Cryptosporidium parvum Isolate-Dependent Postinfectious Jejunal Hypersensitivity and Mast Cell Accumulation in an Immunocompetent Rat Model

Cryptosporidium spp. are a cause of self-limited diarrhea in immunocompetent hosts. In immunocompetent rats, Cryptosporidium parvum infection induced digestive hypersensitivity, a key pathophysiological factor in functional digestive disorders such as irritable bowel syndrome (IBS). In such a rat model, we sought to document whether jejunal hypersensitivity depends on C. parvum isolate and is associated with a mast cell accumulation. Five-day-old rats were orally administered 10⁵ oocysts of either Nouzilly (NoI) or Iowa (IoI) C. parvum isolate. NoI-infected rats exhibited the lowest food intake on days 7 and 14 postinfection (p.i.). On day 7 p.i., small intestine villus atrophy, crypt hyperplasia, and inflammatory cell infiltration were prominent in NoI-infected rats, with higher numbers of Cryptosporidium forms than in IoI-infected rats. Compared to uninfected control rats, jejunal intraepithelial lymphocytes (IELs) were increased only in NoI-infected rats on day 14 p.i. On day 50 p.i., jejunal hypersensitivity to distension was found only in NoI-infected rats; this hypersensitivity is associated with activated mast cell accumulation. The number of mast cells in the jejunal lamina propria was increased from day 36 p.i. in NoI-infected rats and only at day 120 p.i. in IoI-infected rats. Our data suggest that both the severity of infection (weight loss, reduced food intake, villus atrophy, and IEL accumulation) and the onset of a jejunal hypersensitivity after infection in association with an activated mast cell accumulation are isolate dependent and related to NoI infection. This cryptosporidiosis rat model is a relevant model for the study of underlying mechanisms of postinfectious IBS-like symptoms.Cryptosporidium spp. are obligate intracellular protozoans able to infect the gastrointestinal tract of both immunocompetent and immunodeficient animals and humans (37, 51). Symptoms of human cryptosporidiosis include gastrointestinal upset, diarrhea, abdominal pain, fluid loss, cramping, and fever (46). It is worth nothing that the severity of acute experimental human cryptosporidiosis varies among different Cryptosporidium parvum isolates (17, 39). After an acute episode of cryptosporidiosis, a substantial subset of patients describes the onset of gastrointestinal symptoms despite recovery with parasite clearance (27). Symptoms following C. parvum infection are similar to those described by patients suffering from irritable bowel syndrome (IBS), which suggests that C. parvum could be a potential agent for postinfectious IBS. This syndrome occurs in 7 to 31% of patients after a prolonged intestinal infection (16, 22, 26, 47) by either bacterial (due to Campylobacter spp., Salmonella spp., Shigella spp., and Escherichia coli) or protozoan species (i.e., Giardia duodenalis) (31, 38, 45, 49, 51, 37).An enhanced visceral perception of pain with decreased pain threshold during intestinal distension appears to be a major pathophysiological mechanism of IBS and was proposed as a functional marker (5, 8). In a subgroup of patients, peripheral mechanisms are involved in the pain transmission to the brain (5). The peripheral mechanisms include the sensitization of primary afferent endings by inflammatory mediators released by immune cells and particularly mast cells (13).In an unweaned immunocompetent rat model, we have previously reported that C. parvum infection-induced jejunal hypersensitivity to distension lasted more than 100 days after spontaneous clearance of the parasites (30). The present study aims to investigate in this model whether C. parvum-triggered intestinal hypersensitivity to distension in association with mast cell infiltrates depends on parasite isolate.