CRITERIOS DE EXCLUSIÓN

Exogenous dietary particles and their role in intestinal function have been explored extensively by Dr Jonathan Powell and his team since their exact identities have been elucidated by Powell and colleagues in 1996 [147]. Over the years a number of excellent reviews have been published by Powell and co-workers, which discussed the possible biological functions of endo- and exogenous dietary particles in intestinal homeostasis with

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a special emphasis on the relationship between exogenous particles and development of CD [55, 143, 146, 161, 163, 219].

The possible biological functions for the re-secretion of calcium and phosphate ions in the distal small intestine and the resulting formation of particulate calcium phosphate have been the subject of some discussion. It has been observed that these endogenous dietary particles can adsorb luminal antigens [145]. Some studies suggested that this process might assist with the clearance of toxic antigens from the intestinal lumen [145, 235, 236]. However, in regard to the large amount of potential cytotoxic antigens in the intestinal lumen, it seems unlikely that this process would be of biological relevance. Importantly, it has been shown that calcium phosphate particles are also taken up by immune cells in PPs [142, 143]. This observation led to alternative hypotheses regarding the function of dietary calcium phosphate particles. It could be possible that these endogenous particles play an important role in establishing tolerance to dietary antigens.

Induction of tolerance could be achieved through several mechanisms. First, it has been shown that calcium phosphate particles induced apoptosis in intestinal cells in vitro [217], and increased dietary calcium supplementation led to increased apoptosis in the distal colon in mice [237]. The uptake of apoptotic cells by antigen presenting cells results in the induction of tolerance [238, 239]. This could be of relevance for the gastrointestinal tract where endogenous dietary particles cause apoptosis, and these apoptotic cells are subsequently taken up by intestinal phagocytes which then release tolerogenic signals [55, 143, 146]. Another possible mechanism of tolerance induction by endogenous dietary particles could be the result of uptake of these particles by hyporesponsive intestinal phagocytes [55]. It has been shown that intestinal phagocytes do not activate the immune system, but they still retain their phagocytic activity and promote tolerance [240]. It could also be possible that uptake of calcium phosphate particles would directly lead to immune tolerance, but such a mechanism remains elusive [55].

Exogenous dietary particles, on the other hand, could disrupt this natural process of endogenous particle-mediated immune tolerance, regardless of its mechanism. This could result in the development of intestinal inflammation. Similar to endogenous dietary particles, TiO2 and other exogenous dietary particles can adsorb antigen onto their surfaces [198, 241, 242]. It has been suggested that if this exogenous particle-antigen complex is taken up by intestinal phagocytic cells this would not lead to the induction of tolerance, but it would instead induce an inflammatory response. Prolonged exposure could then lead to the development of CD [55, 143].

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Several observations have contributed to the development of this hypothesis. First, it has been noted that exogenous particles accumulate in the region of the gastrointestinal tract that is most commonly affected by CD, namely the PPs [56, 243]. Earlier studies have also shown that when silica dust or sand particles were introduced in the gastrointestinal tract of dogs they developed symptoms with a similarity to CD [244, 245]. Furthermore, it has been shown that soil particles, including silicates and TiO2, are the cause of podoconiosis [246]. This is a disease which resembles elephantiasis and is characterised by swelling of the legs as a result of the occlusion of the draining lymphatics. The disease is only found in certain regions in Africa with volcanic soils. The soil particles are taken up in the feet by walking barefoot, and the disease progression can be stopped by wearing shoes [143, 217]. Interestingly, only a small number of people in the respective areas are affected by podoconiosis despite the fact that the whole population is exposed to these particles. This suggests that there is a genetic component which makes some people more susceptible to develop this disease [146, 147]. Taken together, these observations indicate that exogenous dietary particles might indeed be involved in the aetiology of CD, as proposed already in the first study that documented their occurrence in PPs [56].

As mentioned in the beginning of this literature review (Section 1.1.2), the causes for CD are still unknown, but it is likely that both environmental and genetic components contribute to the disease [247]. It has been noted that the rising incidence in CD corresponds to increased usage of exogenous dietary particles in processed foods [146, 219]. As reported in the previous section, the first study that investigated a direct link between exogenous dietary particles and CD showed that a reduced particle intake ameliorated disease symptoms [232]. However, a follow up study could not reproduce the results from the initial study [233]. This observation suggested that exogenous dietary particles did not play a role in maintaining the disease once it has been established. However, exposure to exogenous particles could still be a crucial factor for the initial establishment of CD [233]. Furthermore, it is possible that only people with a genetic susceptibility to CD would be affected by exogenous particles [55]. It has been suggested that it would be of particular interest to study the consequences of exogenous dietary particle exposure in a mouse model with a defective Nod2 gene to investigate effects of exogenous dietary particles under these circumstances [163].