MEM INST OSWALDO CRUZ, RIO DE JANEIRO, 104(2) March 2009
PAGES: 221-233 DOI: 10.1590/S0074-02762009000200015 Full paper
Small intestinal inflammation following oral infection with Toxoplasma gondii does not occur exclusively in C57BL/6 mice: review of 70 reports from the literature

Maximilian Schreiner; Oliver Liesenfeld+

Institute for Microbiology and Hygiene, Charité Medical School Berlin, Campus Benjamin Franklin, Hindenburgdamm 27, 12203 Berlin, Germany

Abstract

Small intestinal immunopathology following oral infection with tissue cysts of Toxoplasma gondii has been described in C57BL/6 mice. Seven days after infection, mice develop severe small intestinal necrosis and succumb to infection. The immunopathology is mediated by local overproduction of Th1-type cytokines, a so-called "cytokine storm". The immunopathogenesis of this pathology resembles that of inflammatory bowel disease in humans, i.e., Crohn's disease. In this review, we show that the development of intestinal pathology following oral ingestion of T. gondii is not limited to C57BL/6 mice, but frequently occurs in nature. Using a Pubmed search, we identified 70 publications that report the development of gastrointestinal inflammation following infection with T. gondii in 63 animal species. Of these publications, 53 reports are on accidental ingestion of T. gondii in 49 different animal species and 17 reports are on experimental infections in 19 different animal species. Thus, oral infection with T. gondii appears to cause immunopathology in a large number of animal species in addition to mice. This manuscript reviews the common features of small intestinal immunopathology in the animal kingdom and speculates on consequences of this immunopathology for humankind.

Within eight days of peroral infection with Toxoplasma (T.) gondii, susceptible C57BL/6 mice develop severe ileal inflammation resulting in necroses of mucosal villi and complete tissue destruction. Ileitis is caused by a Th1-type immunopathology and is characterized by a CD4+ T cell-mediated increase in pro-inflammatory mediators, including interferon (IFN)-?, tumor necrosis factor (TNF)-? and nitric oxide (NO) (Liesenfeld et al. 1996, 1998). Activation of IFN-? and TNF-? are initiated by production of IL-12 and IL-18 (Vossenkaemper et al. 2004). IL-10 and TGF-? have been identified as counter-regulatory cytokines in the inflammatory cascade (Suzuki et al. 2000, Buzoni-Gatel et al. 2001). Recently, we have shown that the ileal bacterial flora, i.e., LPS derived from Escherichia coli and Bacteroides/Prevotella spp., contributes to the immunopathology (Heimesaat et al. 2006, 2007). Thus, T. gondii-induced ileal immunopathology resembles a large number of inflammatory mechanisms that operate during the acute phases of human inflammatory bowel diseases (IBD) (Liesenfeld 2002, McGovern & Powrie 2007). IBD are characterized by chronic intestinal inflammation with acute episodes (Basset & Holton 2002, Podolsky 2002). Ulcerative colitis is restricted to the colon, whereas Crohn's disease more frequently affects the small intestines, including the terminal ileum. In this article, we review current knowledge on the development of intestinal pathology following oral ingestion of Toxoplasma in different hosts throughout the animal kingdom and discuss consequences for intestinal pathology in humans.

 

MATERIALS AND METHODS

Two separate PubMed searches were conducted on June 1, 2008 using the following search terms: (1) (Toxoplasma OR toxoplasmosis) AND (gastrointestinal OR intestinal OR intestine OR enteritis OR ileitis OR gut OR bowel); (2) (disseminated OR acute OR systemic) AND toxoplasmosis. We excluded the following articles: articles about infections in humans, mice, or genetically modified organisms; articles involving experimental treatment of animals; articles without descriptions of inflammation or necrosis in at least one of the following organs: gastrointestinal tract, mesenteric lymph nodes or liver; and articles describing merely isolation of T. gondii out of one of the above mentioned organs without noting inflammatory changes or necrosis.

The search retrieved 2,654 articles published between 1960-May 2008. Using the exclusion criteria, 70 articles remained and these were included in the analysis. Articles about experimental infections and observations were analyzed separately. The animal species identified in the articles were then grouped according to their taxonomic classes. Lesions were analyzed for the following organ systems: small intestines, other gastrointestinal tract locations, mesenteric lymph nodes and liver. Characteristics of lesions were further separated to distinguish between necrosis and inflammatory changes without necrosis.

 

RESULTS AND DISCUSSION

The Pubmed-based search revealed 70 publications on inflammatory changes in the gastrointestinal tract caused by infection with T. gondii. These publications were subdivided into observational reports and experimental infections. Table I provides an overview of all observational reports on gastrointestinal inflammation caused by T. gondii infection. There were 66 publications that reported the development of inflammatory changes in the gastrointestinal tract. Animals affected belonged to two classes (Mammalia and Aves) and 51 different species. Among the latter, inflammatory changes were most frequently reported in the orders carnivora and primates. Of all gastrointestinal organs reported to be affected, the liver (93.9% of cases) and small intestines (57.6%) were most frequently affected. Additional sites affected with less frequency were the stomach, large intestines and mesenteric lymph nodes. The parasite could be detected in a large number of these studies. Interestingly, the suborder Feliformia, the definite host for T. gondii, was also reported to develop intestinal pathology. Domestic cats, cheetahs, Pallas cats, meerkats and lions were the species reported from that suborder. Gastrointestinal pathology, independent of the species, was characterized by small intestinal necrosis with loss of the physiological villus architecture. Since these publications were observational reports, often from zoos, no information is available regarding source of infection (tissue vs. oocyst), strain or dose of infection.

Table II summarizes results from 20 publications on experimental infections. As in observational studies shown above, these experiments include infections in aves and mammals. In most cases, oocysts were fed orally to animals, doses ranged from 101 to 105 oocysts and type II and III strains were used in most cases. The small intestines (95%) and liver (85%) were the organs affected with highest frequency. In most cases, small intestinal pathology was characterized by a complete loss of the villous architecture and was similar to the pathology described in observational studies discussed above.

Since pathological changes were also similar to changes observed following experimental infection of mice with tissue cysts, the pattern observed appears to be a common feature of oral infection with T. gondii. In mice, the small but not the large intestines show formation of oedema between the epithelial layer and the lamina propria, secretion of fluid from the epithelial layer into the gut lumen, mild desquamation of epithelial cells and moderate to severe necrosis. Pathological changes are most prominent in the distal part of the ileum, but the duodenum and jejunum are usually not affected. In the liver, foci of inflammation can be observed around vessels and in the parenchyma. Intracellular parasites can be detected in large numbers in the lamina propria of the ileum; parasite numbers in the liver are smaller. Intestinal pathology may lead to death in susceptible mice and other animals. The publications reviewed here suggest that the strain of Toxoplasma, the infectious inoculum and the host genetics may impact the development of intestinal pathology. It remains to be investigated whether humans also develop intestinal pathology after oral infection. Intestinal pathology has not been reported thus far, however, the parasite was detectable in AIDS-patients with reactivated disease, intestinal pathology and diarrhoea (Liesenfeld 1999). One reason for the lack of intestinal pathology in humans may be due to the dose required for the development of pathology. In animals, an inoculum of > 102 oocysts and 40-100 tissue cysts (ME49 strain) are required to induce intestinal pathology. Consumption of raw and undercooked meat or ingestion of contaminated environmental sources (i.e., water) may not harbour sufficient numbers of parasites to induce pathology. In this regard, it will be of interest to investigate whether oral infection with T. gondii is associated with IBD in humans. It is tempting to speculate whether the strong local and/or systemic immune response during the acute or latent phase of the infection may contribute to an imbalance in the homeostasis of mucosal immune responses in humans with IBD. As a first step, the prevalence of antibodies against T. gondii could be determined in patients with IBD compared to well-selected control populations; a slightly but significantly higher seropositivity rate (based on Sabin-Feldman dye test results) has been observed previously in a small cohort of Crohn's patients over the age of 40 in Israel (Rattan et al. 1986). Results of studies that include larger patient numbers should be especially interesting since an association of T. gondii infection (based on the presence of IgG antibodies) with psychiatric disorders has been suggested (Yolken & Torrey 2008).

In conclusion, development of small intestinal pathology following oral infection with T. gondii is not uncommon in the animal kingdom and the association of infection with T. gondii and gastrointestinal pathologies, including IBD in humans, deserves further investigation.

 

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Received 10 October 2008
Accepted 2 February 2009

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