The microbiome and its potential as a cancer preventive intervention
Introduction
Cancer is a leading cause of death that is associated with tremendous social and economic burdens. According to the National Cancer Institute (NCI), healthcare costs associated with the diagnosis and treatment of cancer in the United States currently exceed $125 billion per year [1]. This figure is projected to rise because of healthcare inflation and demographics— the obesity epidemic and the aging of the United States population will undoubtedly increase the number of cases. Although targeted therapies such as imatinib (Gleevec; Novartis, Cambridge, MA) and trastuzumab (Herceptin; Genentech/Roche, San Francisco, CA/Basel, Switzerland) are efficacious at treating certain cancer subtypes, the vast majority of cancer cases still rely on conventional anticancer chemotherapeutics with varying degrees of efficacy and adverse effects. Therefore, a major goal is cancer prevention. It is estimated that 25%–30% of cancer cases are due to tobacco use, 15%–20% are due to infections, and 30%–35% of cancer cases are preventable via a healthy diet, physical activity, and maintaining a healthy body weight [2], [3]. There is much interest in understanding the underlying mechanisms of cancer preventive effects, and it is becoming increasingly clear that the commensal microbiota that inhabit our body can inhibit pathogens from mounting infections and that they can also metabolize whole foods into bioactive food components that promote intestinal homeostasis and may prevent cancer. This review will discuss how microbiota that inhabit our body are detected and quantified followed by a discussion of cancer-prevention mechanisms and the prospect for probiotic and prebiotic strategies of cancer prevention.
Section snippets
The human microbiome
The human body harbors ≥1014 microbial cells, which is estimated to be ~10-fold greater than all of our somatic and germ cells combined [4]. They are comprised of bacteria, archaea, eukaryotes (such as yeast and other fungi), and viruses (including bacteriophage). Our microbiota and their collective genomes, which are referred to as the microbiome and harbor ~100-fold more genes than the human genome, are being characterized by metagenomics approaches that combine next-generation sequencing
The microbiome and cancer
Metagenomic sequencing projects have compared the composition of microbial communities in human disease cases to controls (Fig. 1), and these association studies have implicated our microbiota in the prevention of many diseases including various types of cancer [18], [19]. Normal diverse microbial communities can protect against cancer by multiple mechanisms. They can have an indirect effect by competing with pathogens for attachment sites, which limit pathogen abundance and prevent infections
Dietary fiber and colorectal cancer prevention
One of the most extensively studied dietary factors in chemoprevention has been fiber, which is defined as “the edible part of plants or their extracts, or analogous carbohydrates, that are resistant to digestion and absorption in the small intestine, but are utilized after partial or complete fermentation in the large intestine by resident microbiota” [40]. Fiber includes polysaccharides (eg, resistant starch, cellulose, hemicellulose, pectins, and gums), oligosaccharides, and lignins. As
Dietary fiber-microbiota-butyrate axis
Recent studies have demonstrated that fiber consumption alters the composition of our gut microbiome to a greater extent than other dietary factors and increases the number of butyrate-producing bacteria [10], [11], [12]. Furthermore, five or more microbiome studies have reported a significant decrease in butyrate-producing bacteria in human colorectal cancer cases compared to controls. However, one limitation of microbiome studies is that it is difficult to know whether a particular microbiome
Translational potential of the dietary fiber-microbiota-butyrate axis
The idea that butyrate is a tumor-suppressive metabolite is consistent with many published studies which have observed that butyrate inhibits the proliferation of colorectal cancer cell lines while stimulating their apoptosis and/or differentiation [59], [68]. The gnotobiotic mouse experiments described above are valuable because they move beyond “factor dump” experiments where relatively high doses of butyrate are added to colorectal cancer cell lines in vitro. They demonstrate that dietary
Other bacterial metabolites and cancers
Although the vast majority of our microbiota reside in our gut, they can influence diseases beyond our GI tract, such as cardiovascular disease and autism, and this applies to cancer. Many gut microbe-derived metabolites have a much broader bioavailability than butyrate, and the following paragraphs in this section provide some examples relevant to cancer prevention. It should also be noted that bacterial densities are relatively high in close proximity to the mucous membranes of other tissues
Probiotics, prebiotics, and the growing functional food/nutraceutical industry
The previous section provided some examples of how our gut microbiota influence dietary components to potentially prevent cancer (summarized in Table 1), but the reverse is also true. In fact, many more food components are known to influence the composition of our gut microbiota. Undoubtedly, many more will be discovered and some diet-induced changes in microbiota are likely to benefit human health in various ways, including preventing cancer. Of course, there are the prebiotics, which have
Future directions
We have not yet developed culture conditions that support the growth of most microbes that inhabit the human body, particularly anaerobic bacteria that reside deep within our GI tract. This limitation has not prevented us from using metagenomics to characterize microbial populations and to identify microbiome differences between individuals with certain diseases including cancer compared to controls. It is important that microbiome studies continue and that they become integrated with
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