Chemically Induced Responses

Animals that have been intentionally exposed to specific pro-inflammatory or carcinogenic chemicals have been used in studies on the role of microbiota in the development of both cancer and IBD (Table 1). Cancer, or other malignant abnormalities in the gut mucosa, may be induced by the oral administration of carcinogens. Examples of such carcinogens are 1, 2 dimethylhydrazine (DMH), and N-methyl-N0-nitro-Nitrosogua-din (MNNG). These types of models, which are based on either CV or HFA animals, have also been used to assess the effect of both probiotics and prebiotics on the progression of cancer in its various stages from DNA damage through to differentiation of tissue and formation of tumors.

A study by McIntoch and co-workers (52) investigated the effect of L. acidophilus on the incidence of tumor formation as well as the mass of tumors found in animals that had been challenged with DMH. It was demonstrated that the animals that had been given L. acidophilus were associated with less tumors than those animals that were given other probiotic cultures. As a result the most effective culture, in terms of protecting animals against cancer, could be isolated out of a range of LAB cultures.

Another way of investigating the effect of microbiota on the formation of cancer is to assess the occurrence of aberrant crypt foci in the intestinal epithelium. In this type of model, increased occurrence of aberrant crypts indicate increased formation of tumors. This model has been used to assess the effect of GI microbiota and specific dietary factors on the development of intestinal cancer (48,119). In similar studies, animals given azoxymethane were used to assess the effect of L. casei, of human origin, on the formation of aberrant cells (120). Other studies using 3-methylcholanthrene to induce tumor formation, demonstrated that the same strain delayed the onset of tumor formation. It was suggested that this delay was due to an enhancement of cytotoxicity of NK cells (26). Finally, mucosal carcinogenesis may be assessed by determination of the DNA adduct formation (121). This type of methodology allows assessment of carcinogenesis without visual scoring of aberrant crypts. This method has been successfully used to investigate the effects of human intestinal flora on the mutagenicity of dietary factors by assessing DNA adduct formation (36). Assessment of DNA adduct formation has been used as a tool in investigating the protective effect of potentially probiotic cultures against the formation of cancer (122,123). This type of model provides a cost-effective tool used in studies on the GI microbiota and its role in formation of intestinal cancers.

Although both animal models have been used to demonstrate protection against cancer by probiotic cultures, the difference between how cancer that has developed in the chemically modified animal and how it has developed in the diseased human subject raises questions as to what extent such observations are relevant for the human host. The opportunity to test probiotic cultures in humans that have been intentionally exposed to carcinogens does not exist. However, it is known that some of the probiotic cultures that reduce the incidence of tumor formation in animals have a similar effect on cancer in humans (124,125).

Apoptosis is a mechanism inherent to healthy mucosal cells, which ultimately leads to the death of cancerous cells. The effect of various dietary factors on apoptosis can be assessed in animal models. Several studies have investigated the effect of probiotics and prebiotics on apoptosis. Some of these studies have revealed that prebiotics such as Fructo-Oligosaccharides (FOS) and inulin increase incidence of apoptosis and thereby provide increased protection against the formation of intestinal cancers (126).

A wide range of animal models have been applied to studies on IBD. Naturally occurring animal models have been important tools in studies related to human ulcerative colitis and Crohn's disease. IBD-like symptoms have also been induced chemically. The application of such chemicals may induce ulceration of the intestinal mucosa as well as several immunological responses that are typical to IBD in humans. Simple methods for T-cell induced onset of IBD may be initiated by di-nitro chlorobenzene (DNCP) as described by Glick and Falchuk (127). This method involves both systemic and local application of DNCP. Other chemically induced forms of IBD may be induced by intra rectal inoculation of trinitrobenzene sulphonic acid (TNBS) which is dissolved in alcohol. The latter treatment results in inflammation that lasts for several weeks after exposure to these agents (128). Animals not treated with this agent are normally tolerant to sonicates derived from the heterologus intestine of syngenic littermates (BsH). However, in animals with IBD induced by TNBS, both local and systemic tolerance to BsH is broken (129). Interestingly, this study also demonstrated that tolerance to BsH was abrogated by treatment with IL-10 or antibodies to IL-12.

A study using oral therapy with a probiotic culture had no effect on either the severity of colitis or gut permeability in this TNBS model (53). Similarly, oral therapy with L. rhamnosus and a mixture of probiotic cultures has been shown to reduce the extent of colonic damage in TNBS induced colitis (130). However, both L. rhamnosus and the culture mixture significantly ameliorated colitis induced by idoacetamide (130). These studies indicate that inflammation induced by a sulfhydryl blocker (e.g., idoacetamide), as described by Rachmilewitz and co-workers (128), may be a better model for assessing the effect of gut microorganisms on colitis.

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