Following infection, schistosomulae migrate through the host body and a type 1 immune dominated response is elicited, persisting for ~5 weeks. This response is characterized by increased release of Interleukin (IL)-12 and interferon (IFN)-γ and is mainly targeted at worm antigens. However, as the parasite matures and starts to produce eggs (~5–6 weeks postinfection), a shift toward a type 2-biased immune response occurs. Consequently, IFN-γ production decreases, while CD4⁺ T helper (Th) 2 cell polarization is induced. The switch from type 1 to type 2 is elicited by the eggs released by adult female worms. Indeed, whole S. mansoni eggs or their soluble egg antigens (SEA) potently induce type 2 responses when injected into naïve mice (21). Importantly, a defect in switching the type of immune response leads to aberrant intestinal inflammation and fatal disease (22, 23). The protective type 2 immune response is characterized by expansion of Th2 cells, eosinophils, and basophils, increased production of IL-4, IL-5, and IL-13, an isotype switch toward IgG1 and IgE, as well as polarization of macrophages toward the M2 phenotype (24, 25). During the chronic phase of infection (>3 months), the magnitude of the Th2 response decreases, coincident with a reduction in granulomatous inflammation around eggs, and regulatory T and B cells emerge leading to a state of immune hyporesponsiveness.

Granuloma formation around eggs trapped within hepatic and intestinal tissue is a hallmark of schistosome infection and the major cause of pathology in infected hosts. However, the egg granuloma functions for both the host and parasite (26): (a) intestinal granulomatous inflammation facilitates the translocation process for the egg into the gastrointestinal lumen, (b) it ameliorates bacterial translocation from the intestine into the circulation of the host, (c) it protects host tissues from exaggerated immune responses against the antigenic eggs, and (d) it ultimately benefits the adult parasites to keep the host intact.

Female S. mansoni worms deposit their eggs close to the vasculature surrounding the intestines and exploit the host protective mechanism to facilitate egg transgression in order to get them transported through the endothelium and intestinal wall into the gut lumen. It has been estimated that S. mansoni eggs are viable for ~3 weeks indicating that eggs complete the transition through the intestinal wall well within that time frame but in no less than 6 days (27). Therefore, the intestinal granulomas will have characteristics of what is seen in early stage liver granulomas (Figure 1). Moreover, histological analysis has shown that colon granuloma composition differs from liver granulomas harboring more macrophages but less eosinophils, T and B cells (28). However, to date, a comprehensive in-depth characterization of the composition of the intestinal granuloma remains to be published. Due to the longevity of infection and constant egg deposition, assessing the temporal order of events during granuloma formation in the intestine is challenging. Recently, a novel approach has been published, in which S. mansoni eggs are surgically implanted into the sub-serosal tissue of small intestine or colon of mice (29), facilitating the direct and kinetic analysis of egg priming of the immune system in the intestine and within the local draining mesenteric lymph nodes.

The formation of granulomas around eggs disseminated into the liver is better understood (Figure 1). In contrast to intestinal granulomas, the liver granuloma cannot be shed and becomes fibrotic over time. Recently, a histological analysis of granulomas revealed that the majority of productive, collagen rich granulomas during natural and experimental S. mansoni infection develop in the liver, probably as eggs are trapped in the hepatic tissue as opposed to intestinal granulomas, which appear more organized and with fewer, circumferal collagen fibers (30). Interestingly, hepatic granuloma size decreases from weeks 8 to 20 post-infection, at which point it stabilizes for at least another 32 weeks (10). This down modulation of egg granuloma size reflects the hyporesponsive state of immunity that develops as the infection progresses to chronicity. While normal lobular liver architecture is retained, angiogenesis occurs and contributes both to the genesis of schistosomal portal fibrosis and to fibrotic degradation (31). Indeed, experimentally infected and treated mice showed significant remodeling of hepatic schistosomal lesions over time. A notable feature of the granuloma surrounding the the liver is its protective function to encapsulate hepatotoxic secretions from the egg (26)–in particular omega-1 (ω1) (32).

It is important to highlight that the egg is a live and biologically active organism that proactively interacts with the host to manipulate immunity and achieve its successful excretion from the host. The shell of the egg itself, aided by factors released from maturing eggs, likely contributes to the initial attachment of the egg to the endothelium. This activating process facilitates granuloma formation and ultimately egg excretion. Indeed, these egg secretions (ES) are the active interface between the egg and the host (33, 34). The egg shell and its ES bear a number of molecules with potential immunomodulatory (IM) activity. The two major secreted egg IM are described in more detail here as they may play an excretion-promoting role in the intestinal granuloma.

Within the mesenteric vasculature, adult male and female schistosomes reside. Here, they move against the blood toward the endothelium facing the intestinal epithelium as a response to a nutrient gradient. Female S. mansoni worms release roughly 300 eggs per day–equalling approx. one egg every 5 min–a rate that stays constant for at least 1 year (10). Although female worms flex backwards during oviposition (thereby releasing the egg in close proximity to the endothelium), active penetration of eggs through the endothelium is unlikely (34). The metabolic enzymes enolase (phosphopyruvate hydratase) and glyceraldehyde-3-P-dehydrogenase (GAPDH) have been identified as parts of the eggshell and act as surface receptors to bind plasminogen (60, 61) increasing the fibrinolytic activity of the egg. Further, lack of enolase has been shown to decrease binding of other pathogens to the endothelium (62, 63). Although both enolase and GAPDH are present in exosome-like vesicles (ELVs) produced by adult S. mansoni worms (61), it is not known if ELVs are also released from the egg stage. The release of such metabolic enzymes within the surrounding egg milieu induces a localized metabolic niche that modulates local cell functions to achieve egg excretion.

Indeed, human enolase has been shown to activate pulmonary endothelial cells and to increase surface expression of the cellular adhesion molecule ICAM-1 (64). It has been reported that endothelial cells actively migrate over freshly deposited eggs in vitro (65), a process enhanced in the presence of sera. Furthermore, eggs can bind to and activate platelets, which may subsequently activate endothelial cells (66). This process also seems to contribute to extravasation, with thrombocytopenia impairing egg excretion (67). Interestingly, schistosome eggs also bind other host plasma proteins, including von-Willebrand factor, which may assist in the initial attachment to the damaged or activated endothelium (68). Enolase, present in the egg shell, can also act as a plasminogen receptor and induce plasminogen activation and plasmin generation (69). Plasmin can subsequently contribute to blood clot lysis (important for adult worms) and may induce monocyte recruitment (70).

The initial recruitment of immune cells to the site of granuloma formation is dependent on cellular adhesion molecules, such as ICAM-1. ICAM-1 is upregulated by SEA and high expression can be observed within hepatic granulomas (71). Here, it is essential for granuloma formation, especially during early acute stages (72–74). Ileal and colonic granulomas also showed high expression of ICAM-1 as well as LFA-1 and VLA-4 in acute and chronic infection (75). In ICAM-1-deficient mice, VCAM-1 was upregulated in hepatic granulomas, whereas no expression of ICAM-2 or PeCAM was observed (71). Interestingly, close correlation has been identified between soluble ICAM-1 and fecal egg counts from infected patients feces (73) where it was proposed to function as a negative regulator by inhibiting leukocyte recruitment and downmodulation of granuloma formation.

It has been suggested that the presence of the characteristic lateral spine of the eggs may facilitate attachment to the endothelium, perhaps causing cell damage to elicit a danger signal and while intestinal peristalsis may also contribute to the extravasation process, its actual function remains unclear. However, a study published in 2013 showed that the location of egg deposition within the intestinal tract may contribute to efficient egress of eggs (76). S. mansoni eggs are significantly more abundant in areas with Peyer's patches, where egg secretions cause loss of cellularity facilitating transition. Indeed, in support of this, mice without Peyer's patches excrete fewer eggs (76).

The main mechanism that facilitates egg excretion is the formation of the granuloma around the egg. As most findings concerning granulomatous inflammation have been found in hepatic granulomas, the following events have to be treated with caution as experimental data for the formation of intestinal granulomas is largely missing.

It has been noted earlier that the process of S. mansoni egg excretion is an exquisite, immune-dependent process (Figure 3) as illustrated by significant reduction in fecal egg excretion in T cell- (44, 77, 78) and nude mice (79). Severe combined immunodeficient mice were almost incapable of passing parasite eggs in the first weeks of oviposition (80, 81). Indeed, S. mansoni-infected HIV+ patients with acquired immunodeficiency syndrome had fewer eggs in their feces than HIV seronegative patients with the same levels of S. mansoni infection (82, 83), which correlated with CD4 T cell counts after anti-retroviral therapy (84). However, the role for CD4⁺ cells in schistosome egg excretion of humans was not evident in studies on other HIV+ patient cohorts (85, 86).

Strikingly, mice deficient in the Th2-associated cytokines IL-4 and IL-13 passed almost no eggs in their feces (23). IL-4-deficient mice display significantly impaired granuloma formation and increased mortality associated with intestinal pathology (22). This is also observed in mice with a combined deficiency in IL-4 and IL-13 (23) which also develop fatal endotoxemia. Furthermore, IL-4-deficient mice show a significant accumulation of eggs in the intestinal wall, a finding supportive of the function of the granuloma in facilitating egg excretion (23). Similarly, mice with specific deficiency in IL-4 and IL-13 within T cells succumb to acute S. mansoni infection (25). Also, IL-4Rα^−/− mice may develop fatal hemorrhaging following S. mansoni indicative of a protective role of the granuloma from exacerbated immunopathology in the intestine (87). IL-4Rα-signaling involves both IL-4- and IL-13-mediated receptor engagement and the particular role of IL-13 was revealed to drive hepatic fibrosis (23, 88).

While there has been a focus on T cells, other immune cells also contribute to both granuloma formation and the excretion of eggs. Indeed, eosinophils are a major constituent of intestinal granulomas (89). Although their precise role remains unclear, it has been reported that eosinophils may promote egg excretion (90). However, studies using anti-IL-5 antibody-mediated eosinophil blockade found normal numbers of eggs passed in the feces (91, 92), with no marked alterations in hepatic granuloma formation noted in transgenic mouse models of eosinophil deficiency (93). Another possible function of granuloma eosinophils may be the destruction of miracidia within the surrounded (trapped) egg (94), in part explaining the higher abundance of eosinophils in hepatic granulomas (28, 30) and the occurrence of eosinophil pyroptosis in vivo (95).

Basophils can be directly activated by IPSE/α1 to release IL-4 (38) and are present in intestinal granulomas (96). Additionally, a new molecular mechanism of action has been revealed whereby IPSE, a member of the βγ-crystallin superfamily, can bind IgE through the IPSEs crystallin fold thereby activating basophils independently of formal IgE cross-linking (97). Although basophils have been shown to drive Th2 polarization in other helminth infection models (98, 99), whether or not they contribute to intestinal granuloma formation and egg excretion is unclear to this date (25, 100).

While neutrophils are found to acquire a pro-inflammatory phenotype during S. japonicum infection (101), they do not seem to participate in the granuloma formation in S. mansoni infection (87), which may be in part due the presence of the kunitz-type protease inhibitor SmKI-1, capable of inhibiting neutrophil function (102).

The more recently described group of innate lymphoid cells (ILC) have gained a lot of attention as they are capable of initiating type 2 immune responses against certain helminths and during allergic responses (group 2), maintaining intestinal homeostasis (group 3), and enhancing type 1 responses via IFN-γ release [group 1; reviewed in (103, 104)]. To date, only limited data is available on the contribution of ILC, and in particular ILC2, during S. mansoni infection toward granuloma formation and egg excretion. In a pulmonary model of schistosome egg injection we have shown that ILC2 can contribute to pulmonary fibrosis (105). Because ILC2 are abundant in the intestine and they can directly interact with CD4 T cells to enhance polarization toward Th2, they may play non-redundant roles in the excretion process by instructing T cell responses. ILC2 are mainly activated by the alarmin cytokines IL-33, IL-25, and TSLP to produce IL-5 and IL-13. While individual ablation of each of these cytokines did not impair hepatic granuloma formation in chronic schistosomiasis, the combinatorial targeting of all three cytokines led to reduced hepatic fibrosis, impaired eosinophil recruitment and fewer numbers of IL-13-producing ILC2 (106). Thus, while the impact on early intestinal granuloma formation and egg excretion remains obscure, the marked effect of alarmins is highly likely to impact on intestinal granuloma formation. Omega-1 released from eggs within the intestines may–in addition to cytotoxic effects–increase the release of IL-33 and therefore the activation of ILC2. Additionally, ILC3 might exert similar functions as they have been shown to be involved in the maintenance of tolerance toward commensal microbiota through the interaction with CD4 T cells in the gut (107). Interestingly, altered numbers of ILC2 have been detected in the circulation of S. haematobium-infected patients (108). However, further investigation is required to fully elucidate the role of ILC populations in schistosoma infection and granulomatous inflammation.

Dendritic cells (DCs) are capable of processing and presenting schistosome egg antigens (109) and depletion of DCs during an ongoing S. mansoni infection severely disrupts the generation of the Th2-polarized immune response (110). While hepatic conventional DCs act in an immunogenic, rather than tolerogenic, capacity, their function in the intestine may be different (111). Using an injection model for the direct delivery of schistosome eggs into the subserosal intestinal tissue revealed that IRF4-expressing CD11b⁺ DCs promote Th2 responses in the intestine (29). It further has been shown that Omega-1 is the major component conditioning DCs for Th2 polarization (48).

Macrophages are the most abundant cell population in intestinal granulomas (28). During S. mansoni infection of immunocompetent mice macrophages acquire a protective alternatively activated phenotype through IL-4- and IL-13-mediated IL-4Rα-signaling. The M2 phenotype is associated with the increased expression of Arginase-1, an enzyme converting L-arginine to L-orthinine, which is further converted to proline–a critical amino acid for the production of collagen, and therefore, the development of fibrosis (112). While this process is detrimental to host survival through fibrotic liver damage, it might not be as critical in the intestinal granulomatous response as the surrounding granulomas are overall more temporarily restricted. Therefore, other properties of IL-4Rα-mediated M2-polarized macrophages, such as IL-10 production, PD-L2 and Relmα expression, may be more crucial to prevent aberrant inflammation.

When macrophages are unable to respond to IL-4 and IL-13 cytokine signals in IL4RαLysMCre mice the hosts succumb to endotoxemia, which can be in part rescued by antibiotic treatment (87). More inflammatory cells were observed surrounding intestinal granulomas suggesting that M2 macrophages are specifically required to prevent excessive damage to the intestinal wall and promote the efficient transport of eggs into the intestinal lumen. In contrast, Arginase-1-expressing macrophages were shown to limit Th2 responses (113) and prevent the formation of exacerbated granulomas in the liver. Later, it was found that Lyz2lo macrophages were able to escape LysMCre-mediated IL-4Rα-deletion and acquire M2 properties in response to S. mansoni egg injection, which may account for some of the observed differences between studies (114). It was further shown that during S. mansoni infection macrophages require IL-4/IL-13 released from Th2 cells to acquire an M2 phenotype (25). Importantly, granuloma formation was significantly impaired in mice with T cell-derived IL-4/IL-13-deficiency and egg excretion in the feces was compromised, although it did not reach statistical significance. These results suggest that while M2 macrophages contribute to the increased fibrosis surrounding the trapped eggs in the liver, they also promote efficient shielding of the eggs in their transition through the intestinal tissue in order to prevent excessive damage. Macrophage phenotype and granuloma formation is ultimately determined by Th cell polarization.

T cells are the most important cells for successful egg excretion in the intestine. Antibody-mediated depletion of T cells was shown decades ago to lead to impaired granuloma formation, egg retention and exacerbated disease resulting in increased mortality (78). Later targeting of L3T4 (CD4) T cells phenocopied anti-CD3 mediated depletion highlighting the role of the T helper subset (115). In S. mansoni infected mice subjected to anti-CD4 mAb-depletion the size of the granuloma is significantly reduced in liver and intestines [Figure 2C, (116)]. Furthermore, the cellular granuloma composition in CD4-depleted mice consists of fewer eosinophils and more neutrophils, which are virtually absent in the eosinophil-rich granulomas of immunocompetent mice. Similarly, the absence of T cell-derived IL-4/IL-13, e.g., the functional absence of Th2 cells, impairs granuloma formation and egg excretion, and was found to increase mortality (25).

The critical role of Th2 cells for the protection of host tissue from cytotoxic effects and correct granuloma formation is further substantiated by studies showing that injection of the Th1 cytokine IFNγ interferes with granuloma formation and IL-12- deficiency–in fact Th1-ablation–increases granuloma size and Th2-mediated inflammation (117, 118). Although Th1 cells seem to be required for the early release of IFNγ and IL-2 facilitating granuloma formation as part of a delayed type hypersensitivity response, prolongation of the Th1 response led to increased pathology and mortality (44, 117, 119, 120). Furthermore, it was shown that hepatosplenic schistosomiasis in human patients is associated with increased levels of TNFα and IFNγ, while type 2 cytokines are reduced (121).

IL-17-producing Th17 cells have also been implicated in schistosome granuloma formation as IL-17 levels in susceptible and resistant mouse strains correlated with granuloma formation (122). This has been shown to be a direct effect on the IL-23 and IL-1 release of DCs in response to SEA (123, 124). In the context of the roles of egg glycans in immune priming, theses pathological effects are mediated through the C-type lectin receptor CD209a (125).

In the absence of Th1 cells (Tbet^−/−) Th17 cells drive exaggerated inflammation with an increase of neutrophil infiltration into the granuloma, while the combined absence of Th1 and Th17 cells led to smaller granulomas with increased type 2 biased infiltration of M2 macrophages and eosinophils (126).

Regulatory T cells expand during the chronic stage of S. mansoni murine infection and are present in S. mansoni infected patients (127–129). It has speculated that immunosuppression by Treg cell by the release of IL-10 and TGFβ may limit tissue pathology toward trapped eggs during infection (130–132).

The role of B cells and antibodies in S. mansoni infection of mice has been extensively investigated. While B cells were found to be involved in the development of Th2 polarization, their role in granuloma formation is still not entirely clear (133–135). Antibodies specific for SEA arise after egg deposition and expand throughout infection (136) and multiple studies have shown regulatory roles of antibodies in granuloma formation (137–139). Interestingly, immune complexes of chronically infected patients were capable to inhibit granuloma formation in vitro (140). Indeed, infection of Fc-receptor deficient mice (γ or ε) led to the formation of larger and collagen-rich granulomas (138, 139), suggesting regulatory potential of Fc-bearing effector cells within the granuloma or sequestration of egg antigens. Whether this process is involved in the maintenance of intestinal granulomas remains to be investigated.

Identification of regulatory B (Breg) cells in response to schistosome eggs (141) and their production of IL-10 in response to the schistosome glycan LNFPIII (142, 143) led to subsequent studies using live S. mansoni infections (144–146). Indeed, α1 drives the expansion of Breg cells (147). Because Bregs arise late during chronic infection it seems unlikely that they contribute to the natural intestinal granuloma formation facilitating egg excretion and rather may contribute to limit chronic intestinal inflammation.

The functions of the tuft cell as IL-4Rα-expressing IL-13-responsive cell type in the intestine has been described during gastrointestinal nematode infections (148–150). Whether these cells contribute to the intestinal granuloma formation by their IL-25 release or facilitate the egg excretion process during S. mansoni infection has not been investigated.

Taken together, egg excretion through the intestinal wall can only be achieved in the presence of a Th2-biased granulomatous inflammation. All cells described here take part in the shaping of the intestinal granuloma and may therefore influence Th2 polarization, toxicity protection and promote or inhibit egg excretion. While the roles of CD4⁺ T cells and macrophages is well-understood, more research is required focusing on other immune cells function in intestinal granulomas.

Yet, the question remains: What drives the egg+granuloma to transit from the endothelium toward the epithelium?

The mechanism of how the viable egg transits through the intestinal lamina remains elusive, however, some findings suggest a role for the developing granuloma, extracellular matrix degradation, and schistosome egg antigens.

Recently, the collagen, fibronectin and plasmin contents of intestinal granulomas have been investigated (151). After extravasation, fibrinolysis can be observed around the biologically successful eggs, i.e., those that will achieve egg excretion, in contrast to trapped eggs that are not excreted (Figure 3). Plasma fibronectin is part of the blood clotting and wound healing response and it was recently found that S. mansoni is able to express extracellular tegumental calpains that cleave fibronectin (152). Fibronectin was also found in early granulomas, while chronic granulomas are collagen-rich (30, 153). Eggs also express SmCalp1 and may actively contribute to the fibronectin degradation (152). Further, SmEnolase, is highly expressed by eggs, and is able to promote plasminogen activation (69). Plasmin degrades fibrin and fibronectin–among other targets–and thereby contributes to the degradation of extracellular matrix proteins. Indeed, a striking difference exists between hepatic and intestinal granulomas with regard to perioval fibrin and fibronectin deposition (151). While they were found in 23 and 77% in hepatic granulomas, respectively, only 3 and 11% were positive in the intestine. Viable eggs actively degrade fibrin and fibronectin, therefore the increase of these ECM components in hepatic eggs might stem from the increased proportion of dead eggs. However, as the data set is limited, in-depth investigation of the plasmin, fibrin, fibronection, and collagen content of intestinal granulomas is warranted. Fibrinolysis and plasmin around eggs could be a result of macrophage invasion or proteolytic activity of the eggs. At the moment, it remains unclear what the exact order of events in fibrin and collagen deposition, plasminogen activation and fibrinolysis is and thus a more detailed investigation is required.

While collagen deposition leads to immunopathology in the liver, collagen degradation may be more important in intestinal granulomas. Eight weeks after infection the collagen content in hepatic granulomas is already significantly increased but only minimal deposition is observed in the small intestine and even less in the colon (154). While collagen content increased over time in all three organs, in intestinal granulomas collagen marks chronic granulomas–and therefore trapped eggs (153). Furthermore, collagen structure appeared concentric in the liver while a discontinuous deposition was observed in the intestine (154). While eggs themselves were not able to degrade collagen in vitro (155), egg-activated plasmin may contribute to collagen degradation. Furthermore, M2-like macrophages can degrade collagen in a mannose receptor-dependent manner (156). Additionlly, many matrix metalloproteinases are expressed during S. mansoni infection with elevated expression of MMP-2, MMP-3, and MMP-8 transcripts in the colon of chronically infected mice (157), all of which possess collagenase activity.

While this array of ECM-degrading mechanisms may promote the movement through the lamina propria–but where does directionality come from? One possibility is that the influx of immune cells follows the egg through the initial crossing of the endothelium. Therefore, the granuloma first develops basally at the egg. The first cells may shield from the cytotoxic effects of the SEA, while SmEnolase and calpains exert their effects apically and degrade the ECM in front of the egg. Over time, macrophages will surround the egg and become activated by IL-4 and SEA to promote collagen degradation. It was shown that excretion is a relatively quick process compared to the development of liver fibrosis (158), therefore collagen deposition may occur only at the rim or basally of the granuloma to maintain the surrounding tissue architecture, while the apical ECM is degraded and more cells and fluid infiltrates from the basal side displacing the egg forward toward the epithelium. Simultaneously, cells around the egg succumb to the cytotoxic effects of IPSE/α1 and ω1. If the cells infiltrate from the basal side of the granuloma the cells at the apical side are more exposed to the cytotoxic molecules and therefore the first to die from necrosis. Further studies using intravital microscopy approaches are required to get more insight into the mechanisms by which the granulomas move the egg through the intestinal wall.

Another possibility is that because eggs are more or less deposited at the same site in the vasculature and often more than one egg is found in a granuloma, the intestinal tissue may develop an ill-defined “tunnel” structure with more collagen, fibrin and fibronectin deposition at the “tunnel wall,” while the inner tissue has a less rigid composition from repeated ECM degradation. Peristaltic movement of the bowel may also play a supportive role in moving the egg+granuloma along the beaten path. However, to date there is no experimental data available to support this theory, mainly because the larger granulomas surrounding unsuccessful eggs trapped in the intestinal wall may gain more attention and are more similar to what we expect from the research on hepatic granulomas than smaller successful egg granulomas.

The process of actual release of the egg after transit through the intestinal wall into the gastrointestinal lumen has not–to our knowledge–been addressed in detail experimentally. The parasite eggs that are found in the feces of infected humans, as well as experimental mice, are devoid of an encapsulating granuloma suggesting that the egg leaves the granuloma as it enters the fecal matter. This poses the questions: How does it leave the granuloma? What happens to the remaining granulomatous tissue in the intestinal epithelia? A possible mechanism of granuloma resolution may be interaction of microbiota and the immune cells at the outer rim of the granuloma that come in direct contact with the mucous layer and get successively destroyed concomitant to the cytotoxic and fibrinolytic effects mediated by the egg and its secretions. Whether the composition of the mucus layer affects the survival of schistosome eggs is currently unclear. After the egg is released the remaining cells in the granuloma will likely be resolved as part of the intestinal wound healing response, where the already present macrophages may contribute to (Figure 3). Clinically, the colonic mucosa becomes atrophic and acquires a granular yellowish appearance (159), which are probably macrophages from the granulomas shed with tissue remodeling.

One complication observed in patients is the occurrence of colon polyps that are shed and cause intestinal bleeding (160). Probably this may happen when unsuccessful trapped eggs become calcified, losing their fibrinolytic potential and leading to chronic granulomas as seen in the liver.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.