Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
ReviewThe potential mechanisms involved in the anti-carcinogenic action of probiotics
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:
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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
References (94)
- et al.
Probiotics, Cecal microflora and aberrent crypts in the rat colon
J. Nutr.
(1996) - et al.
Probiotic activities of Lactobacillus casei rhamnosus: in vitro adherence to intestinal cells and antimicrobial properties
Res. Microbiol.
(2001) - et al.
Effect of chronic ingestion of a fermented dairy product containing Lactobacillus acidophilus and Bifidobacterium bifidum on metabolic activities of the colonic flora in humans
Am. J. Clin. Nutr.
(1990) - et al.
Lactobacillus strain GG supplementation decreases colonic hydrolytic and reductive enzyme activities in healthy female adults
J. Nutr.
(1994) Diet and colonic microflora interaction in colorectal cancer
Nutr. Res.
(1995)- et al.
Does yoghurt enriched with Bifidobacterium longum affect colonic microbiology and fecal metabolites
Am. J. Clin. Nutr.
(1994) - et al.
The possible role of probiotics as dietary antimutagens
Mutat. Res
(1991) - et al.
Binding of mutagenic heterocyclic amines by intestinal and lactic acid bacteria
Mutat. Res.
(1994) - et al.
Influence of carcinogen binding by lactic acid producing bacteria on tissue distribution and in vivo mutagenicity of dietary carcinogens
Food Chem. Toxicol.
(1997) - et al.
Suppressing effects of Lactobacillus casei administration on the urinary mutagenicity arising from ingestion of fried ground beef in the human
Cancer Lett.
(1993)
A genetic model for colorectal tumourigenesis
Cell
The anti-carcinogenic effects of dietary restriction mechanisms and future directions
Mutat. Res.
Antimutagenicity of an acetone extract of yoghurt
Mutat. Res.
Genes modulated by histone acetylation as new effectors of butyrate activity
FEBS Lett.
Histone acetylation and cancer
Curr. Opin. Genet. Dev.
Prognostic significance of natural killer cell activity in patients with gastric carcinoma: A multivariate analysis
Am. J. Gastroenterol.
Enhancement of immunity in the elderly by dietary supplementation with the probiotic Bifidobacterium lactis HN019
Am. J. Clin. Nutr.
Symposium: probiotic bacteria for humans; clinical systems for evaluation of effectiveness. Immune system stimulation by probiotics
J. Dairy Sci.
Measuring cancer prevalence in Europe: the EUROPREVAL project
Ann. Oncol.
Globocan 2000: cancer incidence, mortality and prevalence worldwide
IARC Cancer Base 5
Colorectal cancer risk in relation to genetic polymorphism of cytochrome P450 1A1, 2E1 and glutathione-s-transferase enzymes
Anticancer Res.
Colon carcinogenesis with azoxymethane and dimethylhydrazine in germ free rats
Cancer Res.
Probiotics in man and animals. A review
J. Appl. Bacteriol.
Functional food science in gastrointestinal physiology and function
Br. J. Nutr.
Probiotics and prebiotics: can regulating the activities of intestinal bacteria benefit health
BMJ
Anti-carcinogenicity of probiotics and prebiotics
Curr. Issues Intest. Microbiol.
Effects of Bifidobacterium longum and inulin on gut bacterial metabolism and carcinogen induced aberrant crypt foci in rats
Carcinogenesis
A probiotic strain of L. acidophilus reduces DMH induced large intestinal tumours in male Sprague–Dawley rats
Nut. Cancer
Inhibitory effect of Bifidobacterium longum on colon mammary and liver carcinogenesis induced by 2-amino-3-methylimidazo[4,5-f]quinoline, a food mutagen
Cancer Res.
The effect of an oral administration of Lactobacillus casei strain shirota on azoxymethane induced colonic aberrant crypt foci and colon cancer in the rat
Oncol. Rep.
Prevention of preneoplastic lesions by the probiotic Lactobacillus acidophilus NCFMTM in F344 rats
Int. J. Oncol.
The effect of Lactobacillus GG on the initiation and promotion of DMH induced intestinal tumours in the rat
Nut. Cancer
Identification of mucin depleted foci in the unsectioned colon of azoxymethane treated rats: Correlation with carcinogenesis
Cancer Res.
Lack of inhibitory effects of lactic acid bacteria on 1–2 dimethylhydrazine induced colon tumours
World J. Gastroentero.
Antitumorigenic activity of the prebiotic inulin enriched with oligofructose in combination with the probiotics Lactobacillus rhamnosus and Bifidobacterium lactis on azoxymethane induced colon carcinogenesis in rats
Carcinogenesis
Effect of lactobacilli, bifidobacteria and inulin on the formation of aberrant crypt foci in rats
Eur. J. Nutrition
Bifidobacterium longum and lactulose suppress azoxymethane-induced colonic aberrant crypt foci in rats
Carcinogenesis
Flow dynamics of digesta and colonic fermentation
Influence of dietary protein supplements on the formation of bacterial metabolites in the colon
Gut
Metabolism of sinigrin (2-propenyl glucosinolate) by the human colonic microflora in a dynamic in vitro large-intestinal model
Carcinogenesis
Antibacterial activity associated with Lactobacillus acidophilus
J. Bacteriol.
Antibacterial effect of the adhering human Lactobacillus acidophilus strain LB
Antimicrob. Agents Ch.
The human Lactobacillus strain LA1 secretes a non-bacteriocin antibacterial substance in vitro and in vivo
App. Environ. Microb.
Bifidobacterium strains from resident infant human gastrointestinal microflora exert antimicrobial activity
Gut
Production of growth inhibiting factors by Lactobacillus delbreuckii
J. Appl. Microbiol.
Colonisation and fecal enzyme activities after oral Lactobacillus GG administration in elderly nursing home residents
Ann. Nutr. Metab.
Effects of Bifidobacterium sp. fermented milk ingested with or without inulin on colonic Bifidobacteria and enzymatic activities in healthy humans
Eur. J. Clin. Nutr.
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2021, LWTCitation Excerpt :Probiotics are defined as “live microorganisms which when administered in adequate amounts confer a health benefit to the host” (FAO/WHO, 2002). Probiotics may have anticarcinogenic properties (Commane, Hughes, Shortt, & Rowland, 2005), modulate and strengthen the immune system (Ouwehand, Salminen, & Isolauri, 2002), have beneficial effect on upper respiratory tract infection (Anaya-Loyola et al., 2019), prevent tooth decay (Alp & Baka, 2018) and gastrointestinal diseases (Elahi, Nikfar, Derakhshani, Vafaie, & Abdollahi, 2008) and effective against coronary heart disease (Upadrasta & Madempudi, 2016). Probiotic microorganisms should be carefully monitored to obtain a safe and functional probiotic food (Temmerman, Pot, Huys, Swings, & 2003).
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