells in the small intestine. Paneth cells are the key player in the innate immunity of the small intestine and are responsible for the robustness of gut immunity [1, 3, 4, 5, 6, 7, 8, 9].
2. Origin, structure and function of the Paneth cell
Paneth cells are found in the small intestine of humans and other vertebrates, including horses, sheep and rodents. Paneth cells are one of the four main derivatives of the intestinal stem cell [10, 11]. The other cells derived from the intestinal stem cells are enterocytes, goblet cells and neuroendocrine cells. These cells are found towards the luminal surface of the epithelium of the small intestine, whilst Paneth cells are located at the base of the intestinal crypt. They mingle with the crypt-based, Leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5+) intestinal stem cells in a 1:1 ratio [4, 12, 13]. Refer to Figure 1 for more detail on the position of Paneth cells. Paneth cells are distinguishable from the Lgr5+ stem cells and other cells in the epithelium of the small intestine, which are found at the base of the intestinal crypt because they are secretory and have eosinophilic apical cytoplasmic granules and an extensive network of endoplasmic retinaculi [1, 12, 14, 15].
Figure 1.
A schematic showing the structure and position of Paneth cells in the villus.
Paneth cells appear in utero from the 13th week of gestation [6, 16]. The number of Paneth cells progressively increase with a much more rapid expansion after the 29th week of pregnancy. A sufficient number of matured and functional Paneth cells is only attained at term [16]. Although Paneth cells are found in the entire colon of human embryos, they disappear soon after birth and are only found in the caecum and the ascending colon [17]. However, the location of Paneth cells in the epithelium of the small intestine is initially haphazard and more towards the luminal surface of the epithelium. Unlike the other derivatives of the intestinal stem cell, the Paneth cells later migrate downwards and end up at the base of the intestinal crypts. The stable number of Paneth cells in the crypt of a particular individual gets established in early adulthood. The overall number of Paneth cells in the intestinal crypt of the small intestine is influenced by factors such as the gestational age at birth, the mode of delivery, breastfeeding [6], weaning diet and period, dietary preference and disease states [17, 18]. The timing of colonization and the type of organisms involved play a role in both the development and number of Paneth cells [9, 19].
Once they are fully established, the Paneth cells are found at the base of the intestinal crypt, and in a healthy person, the number and distribution of Paneth cells remain relatively constant for up to 20 years [20]. Each intestinal crypt contains five to fifteen Paneth cells. The terminal ileum, which is the small intestine area with the highest load of microorganisms, contains the most Paneth cells. The overall number of Paneth cells in the small intestine may increase following a viral infection or a course of nutritional supplementation. Paneth cells may appear in ectopic sites due to metaplasia in certain diseased states, such as chronic inflammation [7, 21]. Similarly, the number of Paneth cells may be reduced due to malnutrition, the infestation of the GIT by parasites, chronic HIV disease, radiation enteritis, smoking, high fat diet, and aging [1, 2, 3].
There are three tiers of intestinal stem cells. The 1st tier of intestinal stem cells are found at the base of the crypt and are the so-called crypt base columnar cells (CBC cells) or Lgr5+ cells. The 1st tier stem cells are found in the most protected environment in the region where the most mature and furnished Paneth cells are. They are paired with Paneth cells on a 1:1 basis for intimate contact and direct communication. These Lgr5+ stem cells are the most vulnerable to radiation injury and require the most protection [22, 23]. It is the reason why they are closely associated with the Paneth cells. They rely on the Paneth cells for both protection and nourishment. The Lgr5+ intestinal stem cells also have the least capacity to repair any damage to their DNA. The second tier of the intestinal stem cells is found high up along the crypt-villous axis at around cell position 4. The 3rd tier of cells with stem cell capability is higher up and closer to the crypt-villous transition zone and are also called intermediate cells. The 2nd and 3rd tiers are normally quiescent and only become activated on-demand, such as following an injury to the intestinal epithelium.
Other cells found in the epithelium of the small intestine are enterocytes and goblet cells. The enterocytes are the most populous derivatives of the intestinal stem cells and are found on the luminal surface of the small intestine. The small intestine has microvilli to increase the surface area to absorb nutrients. The function of the enterocytes is not limited to digestion and absorption of nutrients, as they also participate in the innate immunity of the small intestine. Combined with junctional proteins, enterocytes provide an uninterrupted physical barrier [10, 16, 22]. The enterocytes also secrete cytokines and chemokines, which recruit immune response elements. The lifespan of enterocytes is around five days, and they are being replaced continuously. Apoptotic enterocytes remain structurally intact until they are replaced to prevent the creation of defects on the surface of the epithelium and thus increased permeability. The enterocytes can de-differentiate into the stem cells following the destruction of the intestinal stem cells and Paneth cells. The enterocytes and goblet cells can de-differentiate into stem cells if they have not yet undergone terminal division. However, the plasticity of Paneth cells is far greater as they can be de-differentiating and acquire stemness even after they have been terminally divided [22]. The responsibility of de-differentiating to stem cells is first reserved for the Paneth cells afferent task. The intermediate cells, i.e. intermediaries of the other derivatives, only get involved and regain stemness if the Paneth cells have been irreversibly damaged and cannot play the role [23, 24].
The goblet cells are the second most populous cell type in the epithelium of the small intestine. They are interspersed among the enterocytes on the luminal surface of the epithelium. The lifespan of goblet cells is around five days and thus similar to that of enterocytes. Goblet cells are also found in the colon, where they play a role similar to that performed by Paneth cells in the small intestine [14, 16, 17]. Goblet cells secrete various types of mucins. The mucins produced by the goblet cells are the main constituent of the mucus, which coats the mucosal surface of the epithelium of the small intestine and colon. Even though the layer of mucus which lines the luminal surface of the small intestine is thin and attenuated, it can assist in maintaining a high concentration of antimicrobial peptides and protein in the area adjacent to the surface epithelial cells—the other function of the goblet cells secretion of trophic factors such as the trefoil factor. The goblet cells can de-differentiate and acquire stemness if the stem cells and Paneth cells have been damaged [10, 17, 22].
Paneth cells are tall columnar cells that are pyramidal in shape because of a broader base, have supra-nuclear Golgi apparatus, and zinc-rich apical orientated cytoplasmic granules [6]. The granules contain more than 50 constituents, including antimicrobial peptides like human alpha defensin 5 and 6 (HD5 and HD6), lysozyme, secretory phospholipase A2, osteopontin, and associated pancreatitis peptide, trypsinogen, IgA, TNF-alpha and alpha 1-antitrypsin and catecholamines [6]. The predominant constituent which is contained in the granules of Paneth cell is HD5, which make up about 90% of the components. The HD5 is the main antimicrobial peptide that is secreted by the Paneth cells of the small intestine, which is responsible for the control of luminal microbiota [6]. Degranulation of Paneth cells is induced following stimulation, and the granules are replenished expeditiously, usually within 24 hours.
Paneth cells have autocrine, paracrine and endocrine functions. Similarly, Paneth cells respond to autocrine, paracrine or endocrine signals. Paneth cells also play a key role in innate and adaptive immunity by providing a direct line of communication between the two subsystems. They protect and regulate the functioning of the Lgr5+ intestinal stem cell and its derivatives, ensuring that exfoliating surface epithelial cells are regularly and timeously replaced [23]. Secretions from Paneth cells in the proximal parts of the small intestine influence the growth and function of distally situated small intestine stem cells and their derivatives [9]. The area at the base of the intestinal crypt (stem cell niche) is among the most active region in the body. The proliferation and differentiation of the Lgr5+ intestinal stem cells in the niche area is tightly regulated by secretions of Paneth cells and the cells situated in the connective tissue of the lamina propria around the base of the intestinal crypt [23]. The niche factors predominantly released by the Paneth cells influence the timing and type of division the intestinal stem cells should undergo while balancing the maintenance of the stemness and production of their progenies. The intestinal stem cell division may be symmetrical or asymmetrical [6, 10, 17].
A symmetrical division of the intestinal stem cells leads to the proliferation and production of daughter stem cells to expand the pool, whereas differentiation is prioritized during asymmetric division. The derivatives of the intestinal stem cell are generated following an asymmetric division. Both symmetrical and asymmetrical divisions are initiated and regulated by the niche factors which are produced by the Paneth cells and cells in the adjacent mesenchyme of the lamina propria in the peri-crypt space region. These niche factors, which include Wnt and Notch act as signals for the intestinal stem cells [23]. Even though they are in intimate physical contact, Paneth cells also have ligands for engagement with factors produced by the intestinal stem cells for cross-talk [23]. As indicated previously, When conditions are extremely hostile, and the stem cells have been destroyed, paneth cells can de-differentiate and acquire stem-ness.
Paneth cells have pattern recognition receptors that include nucleotide-binding oligomerization domain-like (NOD) and toll-like (TLR) receptors which they use to continuously sample the microbiome’s composition in the lumen of the gut to prevent dysbiosis and or invasion by pathogenic organisms [24]. Paneth cells in the terminal ileum where Peyer’s patches jointly sample the luminal contents and directly communicate with the M-cells. Paneth cells communicate remotely with the active immune cells and mesenchymal tissue in the lamina propria of the gut epithelium. Secretion from the Paneth cells is continuous with augmentation following a stimulus. The net effect of the Paneth cells’ secretions depends on both their composition and volume. The secretions from the Paneth cells help to regulate and fine-tune the gut microbiome [9, 13, 24, 25]. The antimicrobial peptides secreted by the Paneth cells selectively kill pathogenic organisms while sparing the commensals. Ultimately, several microbial niches are created along the entire length of the small intestines where the microorganisms are naturalized and live in a symbiotic relationship with the host. Some of the organisms in the established niches assist during the digestion of food. Additionally, the composition of the flora freely floating in the lumen of the small intestine is different from the area close to the surface epithelial cells. The region closest to the epithelial cells’ surface has the highest concentration of antimicrobial peptides and, therefore, the most repulsive to non-commensal organisms [26, 27].
Once established, the commensal organisms in the gut assist with digestion and absorption of essential nutrients in either the small intestine or colon, preventing the overgrowth of potentially pathogenic microorganisms and immune regulation [24]. Some of the ingested compounds in the food would not be digestible were it not for certain species of resident microorganisms. The overall number of nutrients available in a particular site is a secretion of antimicrobial molecules that creates areas of zonal dominance by some species of microorganisms. The task of the Paneth cells is to accept the dominant organisms in various niches and for the sustenance of the symbiotic relationship. A deviation from the established normality is detected by the Paneth cells through their pathogen recognition receptors leading to degranulation and release of antimicrobial peptides. The change in the microbiome may occur following the use of broadspectrum antibiotics, change in diet, change in the anatomy of the GIT, alteration of gut transient time or a state of suppressed systemic immunity [25].
The other role of the Paneth cells is to nourish the intestinal stem cells [11, 12, 22]. Paneth cells derive their energy from the glycolytic pathways, whereas the intestinal stem cells’ Adenosine triphosphate (ATP) is derived from aerobic metabolism in their mitochondria. The lactic acid which is produced by a Paneth cell is shunted into adjacent intestinal stem cells for their metabolism. Paneth cells can sense the fed-state of the body and, after that, influence the intestinal stem cell activity accordingly. If the epithelium is damaged, they become more active. Paneth cells are found in the normal human small intestine from the duodenum to the terminal ileum [26, 27]. They are most abundant in the region of the terminal ileum. The hostility of the environment, which increases as one move distally along the small intestine due to increment in the number and species of microbes, is a plausible explanation of the need for more Paneth cells at the region of the terminal ileum [26]. Paneth cells are not found in a healthy stomach and colon, except for a few in the caecum and the ascending colon [26]. Paneth cells may develop following metaplasia associated with chronic gastritis and inflammatory bowel disease in the stomach and colon. The effects of paneth cell secretions are enumerable and continue to be added. The result of the secreted factor varies depending on the type, volume and concentration of secretions. These effects include antimicrobial activity, inflammation and regulation of intestinal stem cells’. The antimicrobial peptides secreted by Paneth cells help sterilize the intestinal crypt environment, the so-called “stem cell zone; and thus protect intestinal stem cells [7, 13, 22, 28, 29, 30].
The antimicrobial peptides which are produced by the Paneth cells are of three types: Type 1 is cationic, Type 2 is amphipathic, and Type 3 is composed of hydrophobic peptides [31, 32]. The micro-biocidal effects of Type 1 and Type 2 are based on induction of damage to the surface of the cell membrane and creation of large pores as it penetrates deeper into the hydrophobic cell membrane and its bi-layer, respectively. Type 3 peptides cause micellization of the cell membrane of pathogens. The antimicrobial peptides produced by various cells in humans include cathelicidins and alpha and beta-defensins. Beta-defensins are produced in almost every cell in the body, including neutrophils. The Paneth cell is the only source of cathelicidins, HD5 and HD6 in humans. The synthesis of cathelicidins ceases when the foetus reaches term and is then replaced with HD5 and HD6 [6, 24]. The antimicrobial peptides from human Paneth cells are secreted in a pro-active form and become activated in the lumen of the small intestine [32]. The Paneth cell secretions are secreted together with water and chloride ions and assisted by peristalsis to bathe the crypt environment to make it conducive to functioning the tiers of intestinal stem cells [6, 22, 33]. The solvent load and anionic composition in the secretion assist in the after-release potentiation of the antimicrobial peptides [31]. In addition, the bile salts in the small intestine influence the killing activity of paneth cell-derived antimicrobial peptides. The human alpha-defensins are active against bacteria, fungi, parasites, and viruses [31, 32]. The HD5 is microbicidal, and the HD6 binds the antigens to prevent invasion until it is eliminated. The action of HD6 is similar to that of the IgA antibodies. The binding of antigens by HD6 buys time for the other elements of innate immunity of the gut to arrive [31, 32].
Matured Paneth cells are found at the base of the intestinal crypt of the small intestine, where the most vulnerable but essential intestinal stem cells are found. The loss of senescent Paneth cells like absorptive enterocytes, goblet cells and neuroendocrine cells is programmed [6]. The senescent Paneth cells die and are removed through phagocytosis following apoptosis. The other mechanism involved in the death of Paneth cells is autophagy, which ensures that some essential constituents found in the cytoplasm are recycled. Apoptotic enterocytes located at the tip of villi remain structurally intact until they are replaced by a carpet of new cells arriving from the stem cell zone. A perfect balance between the rate of proliferation and loss through exfoliation is sustained to ensure that defects are not created, and the epithelium of the small intestine becomes permeable to microorganisms and their products [11, 16].
A healthy life without a normally functioning small intestine is not possible. The influence of the Paneth cells on the GIT starts soon after birth. Henceforth, the Paneth cell influences everything that happens in the gut, whether physical or biochemical barrier, absorption of nutrients, and linkage with the body’s overall immune system. Paneth cells play a role in the development and maturation of the innate immunity of the gut and subsequently of the entire body. The immune system is a dominant player in systemic immunity, including adaptive immunity. Paneth cells maintain the integrity of the gut by controlling the microbiome, regulating proliferation and differentiation of the intestinal stem cells, influencing the quality of mucin in the mucous, and keeping the crypt environment relatively sterile for the protection of the intestinal stem cells. Paneth cells also release growth signals that influence the growth and function of the enterocytes, goblet cells, and neuroendocrine cells [7, 9, 11]. Chemokines and cytokines produced by Paneth cells can also recruit and influence components of adaptive immunity in the adjacent lamina propria [34]. Among the cytokines which are produced by the Paneth cells is TNF-alpha. There is also cross-talk between the Paneth cells and elements of adaptive immunity [34, 35].
A plethora of acute and chronic conditions are driven from the gut. These conditions may be initiated by a changing diet, starvation, trauma or sepsis. The normal development of the crypts and villi of the small intestine and control of the microbiome is dependent on the Paneth cells. Paneth cells continuously sample the luminal contents for the gut microbiota composition to prevent dysbiosis. Dysbiosis leads to increased gut permeability and translocation of bacteria and endotoxin [3]. Usually, when the body experiences significant physiological stress, the gut mucosa is strategically sacrificed; a typical example is the shunting of blood from the GIT in various shock states. If prolonged, what is meant to be a short-term survival strategy leads to dysbiosis, across the intestinal epithelium. Translocation of bacteria and endotoxins is the driver of systemic inflammation. The gut is the most trusted and potent site for eliminating invading pathogens [35, 36]. Shunting of invading pathogens to the GIT also applies to viruses, including HIV. Should the gut immune system fail to eliminate the pathogen, as it happens following HIV infection, the gut ultimately becomes a long-term reservoir and haven of mutated strains of the virus, which is currently impossible to eradicate despite the availability of potent antiviral drugs [36, 37].
3. Paneth cells and diseases
Paneth cells are involved in the fight against and pathogenesis of diseases. Paneth cells’ effect on diseases is evidenced by changes in their granules, the total number, position, or distribution pattern. The health status of Paneth cells is assessed by checking their presence, position, number and intensity of staining of their granules [3, 10, 15, 27, 34, 38, 39]. The integrity of the intestinal epithelium is assessed directly by measuring the depth of the intestinal crypt, the height of the villi, mitotic count [27], Ki67 index, markers of apoptosis and epithelial integrity as evidenced by, for example; the presence of bacteria inside intestinal epithelial cells and translocation. Dysbiosis is one of the key steps in the pathogenesis of many medical and surgical diseases [19, 40]. Translating bacteria and endotoxins induces an immune response leading to a systemic inflammatory response. Immune activation and resulting systemic inflammation are deleterious to the body as it has been proven to be the underlying reason behind most metabolic diseases such as type 2 diabetes mellitus, cardiovascular disease, and obesity. Chronic immune activation and systemic inflammation are paradoxically the major drivers of complications associated with chronic HIV infection regardless of treatment with antiretroviral drugs [41, 42, 43, 44, 45]. A chronic inflammatory state is one of the main reasons why HIV currently can neither be cured nor eradicated.
Duodenal Paneth cells are reduced in individuals with idiopathic autoimmune enteropathy [21]. Cells with the characteristic of the Paneth cells and goblet cells, the so-called intermediate cells, may appear high up in the intestinal epithelium crypt above position eight in patients with inflammatory bowel disease [46]. The number and size of paneth cells are increased in individuals who have autism with gastrointestinal tract symptoms [47]. Among the conditions which are associated with dysbiosis and increased permeability of the intestinal epithelium are chronic HIV/AIDS [2, 42, 43, 48, 49, 50, 51, 52, 53] and HIV-linked surgical conditions such as necrotizing enterocolitis [54], obstructive jaundice, inflammatory bowel disease [55, 56, 57], obesity [40, 58, 59] fasting and prolonged total parenteral nutrition [3, 38]. The above conditions have either been proven or are possibly linked to dysfunction of Paneth cells in the small intestine.
Diseases that have been conclusively linked with change in the appearance of paneth cells include necrotizing enterocolitis [1, 60], starvation [38] prolonged total parenteral nutrition [3], inflammatory bowel disease [7, 20, 36], mesenteric ischaemia, radiation enteritis [61], coeliac disease [27], colorectal carcinoma [62], autism [47] and HIV infection [63, 64, 65]. The other evidence of ill health in the gut include atrophy of small bowel mucosa, the appearance of defects in the mucosa, translocation of bacteria and toxins, systemic sepsis and development of inflammatory bowel diseases or the appearance of malignant neoplasms. In this chapter, we illustrate the direct role played by the Paneth cells in their pathogenesis using the diseases below.
3.1 Necrotizing enterocolitis
Current knowledge of the function of Paneth cells has enhanced the understanding of the crucial role in the pathogenesis of Necrotizing enterocolitis (NEC). NEC is a common condition that affects neonates and is manifested by acute inflammatory changes in the bowel wall. The risk factors of NEC include prematurity, low birth weight (<1.5Kg), formula feeding, antibiotic use and HIV status of the mother [2, 66]. Some studies attribute the pathogenesis of NEC to premature colonization of the gut in the neonate or an ischaemic event [60, 66, 67, 68]. Necrotizing enterocolitis is linked with untimely colonization of the gut when the gut immune system has not matured. A sufficient number of Paneth cells and their maturity only get established around the term. When they are well developed, Paneth cells can secrete an adequate amount of antimicrobial peptides, including HD5 and HD6, for innate immune defense. The switch from cathelicidins to defensins only occurs during the third trimester of pregnancy [60].
Consequently, preterm babies are prone to colonization by pathogenic organisms, followed by bowel invasion by pathogenic bacteria and inflammation. Early oral feeding of infants leads to dysbiosis, increased permeability, bacterial translocation, and an inflammatory state in the intestinal epithelium. The ongoing inflammation would then lead to ischaemia. The inflammatory process causes thrombosis of vessels in the submucosa and the lamina propria. In some cases, the initiating event for NEC is ischaemia and then inflammatory response. The most feared complication of NEC is bowel necrosis, leading to perforation and severe sepsis. In some cases of NEC, ischaemia is the initiating event. Both premature colonization and ischaemic events are associated with abnormality in the functioning of the Paneth cells [1, 60].
3.2 Colorectal carcinoma
Colorectal carcinoma is among the top five most common malignancies worldwide. The common sites involved in colon cancer are the rectosigmoid area, caecum and the transverse colon. The majority (>90%) of colorectal cancers are sporadic. The development of sporadic colorectal cancer is preceded by an adenomatous polyp, the so-called adenoma-carcinoma sequence. Colonocytes rely on nutrients derived from the fermentation of indigestible fibers by resident bacteria. Some sporadic cancers are associated with dysbiosis [69, 70]. Abnormalities of Paneth cells, including metaplasia, have been reported in colorectal cancer [62]. Furthermore, Paneth cells in the colon of patients diagnosed with adenomatous polyps or invasive cancer are associated with aggressive disease and poor prognosis [70].
3.3 Inflammatory bowel disease
Inflammatory bowel diseases (IBD) include Ulcerative colitis (UC) and Crohn’s disease (CD). Although the main manifestations of ulcerative colitis are mainly limited to the colon, Crohn’s disease is a systemic disease that can affect any organ in the body. The exact cause of either UC or CD remains unknown and is presumed to be environmental [46, 56, 57]. However, what is common in the pathogenesis of UC and CD is the failure of the innate immune system. In UC, there is dysbiosis with an overgrowth of pathogenic organisms. The pathogens are recognized as foreign by the Paneth cells, leading to an inflammatory response in the bowel wall [9]. Some cases of Crohn’s disease are due to genetic defects, which diminishes the ability of Paneth cells to sense and regulate the gut microbiome. Mutation of NOD 2 receptor is linked with the development of CD as the Paneth cells of the affected individuals in CD cannot secrete sufficient antimicrobial peptides to prevent dysbiosis [57].
3.4 Paneth cells and the human immunodeficiency virus and other viral infections
The GIT is the trusted site for sequestration and subsequent elimination of pathogens following a viral infection. Immediately following the invasion by HIV or other viral infections, the virus is transported to active immune sites within the GIT. Some of the viruses are eliminated, whereas others remain dormant in tissues of the GIT. Paneth cells are involved during early and later phases following a viral infection. Regardless of the treatment status, diabetes mellitus, cardiovascular disease, dyslipidemia, and malignancies are more prevalent in HIV positive individuals than HIV negative individuals with the same conditions [51, 58]. Non-communicable diseases are responsible for a persistent reduction in the life expectancy of HIV positive individuals despite treatment with potent antiretroviral drugs [45]. A similar inflammatory process resulting from dysbiosis happens during chronic HIV infection and or treatment with ARVs, resulting in the same consequences of obesity and other non-communicable diseases [48, 51, 58, 71].
3.5 Paneth cells and obesity
The quality of Paneth cells is influenced by an individual’s nutritional status and dietary intake. A diet that is high in fat is detrimental to the Paneth cell. Obesity affects a significant proportion of the citizens of most countries in the world regardless of their socioeconomic status [68, 72, 73]. Individuals who are obese are at an increased risk of diabetes mellitus, cardiovascular disease, liver dysfunction, and colorectal cancer, all characterized by a state of a persistent inflammatory response. The development of obesity is preceded by dysbiosis, bacterial translocation and persistent systemic inflammation [40]. The link between dysbiosis and Paneth cells has been established in the sections above.
3.6 Obstructive jaundice
The common causes of obstructive jaundice are biliary atresia in children and gall stones or malignancy in adults. Sepsis is the most dreaded complication of obstructive jaundice before or after surgical intervention. The sepsis in obstructive jaundice is preceded by dysbiosis, increased epithelial permeability and translocation of bacteria [74, 75]. A state of relative immunosuppression that generally exists in the gut is lost, and a pro-inflammatory state ensues as evidenced by increased baseline interleukin-6 and C-reactive protein [76, 77].
4. Conclusion
The large surface, a thin barrier, and a microbiome of approximately 100 trillion microorganisms make the GIT the area of the body most at risk of pathogenic invasion [78]. More than 60% of active immune cells are found in tissues of the GIT. The immune system of the GIT is kept dampened to prevent an immune response and persistent inflammation in the gut, which may spill over systemically. Hence the need to maintain gut integrity. The crucial role Paneth cells play in the provisioning and regulation of the innate immune system of the gut cannot be underestimated. The Paneth cell is a nurse, guardian and chaperone, fine-tuning the gut microbiome to prevent dysbiosis, controlling the physiological function, proliferation and differentiation of the intestinal stem cells, and acquiring stemness to replace damaged intestinal stem cells. These cells liaise with cells in the mesenchymal and recruitment of adaptive immunity to prevent pathogenesis, earning the term of gatekeeper of the gut.
Acknowledgments
The authors would like to acknowledge the Department of Surgery at the University of the Witwatersrand and Charlotte Maxeke Johannesburg Academic Hospital.
Notes/thanks/other declarations
The authors would like to thank the University of the Witwatersrand for supporting this work and related academic projects.
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