Gut Microbiome and Cancer Treatment:  Nutritional Implications

By Matthew Grant, MS, RD, LDN

The human microbiome is a complex system of the smallest and most populous organisms, including bacteria, fungi, and viruses.  It is comprised of approximately 100 trillion cells – which outnumbers the host cells by a factor of ten and the cumulative genes of which represent more than 100 times the number of genes in the human genome (1).  This highly structured community of microorganisms also includes a multitude of metabolites which help or hurt one’s immune system.  Relationships between the microbiome and host are categorized as mutualistic, parasitic, or commensal- the most latter of which refers to when one organism derives food or other benefits from another organism without hurting or helping it (1).  Many of the microbes described in this literature review are of this variety.

What can affect a person’s microbiome – the species, composition of the microorganisms in the gut?    Genetics is one of them as research demonstrates up to nearly 9% of twins have identical microbiomes (1).  Immune health, metabolism, age, biological sex, pet ownership, and geography which can also impact it (7).  Interestingly, there are only three modifiable variables to influence the gut microbiome, including medication, exercise, and diet.    Of all factors which can influence the microbiome in humans, it is found that diet contributes up to 20 percent of its composition and in mice is it closer to 50 percent (2,3).  Diet is the most influential and most modifiable (4).

Nutrition, Immunity, and Microbiome:  The Basics

The relationship between diet, the immune system, and the microbiome has been extensively investigated.  Several diet-derived nutrients such as resveratrol and curcumin increase antioxidant activity, vitamin A, vitamin E, omega-3 fatty acids, and in combination with microbe-derived SCFAs, act to increase anti-inflammatory cytokines, while down-regulating pro-inflammatory cytokines (8).

In a study of normal weight children who followed a Mediterranean Diet (MD) for one year compared to age-matched controls who disregarded healthy nutrition recommendations, children in the control group had increased levels of inflammatory cytokine interleukin-17 (IL-17) in saliva, whereas those who followed MD had decreased salivary levels of this cytokine. Interestingly, the latter group also had increased levels of IL-10, an anti-inflammatory cytokine compared to decreased levels of it in control groups (5, 6).

Gut flora impact the immune system in the following ways:

• Promotes maturity of dendritic cells
• Activation of Naive T cells
• Differentiation into T effector, regulatory (Tregs), and helper cells (Th)
• Response is local and systemic  (4)

Tregs work to suppress the immune response, by secreting anti-inflammatory cytokines, Teffector cells can release germ-specific antibodies into circulation, and Helper T-cells help activate B cells to secrete antibodies and macrophages to destroy ingested microbes.  They also help activate cytotoxic T cells to kill infected target cells – these are important for adaptive immunity (4).    There is a bidirectional relationship between all three components:  diet, gut microbes, and immunity.   The diet provides nutrients, substrates for resident microbes, such as Vitamin A, Iron, Fat, sugar, and various forms of fiber which will be fermented.  Diet will also provide needed folate, iron, vitamin A for its role in helping nutrient absorption.  Metabolites from microbes such as SCFA can provide helpful components for immunity (2).

Microbiome and cancer development

Just as it can influence functioning of the immune system and inflammation, gut microbes are involved in other pathologies such as cancer.   Dysbiosis—the disruption of microbiota homeostasis—can be categorized into three types:  excessive growth of potentially harmful organisms, loss of beneficial organisms, and loss of microbial diversity.  These three groups most often occur at the same time (7).

Tumor growth can be triggered by certain bacterial pathogens due to negatively affecting the host’s metabolism or the host’s gut and immune functions.  These pathogens have been found to drive 20% of tumor development and various cancers, such as colorectal, are linked to dysbiosis.  Preclinical studies using germ-free mice have demonstrated how the gut microbiome is able to affect cancer progression via different mechanisms (3).  We know this is not limited to bacteria as viruses such as Epstein-Barr and HPV are established contributors to nasopharyngeal cancer and cervical cancer, respectively (6).  The following bacterial species have been linked with colon cancer:  Fusobacterium nucleatum, Streptococcus gallolyticus, Enteroccus faecalis.  Moreover, H. pylori has a known association with gastric cancer, while Clostridium spp. and Porphyromonas gingivalis are linked to liver cancer and pancreatic cancer, respectively (8).

Like other cancers, colorectal cancer is related to inflammation of the tissue.  Diet, microbiota, and gut environment may be modifiable variables and are increasingly demonstrated to have a role in inflammation and colorectal cancer development and progression.  It is important to note that butyrate—and other SCFAs—instead of glucose—is the primary source of energy for colon cells.  The SCFAs are derived from local fermentation of dietary fiber by local microbes in the colon (8).  Both colonic butyrate and short-chained fatty acids (SCFAs) are decreased in the presence of colorectal cancer in addition to dysbiosis.  Additionally, the presence of the species Lactobacillus casei and Lactobacillus rhamnosus prevents the infiltration and advancement of colorectal cancer (8).

Microbiome and Cancer Therapy

How cancer therapy can affect the microbiome composition and subsequent symptoms has also been studied.   Disruption in microbial balance in the gut is associated with early and late radiation enteropathy.   Altered oral bacteria can also increase radiation-induced mucositis.     Reduced responses to chemotherapy agents, such as platinum and cyclophosphamide for multiple cancers has been found by selectively altering gut flora using antibiotics.   The microbiota can influence tumor sensitivity to oxaliplatin and cyclophosphamide (9).

Among the first studied probiotic species, Lactobacillus rhamnosus GG (LGG) was found to help prevent gut flora imbalance and keep intestinal barrier function intact in animal models.  Specifically, when taken with food, LGG reduces 5-FU-mediated and radiation-mediated gut epithelial injury.   There are several clinical trials underway to investigate the role of LGG use in preventing or reducing toxic side effects of anti-cancer therapies (3).

It is well recognized that the gut microorganisms affect drug toxicity and metabolism.  Immune checkpoint inhibitors (ICI) are commonly used in the treatment of melanoma, lung, renal, and colorectal cancers and lymphomas.  These agents block the inhibitory action of T-cells: programmed death receptor-1 (PD-1) and cytotoxic T lymphocyte antigen-4 (CTLA-4).  ICI include:  pembrolizumab, ipilimumab, nivolumab, atezolizumab (9).

Modulating cancer immunotherapy outcomes have had increased interest over the past several years in preclinical mouse model studies.  Siven et al. found oral administration of Bifidobacterium in mice with melanoma improved tumor-specific immunity and response to PD-1-specific antibody therapy.  This study demonstrated how this microbe species was able to significantly control tumor growth in the mice with this particular immunotherapy (10).    Similarly, other research found that gut flora were different between responders and non-responders of anti-PD-1 therapy.   Those patients who were “responders” had the species Akkermansia which was associated with increased infiltration of immune cells in tumor sites in mice (11).  Additionally, in human subjects with metastatic melanoma the gut microbiome was more diverse in responders to PD-1 blockade immunotherapy.  Conversely, non-responders had reduced diversity of intestinal microbiota (11).

There is also evidence that certain species can reduce or increase toxic side effects, such as colitis, in patients receiving immunotherapy.  This was the case for mice with melanoma receiving an oral mixture of Bacterioides fragilis and Burkholderia cepacia when treated with anti-CTLA4 antibody (12).  Another study found same that patients given the same immunotherapy agent had decreased side effects, which was associated with increased Faecalisbacterium and a decrease in Bacterioides (3).

It is well established that the gut flora provides some form of modulation of one’s response to cancer therapies, especially immune checkpoint inhibitors (ICI).   However, until recently it was unclear to what extent diet plays a role.  Spencer et al. investigated the impact of dietary fiber intake and probiotic supplementation on immunotherapy response and progression-free survival (PFS) in late-stage melanoma patients (13).  In this study of 128 participants receiving anti-PD-1 therapy, those with adequate dietary fiber intake of greater than 20 grams per day demonstrated a greater PFS than those with inadequate fiber intake.  Furthermore, every 5% increase in daily dietary fiber intake was associated with a 30% lower risk of progression or death.  Interestingly, the authors examined these endpoints across subgroups, including patients who had sufficient dietary fiber intake with and without probiotics in addition to those with insufficient dietary fiber intake with and without probiotics.   When compared to all other groups, subjects with significantly longer PFS were the those with sufficient dietary fiber intake and no probiotic use (13).   These findings more clearly defined the potential for using diet as an intervention for helping to improve outcomes of immunotherapy for melanoma.

Diet and Microbiome

Several factors can clearly influence the microbial population of the gut:  Fecal microbial transplantation (FMT), antibiotics, prebiotics, probiotics, and diet are key factors.

The Mediterranean diet has been associated with health in various studies.  NU-AGE 1-year Dietary Intervention across five European countries:  Adherence to the Mediterranean diet led to increased abundance of specific gut microbes that were positively associated with several markers of lower frailty and improved cognitive function, and negatively associated with inflammatory markers including C-reactive protein and interleukin-17.  These associations were independent of host factors such as age and body mass index.  Diet-modulated microbiome change was associated with an increase in short/branch chained fatty acid production and lower production of secondary bile acids, p-cresols, ethanol and carbon dioxide.  Mediterranean diet intervention alters the gut microbiome in older people, reducing frailty (14).

In a small, 20-day crossover study comparing two treatment groups--plant-based and animal-based diet (15), subjects ate habitual diet for four days prior to intervention and fecal samples were collected during habitual diet and each diet arm.   The authors found the altered microbial community structure overwhelms interindividual differences in microbial gene expression.

Gut microbes returned to baseline within 3 days (15).  Though a smaller study, this helped to demonstrate the potentially quick impact that diet may have on the microbiome.

Favorable impact of the Mediterranean diet on the gut flora was also found in 7-day longitudinal study (16).  These researchers compared microbe profiles between 3 habitual diet groups of 51 participants:  omnivore, vegetarian, and vegan.  After 3 weeks and obtaining a fecal sample for each week, consumption of plant foods was found to be associated with beneficial microbiome-related metabolite interactions.  As Ghosh et al (14) found in their NU-AGE study, Filippis et al also discovered significant associations between vegetable-based diets and increased levels of fecal SCFA, Prevotella and Firmicutes (16).

Probiotics via diet and supplements have increased in popularity in recent years.  In a randomized, parallel controlled trial, investigators collected stool samples from 12 human subjects consuming 180 ml kefir daily and those of a control group of 10 subjects who consumed 180 ml unfermented milk daily (17).  After 12 weeks, the only significant finding was that of increased relative abundance of Actinobacteria—one of four major phyla in human microbiota and is important in maintaining intestinal homeostasis (17).  Small sample size is a remarkable limitation, but this is not unlike other studies in this area.

There are dietary patterns listed in Table 1 which help to promote eubiosis or dysbiosis (18).

Table 1

Discussion/Future Implications:

There are complex interactions of the human microbiome, nutrition, and cancer immunotherapy and not all mechanisms are fully understood.  Clearly, modifying the gut microbiome to help modulate one’s response to immune checkpoint inhibitors is gaining more attention in the literature.  Dietary components such as prebiotics (fiber), overall diet, and probiotics each have role in microbiome composition.  A low-meat, fiber-rich diet is associated with protective bacterial species.  Moreover, diversity of microbial communities appears critical to better overall health benchmarks and is associated with dietary fiber intake.    More interventional studies with larger numbers of human subject are needed to better define the role of dietary changes in modulation the cancer patient’s response to immunotherapy or other cancer treatments.

Indeed, it may be indicated that some oncology patients have baseline microbiome analysis prior to receiving treatment so that outcomes are optimized via nutritional interventions.

Clinical trials underway involving dietary or probiotics intervention, immunotherapy and impact on cancer outcomes (clinicaltrials.gov):

• NCT03829111: Probiotics (Clostridium butyricum CBM 588 Probiotic Strain)  Nivolumab, and Ipilimumab in Treating Patients With Stage IV or Advanced Kidney Cancer  (n=30)
• NCT03700437: Dietary intervention Fasting-Mimicking Diet 72hrs  before & 24hrs after chemo-immunotherapy for NSCLC receiving Carboplatin/Pemetrexed & Pembrolizumab (n=40)
• NCT03950635: Dietary intervention: fiber-rich (group 1) or ketogenic (group 2) diet.    History of melanoma, currently with no evidence of disease (n=20)
• NCT03595540:  Fasting-Mimicking Diet for 5 days Patients receiving hormonal, targeted or immune-therapies (n=60)
• NCT03686202: Bacterial consortia/mixture of live strains cultured (MET-4)                                         Advanced solid tumor receiving Immune Checkpoint Inhibitors  (n=65)
• NCT05303493: Camu-Camu Prebiotic and Immune Checkpoint Inhibition in Patients With Non-small Cell Lung Cancer and Melanoma  (n=45)
• NCT03870607: Prebiotics and Probiotics During Definitive Treatment With Chemotherapy-radiotherapy SCC of the Anal Canal (BISQUIT)  (n=75)
• NCT01170299:  Low-Fiber Diet or High-Fiber Diet in Preventing Bowel Side Effects in Patients Undergoing Radiation Therapy for Gynecological Cancer, Bladder Cancer, Colorectal Cancer, or Anal Cancer  (n=177)

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