Review
The potential mechanisms involved in the anti-carcinogenic action of probiotics

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Abstract

Probiotic bacteria are live microbial food ingredients that provide a health benefit to the consumer. In the past it was suggested that they served to benefit the host primarily through the prevention of intestinal infections. More recent studies have implicated probiotic bacteria in a number of other beneficial effects within the host including:

  • The suppression of allergies.

  • Control of blood cholesterol levels.

  • Modulation of immune function.

  • And the prevention of cancers of the colon.

The reputed anti-carcinogenic effect of probiotics arises from in vivo studies in both animals and to a limited extent in man; this evidence is supported by in vitro studies with carcinoma cell lines and anti-mutagenicity assays. However, the mechanisms involved in any effect have thus far been difficult to elucidate; studies offer evidence for a variety of mechanisms; we have reviewed these and come to the opinion that, the anti-carcinogenic effect may not be attributable to a single mechanism but rather to a combination of events not yet fully elucidated or understood.

Introduction

The EUROPREVAL project estimates a lifetime risk for colorectal cancer development at 2% for the European population [1]. Epidemiological studies show that colon cancer is of especially high incidence in the developed western world [2]. Whilst this may be, in part, related to a genetic susceptibility [3], the high fat low fibre diet typical of western culture is implicated in the aetiology of the disease. The broad variety of bacteria in the gut produces diverse, and often physiologically active, metabolites that influence the normal development and function of the host. Given the purported role of the intestinal microflora in colonic carcinogenesis [4], it may be postulated that factors that modulate composition and/or activity of the microflora may inhibit cancer development. Probiotic ingredients represent one such modulatory factor.

A probiotic, as originally defined by Fuller is “a live microbial feed supplement which beneficially affects the host animal by improving its intestinal microbial balance” [5]. A definition more appropriate to human nutrition has been outlined by Salminen et al. [6], describing a probiotic as, “a live microbial food ingredient that is beneficial to health.” Many probiotics are members of the genera Lactobacillus and Bifidobacteria [7].

To date, experimental evidence for anti-carcinogenic activity of probiotics comes primarily from in vitro studies of anti-genotoxic effects (reviewed by Burns and Rowland [8]) and in vivo work, showing the suppression pre-neoplastic lesions and chemically induced colon tumours in rodent models. A medline literature search (1996–2004), carried out for the purpose of this review, showed that, of 12 animal studies, only 2 reported no anti-carcinogenic effects of probiotics, against chemically induced tumours or pre-neoplastic lesions known as aberrant crypt foci (ACF) (Table 1). Typically, rodent models support anti-carcinogenic effects for probiotics. It has also been shown that the additional presence of prebiotics (such as non-digestible oligosaccharides) may result in amplification of this anti-carcinogenic effect. It must be noted that the rodent model of colon carcinogenesis is not ideal, especially in relation to the activities of the gut flora. The rat caecum and colon are anatomically distinct from that of the human [21]. Further, it may be argued that rodent based models are essentially offering evidence for a laboratory based phenomenon, given the high levels of dietary carcinogens and/or toxicants to which the animals are exposed and the relatively short time period for these studies. In their defence, the findings of the rodent studies are supported by data from in vitro and ex vivo studies. The ethical, technical and financial problems associated with conducting long-term human studies, using the ideal endpoint for anti-carcinogenic assessments (i.e the disease state itself), means that, we must continue to question the validity of our models and the appropriateness of the selected biomarkers. However, data thus far point to a role for probiotics in cancer prevention.

Section snippets

Potential mechanisms of anti- cancer activity

Colorectal cancers arise by a well-defined series of histological changes (the adenoma-carcinoma sequence), which is paralleled by mutations, activations, and deletions of oncogenes and tumour suppressor genes (Fig. 1). There is much debate in the literature as to where in this process probiotics may be exerting their effects. It is probable that different probiotic strains may be exerting effects at different stages of carcinogenesis. A number of potential mechanisms are summarised in Table 2

Modulation of the intestinal microflora and its metabolism

The faecal stream is a rich source of cancer inducing agents, and also substances that may protect against cancer. Bacterial transformation of components in the lumen is associated with carcinogen production [22]. It must also be said that, the bacterial conversion of other compounds in the lumen (e.g. glucosinolates), may increase anti-carcinogenic activity [23].

It has been proposed that probiotics modulate the metabolic activities of the gut microflora by at least three possible mechanisms:

The anti-genotoxic activity of probiotics

In vivo and in vitro studies reveal that certain probiotics possess anti-genotoxic activity. For example, Pool-Zobel et al. [41] demonstrated the ability of a probiotic application of L. casei Shirota to inhibit DNA damage in the colon of rats exposed to the mutagen N-methyl-N-nitro, N-nitrosoguanidine. A subsequent study confirmed the anti-genotoxic effects for different species of lactobacilli in rats against the colon carcinogen 1,2-dimethyl hydrazine. This anti-genotoxic activity was

Effects of probiotics on the promotion phase of carcinogenesis

Rowland et al. [10] studied the effects of the oral administration of probiotics on colonic aberrant crypt foci (ACF) formation in rats. ACF are considered to be pre-cancerous lesions and are observed in both humans and carcinogen treated animals. They were able to show that dietary B. longum 25 inhibited azoxymethane (AOM) induced ACF formation, in addition the simultaneous administration of probiotics with the prebiotic inulin, increased the effect. Interestingly, faecal ammonia, (which is

The role of the metabolites of probiotics

In a study using several dietary mutagens in the Ames mutagenicity test, Nadathur et al. [56] measured the anti-mutagenicity of an acetone extract of a L. bulgaricus 191R fermented yoghurt. They observed a significant dose dependent anti-mutagenic activity against several mutagens including MNNG, 4-nitroquinoline-N-oxide, 3,2-dimethyl-4-aminobiphenyl, 9,10-dimethyl-1,2-benz[α]anthracene and Trp P2. This study suggests that a metabolite of the LAB may be responsible for their anti-carcinogenic

Immune system stimulation

Certain probiotics are immunogenic and regular consumption of these microorganisms leads to contact with the immune components of the GI tract; it is argued that they may prime the immune system against infection [68], [69]. Probiotics inhibit tumour development at extra intestinal sites, this has been attributed to the induction of an immune response. In double blind studies of human cancer patients fed L. casei preparations (BLP, Yakult Honsha Co LTD, Japan) Aso et al. [70], [71] report the

Conclusions

There is significant evidence to conclude that, certain probiotics are capable of an anti-carcinogenic effect, this effect may be species/strain specific. The mechanisms behind the observed effects have been difficult to elucidate, although several have been discussed here.

The interactions between the commensal microflora and the host in relation to carcinogenesis are not yet fully understood. Although the effects of probiotics on this relationship appear to be beneficial, at least in rodent

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