*2.2. The Complex Life Cycles of the Trematoda and Cestoda*

This group of organisms presents complex biological cycles in which some may have free-living stages or need one or more intermediate hosts of invertebrate or vertebrate origin to finally invade a definitive host in which they move until they find the tissue or organ, where they settle and reproduce sexually.

Trematodes, also known as flukes, have as their main characteristic the retention of the cecum, although they can also absorb nutrients and carry out gas exchange through their body wall (also called tegument) [28]. Their first intermediate hosts are generally mollusks, and adults can have a wide variety of diets, from blood to epithelia [29]. Some of the species in which pioneering studies on the biochemistry and immunology of trematodes have been made belong to this group: *Clonorchis sinensis*, *Fasciola hepatica*, and *Schistosoma mansoni*.

Cestodes are one of the most successful groups within the parasitic flatworms. This is due in part to their complete adaptation to parasitic life, including the total absence of an internal digestive system, the lack of an intermediate free-living form, the appearance of structures specific for attachment to the intestine of the definitive host, and serial repetition of a hermaphroditic reproductive complex [30]. This group has been problematic to study due to the difficulty in accessing and maintaining the biological material, the fragility of the specimens outside their hosts, and the contradictory information from the first studies [17]. Within this group, we have well-known species such as *Hymenolepis diminuta*, *Echinococcus granulosus*, and *Taenia solium*.

A representative life cycle of this group is found in *T. solium* (Figure 1). After the ingestion of feces contaminated with embryonated eggs (also called hexacanth larva) by a pig, the protective cover of such eggs is eliminated and the larval oncosphere form emerges. This oncosphere crosses the intestinal mucosa and migrates through the systemic circulation to lodge in various tissues, with a preference for the skeletal muscle and the nervous system. Already there, the larva develops to its metacestode form (also known as cysticercus), where it can stay for years, asymptomatically. Finally, when the definitive host (man) ingests pork meat contaminated with cysticerci, it carries out its last metamorphosis, which is a distinctive characteristic of cestodes [31]. It consists in the activation of the larva by means of pepsin and stomach acid, as well as the bile salts, of the definitive host, causing evagination of a fixing structure, the scolex, which will allow it to anchor itself to the intestinal epithelium. At this point, the adult tapeworm form rapidly begins to develop and matures sexually to generate a series of hermaphrodite structures called proglottids, each of which contains a complete set of male and female reproductive organs that mate with their other proglottid counterparts. Eventually they are filled with millions of fertile eggs (becoming gravid proglottids) that will detach and leave the host along with the feces to later be eaten by the pig to close the life cycle. Occasionally, man can accidentally ingest the eggs of *T. solium* that give rise to the development of the larva (metacestode) and that produces cysticercosis.

At this point, it is possible to assume that, during their free-living phase (in the case of trematodes) or the intermediate step between hosts, these endoparasitic flatworms are exposed to a higher O2 tension that they can face inside the hosts cells, hence, their energy metabolism will preferably be aerobic [32]. During their transit and accommodation in the host, they are exposed to variable concentrations of O2, so their anaerobic energy metabolism is expected [33–36] (Figure 2 and Table 1). For example, in their adult state, tapeworms settle in the intestine of their vertebrate host. In this organ, the partial pressure of O2 (pO2) can vary from 0 to 16 mmHg, with a three-times higher pressure in the mucosa than in the intestinal lumen, where it can reach zero [37]. Additionally, the presence of O2 is also modified according to the postprandial state because an increase has been observed in O2 when the digestion process begins as well as in this tissue's blood supply [38].

**Figure 1.** Life cycle of *Taenia solium.* Parasite stages and its migration through the interior of its intermediate host (e.g., pig, in green) and its definitive host (e.g., man, in purple), is illustrated.



\* Human measurements. \*\* Mice measurements.

**Figure 2.** Adult form of the cestodes is exposed to the intestinal oxygen concentration. The image shows a structural drawing of the adult tapeworm form of *Echinococcus granulosus* (left; size range 2–7 mm) and *Taenia solium* (right; size range 2–7 m), attacking the intestinal epithelium of their definitive host. Oxygen tension in the intestinal tissue decreases the further away parasites are from the intestinal capillaries, while the oxygen concentration in the intestinal lumen decreases as parasites move towards the colon, where the environment is practically anaerobic. Oxygen concentrations were obtained from references [33–36]. The size of the parasites was obtained from the Laboratory Identification of Parasites of Public Health Concern website (https://www.cdc.gov/dpdx/ (accessed on 17 February 2022)).

The aforementioned indicates that the different habitats occupied by these parasites during their life cycle determine their energy metabolism and their transition from an aerobic to an anaerobic metabolism [39–41]. An example of this adaptation has been reported in trematodes such as *F. hepatica*. It was observed that its free-living larva has an aerobic metabolism, but when it invades the bile ducts of the vertebrate host, its metabolism is basically anaerobic [42,43] (see below).
