Nutrition and Cancer in the Microbiome Era

Abstract

Popular views of what constitutes a healthy diet may shift, but the professional consensus is comparatively static and largely supported by our growing understanding of diet–microbiota interactions. The gut microbiome’s responsiveness to diet and ability to calibrate immune and metabolic function shape new research opportunities across the cancer continuum.

Evidence-based dietary recommendations to eat more plant foods and less of just about everything else has long been a key and consistent public health message to decrease cancer risk, as well as overall morbidity and mortality, statements supported by prospective research initiated some 40+ years preceding the golden age of the microbiome^{i, ii}. However, now, we are learning that dietary factors that increase (ultra-processed foods, added sugars, refined grains, red meat) or decrease (whole grains, nuts and seed, legumes, fiber) the risk of cardiovascular disease and cancer are also determinants of the composition of the gut microbiome [1–4]. As such, there is growing interest in the microbiome as a key mediator in the nutrition-cancer link.

The bacteria that inhabit our gastrointestinal tract eat what we eat. They change us and we change them. Although the diet–microbiota–cancer axis has been most well-studied in colorectal cancer, diet–microbiota interactions impact human health and disease well beyond the mucosal lining of our lower gut [1–3, 5]. The role of eating habits in shaping the gut microbiome, coupled with how host metabolism and metabolites interact with the gut microbiota and diet to shape gut health and immunity, hint that the fitness of this codependent relationship broadly affects cancer risk and outcomes (Figure 1).

Figure 1. Diet and the Microbiome across the Cancer Continuum.

Collectively, observational and experimental studies have yielded important insights into the effect of diet and the gut microbiome on cancer risk and outcomes, as well as the underlying biological processes (i.e., immunity, inflammation, and metabolism) involved. However, new prospective cohorts with biospecimens collected for microbiome research have yet to mature, and interventional studies across the cancer continuum are ultimately needed to examine causality.

Accessibility and Complexity: A Recipe for Public Confusion

Nutrition, and increasingly the microbiome, draws in cancer patients, as well as individuals at risk of developing cancer, who seek control over their own health and the health of their families. Nutrition is one of the more (if not most) accessible scientific fields, largely because we all eat and can tweak our own diets. However this level of accessibility, and a reductionist paradigm focused on specific parameters (e.g., ‘fat’ or specific ‘miracle foods’), has led to public confusion and perseveration on ‘eat this, not that’. The focus on specific micronutrients (e.g., beta carotene) in cancer prevention led to multiple clinical trials testing various dietary supplements, some of which unfortunately provided an excellent lesson in the dangers of reductionism [6]. While early epidemiological data suggested higher intake of these nutrients (largely from healthy foods) may be beneficial, interventional studies showed no benefit for cancer risk and other outcomes, and even potential harms at high doses [6,7]. Interestingly, however, the direct-to-consumer dietary supplement market continues to thrive, including among cancer patients^vi [8].

Lessons learned from the nutrition and cancer field should inform the approach to the newer microbiome field, with a focus on overall balance rather than singular factors. Just as good nutrition has never been achieved with focus on a single food or nutrient (or in a bottle), identifying single species or strains is unlikely to be an effective strategy to define a cancer-fighting microbiome. In a healthy and stable microbiome, space and resources are occupied by commensal species, providing colonization resistance to potential pathogens that may pass through, or reside within, the gut. Overall, the data suggests that a healthy gut microbiome evolves and flourishes with a high-fiber diet (Figure 1). Gut microbes use indigestible carbohydrates, largely found in fiber- and resistant starch-rich plant foods (e.g., vegetables, fruits, legumes, and whole grains), as their primary energy source. In turn, bacteria ferment these ‘microbiota accessible carbohydrates (MACs)’ to produce short chain fatty acids with important physiological effects on host health, signaling pathways, and immunity [9]. In times of MAC restriction, glycoproteins of the protective intestinal mucus layer provide an alternate energy source; and over time this can result in a breakdown of the gut barrier (e.g., leaky gut) [10]. Perturbations caused by antibiotics or acute infections disrupt the resident microbes and colonization resistance. Nutrient networks become compromised, allowing pathogens to exploit temporary availability of resources and expand [9].

The Role of the Microbiome in Cancer Therapy Begs a Closer Look at Patients’ Diets

The mounting evidence that the gut microbiome influences response to cancer therapy is shaping new priorities for nutrition research in cancer patients, with the gut microbiome as a modifiable target. The focus of nutritional counseling for patients with cancer is largely centered on anorexia and cachexia related to advanced malignancies or harsh therapies, whereas the modern cancer patient is more likely to be overweight or obese than under-weight [11]. Meanwhile, contemporary targeted and immune therapies do not cause weight loss, but do have very heterogeneous outcomes, ranging from durable complete response to primary progression, and so the question of ‘Doc, what can I do?’ to influence outcomes becomes even more relevant.

Cancer patients are generally advised, barring any specific dietary issues related to their disease or treatment, to follow the recommendations for cancer prevention, before, during, and after their treatment^{iii, iv, v}. This includes eating a diet composed largely of fiber-rich plant foods (whole grains, vegetables, fruits and beans) and limited in processed foods, red and processed meats, added sugars, and alcohol, and specifically recommend against supplement use. Studies with standardized dietary assessments incorporated into randomized clinical trials support that this type of ‘prudent’ diet may be linked to improved outcomes in patients on active therapy [12] (Figure 1). However, interventional evidence that implementing a diet change will actually influence cancer outcomes is inconsistent, although there are ongoing studies addressing this question. Ultimately, the strength of a dietary recommendation from an oncologist to a patient initiating therapy will be driven by the strength of the data showing that nutrition influences biology and response to therapy. Recent studies demonstrating a link between the gut microbiome and response and toxicity to multiple types of cancer therapies have inspired a new angle for the study of diet–microbiota–cancer interactions [13]. Perhaps the most transformative studies have been those showing that the gut microbiome influences response to immune checkpoint blockade, the revolutionary therapies for which the 2018 Nobel Prize in medicine was awarded to Drs James Allison and Tasuko Honjo. In multiple independent cohorts, the gut microbiome profile was strongly associated with response to immunotherapy, and, importantly, microbiome modulation shaped therapeutic response in preclinical models [13].

Given the key role the diet plays in determining the gut microbiome, the next obvious questions are: (i) how is diet, the microbiome, and immunity linked in these patients; and (ii) can diet be used to target the microbiome to enhance response to therapy (Figure 1).

Is the Microbiome Our Best Tool for Developing Evidence-Based Nutrition Strategies in Cancer?

Although specific gut microbes have been causally linked to gastrointestinal cancers (e.g., Helicobacter pylori and Fusobacterium nucleatum) [5], associations with diet are considerably more nuanced and variable. There is significant promise that gut microbiota can be altered by dietary interventions to prevent and treat various diseases; however, the mechanisms by which foods or food-derived products (e.g., prebiotics) modulate commensals remain largely unknown. Similar to the multiple and interacting components of foods, when it comes to the microbiome, the whole also appears to be greater than the sum of its parts. Although some microbes have specialized metabolic capabilities, each is also dependent on its neighbors; and it seems that we need the right formula to unlock the potential of food [4]. The collective metabolic activities of the microbiota appear to be more resistant to dietary strategies [14] and identifying predictable or durable targets and responses across individuals can be challenging, to say the least. Improved understanding of diet–microbiome interactions, which impacts who is there and what they are doing, reveals a complex, but essential layer impacting host response to nutritional interventions and their ultimate impact on health.

Diet and gut microbiota, individually and jointly, may be causal, diagnostic, and/or prognostic and highlight the potential of effective coupling and modulation to transform personalized medicine in a very approachable way. The hope for the microbiome is that it is the biomarker we have all been waiting for and will help us to improve the quality of our research to refine and inform evidence-based dietary recommendations for cancer prevention, cancer patients, and cancer survivors (Figure 1). However, nutrition has broad effects on health via systemic metabolism and we are only beginning to appreciate the potential effects of host-level metabolism on tumor metabolism and treatment efficacy [15]. The disease silos in which we conduct diet–microbiome research (cancer, cardiovascular, liver, and kidney disease) are unlikely to serve the scientific community well. Cross-disciplinary funding initiatives and collaborative research centers are critical to facilitate broad progress. Improved understanding of diet–microbiome interactions is likely to be a key (and potentially) common upstream mechanism we can use to solve problems or to provide more convincing clarity to the public: our greatest audience, consumer, and advocate.