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The gut microbiota, bacterial metabolites and colorectal cancer

Nature Reviews Microbiology volume 12, pages 661–672 (2014)Cite this article

Subjects

Key Points

  • Dietary intake has an important effect on the gut environment, much of which is mediated by the metabolic activities of the intestinal microbiota on dietary compounds. Different microbial metabolites have the potential to promote and protect against colorectal cancer (CRC).

  • Accumulating evidence suggests that microbial-derived short chain fatty acids control inflammation and regulatory T cell populations. This involves the inhibition of host histone deacetylases and interactions with cell surface receptors.

  • Multiple species in the gut microbiota have complex roles in releasing and converting diet-derived phytochemicals and host-derived bile acids and glycoconjugates, all of which influence the overall microbial metabolome.

  • Alterations in the composition of the gut microbiota can be detected both in faecal samples and in tumour-associated communities that are associated with CRC. Although many of these changes may be consequential, some specific pathogens seem to contribute to causation and disease progression.

  • It is unlikely that the aetiology of CRC can be ascribed to the presence and activities of single pathogenic species, and it is proposed that the cumulative effects of microbial metabolites should be considered to better predict and prevent cancer progression.

Abstract

Accumulating evidence suggests that the human intestinal microbiota contributes to the aetiology of colorectal cancer (CRC), not only via the pro-carcinogenic activities of specific pathogens but also via the influence of the wider microbial community, particularly its metabolome. Recent data have shown that the short-chain fatty acids acetate, propionate and butyrate function in the suppression of inflammation and cancer, whereas other microbial metabolites, such as secondary bile acids, promote carcinogenesis. In this Review, we discuss the relationship between diet, microbial metabolism and CRC and argue that the cumulative effects of microbial metabolites should be considered in order to better predict and prevent cancer progression.

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Figure 1: Pathways that are responsible for the biosynthesis of the major microbial metabolites that result from carbohydrate fermentation and bacterial cross-feeding.
Figure 2: Anti-inflammatory and anti-apoptotic effects of colonic bacteria and their metabolites that are thought to mitigate colorectal carcinogenesis.
Figure 3: Pro-inflammatory and DNA-damaging effects of colonic bacteria and their metabolites that are thought to contribute to colorectal carcinogenesis.
Figure 4: Major microbial metabolites formed from dietary and environmental compounds that are involved in the initiation and/or progression of colorectal cancer.

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Acknowledgements

P.L. and H.F. acknowledge support from the Scottish Government Food Land and People programme. The authors thank A. Walker and R. Barker for critical reading of the manuscript.

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Authors and Affiliations

  1. Microbiology Group, Rowett Institute of Nutrition and Health, University of Aberdeen, Greenburn Road, Bucksburn, Aberdeen, AB21 9SB, UK

    Petra Louis & Harry J. Flint

  2. Division of Applied Medicine, Gastrointestinal Research Group, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK

    Georgina L. Hold

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  1. Petra Louis
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Correspondence to Harry J. Flint.

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PowerPoint slides

Glossary

Resistant starch

The fraction of dietary starch that is not digested in the small intestine by host enzymes and reaches the colon.

Non-digestible carbohydrates

Dietary carbohydrates that are not digested by mammalian enzymes in the small intestine and reach the colon, where they may be used as substrates for the resident microbiota.

Mucin

A high molecular weight glycoprotein that is produced by the gut epithelium and forms the mucus layer that lines the gut wall; it can be used as an energy source by some gut bacteria.

Non-starch polysaccharides

Non-digestible carbohydrates other than resistant starch, including cellulose, arabinoxylans, xyloglucans, pectins and gums.

Acetogenic

A term used to describe bacteria that produce acetate from carbon dioxide and hydrogen (or formate) via the Wood–Ljungdahl pathway.

Methanogenesis

The process by which methane is formed from carbon dioxide and hydrogen (or formate) by methanogenic archaea.

Wood–Ljungdahl pathway

The collection of sequential biochemical reactions that lead to the formation of acetate from carbon dioxide and hydrogen. Several bacteria use this pathway for the generation of energy, and it is also used by certain bacteria and archaea for the assimilation of carbon dioxide into biomass.

Acrylate pathway

The collection of sequential biochemical reactions that lead to the conversion of lactate to propionate by certain Firmicutes bacteria.

Propanediol pathway

The collection of sequential biochemical reactions that lead to the conversion of deoxy-sugars (such as rhamnose and fucose) to propionate by certain gut bacteria.

Histone deacetylases

(HDACs). Enzymes that remove acetyl groups from histones, which are structural proteins that package DNA into structural units. Deacetylation leads to more condensed chromatin, which alters gene expression.

Colonic regulatory T cells

(cTReg cells). A subset of T lymphocytes that are found in the colon and are crucial for the maintenance of immune tolerance.

AP-1 signalling pathway

A pathway that regulates gene expression via the transcription factor activator protein 1 (AP-1).

Polyphenols

Organic compounds that contain phenol moieties; they are produced by plants and are involved in many biological processes, including defence against herbivores.

Glucosinolates

Sulphur-containing natural compounds that are present in Brassica vegetables. They are converted to secondary compounds (including isothiocyanates) that are thought to have health-promoting effects.

Phytochemicals

Natural compounds that are produced by plants and belong to a range of biochemical classes.

Xenobiotic

A chemical compound that is not normally found in an organism, such as a drug or environmental pollutant.

Glycosides

Chemical compounds that are bound to a sugar residue via a glycosidic linkage.

Glucuronides

Chemical compounds that are bound to a glucuronic acid residue via a glycosidic linkage.

Aglycones

The compounds that are produced following the removal of the sugar or sugar acid (such as glucuronic acid) residue from a glycoside or glucuronide.

Nitrosation

The process by which compounds are converted to nitroso group (-N=O)- containing derivatives.

Secondary bile acids

Metabolites that are produced by enteric bacteria from primary bile acids.

Primary bile acids

Steroid acids that are synthesized in the liver and secreted into the gut to promote fat digestion.

Pattern recognition receptors

(PRRs). Innate immune proteins that are essential for recognizing and responding to microorganisms. The most common PRRs include Toll-like receptors, NOD-like receptors, RIGI-like receptors and DNA receptors (that is, cytosolic sensors for DNA).

Microorganism-associated molecular patterns

(MAMPS). Conserved microbial components, such as lipopolysaccharide, peptidoglycan, flagellin and nucleic acids, that are detected by the host innate immune system via pattern recognition receptors.

Colitis

Inflammation of the colon or large intestine.

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Louis, P., Hold, G. & Flint, H. The gut microbiota, bacterial metabolites and colorectal cancer. Nat Rev Microbiol 12, 661–672 (2014). https://doi.org/10.1038/nrmicro3344

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