Munching microbes: diet–microbiome interactions shape gut health and cancer outcomes

Consumption of a sub-optimal, Western-style diet (WD) – containing proteins from processed meats, saturated fats, refined grains and sugars, while lacking plant-derived, fibre-containing components¹ – has been identified as a key driver of various disadvantageous health states such as colorectal cancer (CRC)^2–4, obesity⁵, Crohn’s disease⁶, and irritable bowel syndrome (IBS)⁷. Researchers have been seeking to understand the mechanisms behind these significant associations, including the impact of diet on the microbiome and the relationship between gut microbes and their host, particularly the epithelial barrier.

When examining the relationship between diet and the gut microbiome it is important to consider the nature of the gut environment and nutrient availability from the perspective of microbes. After digestion and absorption in the small intestine (Figure 1), the nutrients available to microbes in the large bowel are those unable to be digested by host enzymes, those surplus to requirements, or derived from host cells. Different microorganisms will have varying preferences and capabilities for consumption of dietary or host-derived carbohydrates and proteins^8,9. Interactions between nutrients and the ratios of macronutrients available are also important in favouring the growth of microbes with particular nutritional strategies¹⁰. Therefore, in the context of the large bowel, which is the primary site of microbial fermentation in the gut, overall dietary intake will shape microbial community composition.

Figure 1.  Digestive processes and microbial metabolism in the small and large intestine. Digestion and absorption of monosaccharides, amino acids and lipids occurs in the small intestine. Host-indigestible carbohydrates (fibre), along with unabsorbed nutrients and by-products of digestion pass into the large intestine where the majority of gut microbes are present. Microbial metabolic processes in the large bowel results in a variety of metabolites that can be beneficial or detrimental for gut health.

The intestinal epithelium and mucosal layer is a key site of interaction between the host, dietary nutrients and gut microbes¹¹. It is a physical and immunological barrier and plays a fundamental role in the maintenance of host health and disease prevention. The layer of epithelial cells separates the luminal contents of the gut, including microbes, from the underlying tissue¹². The epithelial layer itself is protected by a mucin layer, which prevents direct contact with microbial cells (Figure 2). A number of microbes are able to cleave mucin molecules and therefore gut microbe-mediated mucin turnover is part of healthy gut function¹³.

Figure 2.  Dietary intake and nutrient availability shapes the balance between pro and anti-inflammatory properties of the gut microbiome. (A) In healthy, high fibre environment, microbes will degrade complex carbohydrates resulting in SCFA production. Healthy mucin turnover occurs through interaction with mucin degrading microbes. Optimal intestinal barrier function and immune regulation are favoured. (B) In diets lacking dietary fibre, and high in fats and/or protein, there is reduced production of beneficial short chain fatty acids, degradation of the mucin layer through excess microbial degradation, and production of potentially detrimental metabolites. This can result in increased permeability of the intestinal barrier leading to inflammation and excess proliferation of epithelial cells.

One consequence of fibre-deprived diets such as the WD is decreased abundance of fibre-degrading microbes, and their beneficial metabolites, including short chain fatty acids (SCFAs) such as butyrate, acetate and propionate. SCFAs are key microbial metabolites involved in immune regulation and gut barrier integrity. While butyrate and propionate are dominantly utilised locally in the gut or liver, acetate can readily be detected in systemic circulation suggesting that it could also modulate immune function at more distant sites. These SCFAs can bind to key receptors including GPR43 and GPR109A on intestinal epithelial cells, which promotes epithelial barrier repair and turnover via NLRP3 inflammasome activation^14,15. Butyrate is also the primary energy source for epithelial cells and is vital in modulating host immune responses^14,16 and maintains the epithelial barrier by decreasing epithelial permeability through upregulating tight junction proteins (Figure 2), including zonula occludens protein 1 and members of the claudin protein family¹⁷. SCFAs can also promote the differentiation and accumulation of regulatory T-cells (Treg) in the gut, central to the maintenance of immune tolerance^18,19.

While fibre is the dominant dietary-derived nutrient source in the large intestine, some microbes are able to utilise glycoprotein-rich mucins as an alternative energy source²⁰, including Akkermansia mucinophila and members of the Bacteroides genus¹³. Mucin turnover is critical for maintaining intestinal integrity, although a tight balance between mucus degradation and renewal is required, with an essential role for mucin-degrading microbes. However, fibre-deprived environments select for microbes with the ability to utilise mucins, and can lead to excessive degradation of the mucus layer exposing the underlying epithelial cells to luminal antigen, promoting inflammatory responses (Figure 2). Furthermore, as mucin is an endogenous source of sulfur, an additional outcome of excessive mucin degradation is increased production of hydrogen sulfide (H₂S) by sulfate-reducing bacteria such as Bilophila spp. and Desulfovibrio spp. H₂S is a genotoxic compound that has been shown to damage DNA and trigger chromosomal instability²¹.

Increased levels of primary bile acids are also associated with the WD, required for emulsification of dietary fat (Figure 1). While much of the bile acid pool is reabsorbed in the ileum, bile acids are subject to extensive microbial metabolism including deconjugation of amino acids taurine and glycine, and conversion to secondary bile acids (SBAs)²². Certain SBAs such as 3-oxolithocholic acid and isoallolithocholic acid have immunomodulatory properties, inhibiting the generation of T helper 17 cells and promoting the differentiation of regulatory T cells respectively²³. The SBA 3β-hydroxydeoxycholic acid also shapes the gut immune response by inhibiting the ability of dendritic cells to activate adaptive immune cells, leading to an increase in regulatory T cells in the colon²⁴. Activation of the bile acid receptor TGR5/GPBAR1 has also been shown to promote macrophage polarisation towards the anti-inflammatory M2 phenotype, and reduce the expression of inflammatory genes in a mouse model of colitis²⁵. The immunoregulatory effects of these SBAs may be beneficial in mitigating inflammatory bowel diseases, and may help to prevent the development of colorectal cancer. However, other microbe-transformed bile acids such as deoxycholic and lithocholic acid have pro-carcinogenic properties (Figure 2) and predominantly act via the downregulation of p53, a tumour suppressor gene, and the generation of ROS to induce DNA damage and genomic instability, eventually resulting in increased cell proliferation^26,27. Furthermore, during SBA production, sulfur-containing taurine is available for H₂S generation²².

Therefore, the synergistic effect of the removal of fibre and high levels of saturated fat in the diet, as seen in the WD, can lead to reduced epithelial barrier function, erosion of the mucosal layer, inflammation and an increased susceptibility to luminal pathogens and carcinogens. The altered nutrient availability can also result in unfavourable gut microbiome compositions that have the potential to drive inflammation within the gut, therefore resulting in poor gut health.

In addition to inflammation-associated disorders of the gut such as IBD, these impacts on the gut epithelium are relevant to both local and systemic cancer outcomes. Locally, colorectal cancer (CRC) is linked to long term consumption of a WD²⁸. CRC risk is determined by complex diet–microbe interactions, where the production of toxic microbial metabolites are capable of driving pro-carcinogenic responses that transform the epithelium²⁹. In addition, increased epithelial permeability permeability – often referred to as ‘leaky gut’ (Figure 2) – enables the translocation of luminal antigens across the epithelium, promoting a local inflammatory response, while disruption to the mucus layer exposes stem cells to microbial metabolites that promote cell replication³⁰. The outcome is uncontrolled proliferation of epithelial cells, resulting in tumour formation. However, predicting which individuals are most at risk of CRC development remains a challenge and further understanding of individual microbiome profiles, and how these interact with dietary intake, is required.

More recently, systemic impacts of the gut microbiome in the context of cancer immunotherapy distal to the gut have been identified. Immunotherapy acts to induce the immune system to target and eliminate cancer cells and has been used in various cancers including melanoma, lung and renal tumours^31–33. Emerging evidence indicates that higher fibre consumption is associated with improved response rates to therapy³⁴, and the microbiome represents a promising target to overcome therapeutic resistance³⁵ and reduce side-effects such as colitis³⁶. While the specific taxa linking response to treatment across cohorts lack consensus^31–33, shared functional properties such as fibre fermentation and mucin turnover that support intestinal epithelial barrier integrity may be the underlying common features. However, whether fibre supplementation will be effective at modulating the microbiome in a feasible timeframe to improve treatment responses requires further investigation.

Although diet is well established to shape the composition of the microbiome, how an individual responds to a particular dietary intervention is dependent on the composition of an individual’s baseline microbiome. For example, individuals have been shown to respond differently to supplementation with the same type of fibre^37,38. This has been linked to interspecies competition and functional redundancy within microbiome³⁹. Inter-individual variation therefore presents a significant challenge in terms of designing effective therapeutic dietary interventions, as variable responses dependent on the assemblage of the microbiome would be expected. Additionally, different types of fibre are known to have different prebiotic effects, for example, not all fibre sources are equally capable of stimulating SCFA production^40,41. Given the impact of inter-individual variation impact of an individual’s baseline microbiome a ‘one-size fits all’ approach will likely be ineffective, rather more personalised approaches will be necessary to enhance the reproducibility and success of nutritional interventions in the clinic.

While a significant body of research has emerged in this area, there remains much to be understood. What mechanisms underly the various host–microbe interactions at the epithelial interface, in response to different diets, in a clinical setting? How do individual gut environments and microbial ecosystems impact responses to treatments such as immunotherapy? Can tools be created to predict and modulate these outcomes? Understanding these issues could enable the implementation of personalised medicine, where the individual’s native microbiome, genetics, and dietary history could be considered prior to implementation of medical interventions, resulting in greater treatment effectiveness and fewer side-effects.

The authors declare no conflicts of interest.

This research did not receive any specific funding.