How Gut Microbiome Metabolism Serves a Critical Role in Immune System Modulation

Can you imagine bacteria, viruses, fungi and parasites, all coexisting in perfect synergy? Well, that is exactly what we call a healthy microbiome or microbiota. A natural reservoir of trillions of microorganisms from thousands of different species working as a symbiotic ecosystem to support intestinal health and promote homeostasis through daily vital functions in the human body.

The gut microbiota (GM) is where 70% of our immune system resides, playing an essential role in activating, training, and modulating the host immune response and inflammation.¹ At Hope4Cancer Treatment Centers, we understand the critical role that the GM plays in the modulation of the immune system, which indirectly affects treatment outcomes.² In fact, restoration of the microbiome is one of Dr. Jimenez’s 7 Key Principles of Cancer Therapy, the basis for our integrative cancer treatment protocols.^{3, 4}

So, what happens when dysregulation sets into the GM? Research has shown that dysbiosis (imbalances in the microbiome) can promote inflammation and induce carcinogenesis through the release of genotoxins that can damage DNA.^5-7 This can directly promote an immune dysregulation between the inflammatory Th1-type immunity (which tends to activate immune cells such as macrophages and natural killer cells) and the anti-inflammatory Th2-type immunity (responsible for the release of cytokines that stimulate the production of antibodies). This complex bioregulatory malfunction can ultimately lead to tumor growth and decreased responses to cancer treatment – particularly bio-immunotherapy.^8-12 Th-1 type immunity is often referred to as cell-mediated immune response, while Th-2 is considered a humoral response—the reality is somewhat more complicated than that, but outside the scope of this article to discuss. It should suffice to know here that the body requires a delicate balance between the two immunity types to stay healthy, and much of that regulation happens at the level of the microbiome. To learn more about these complexities, you can refer to one of our previous articles on the adaptive immune system.

Among different epigenetic stressors, diet is one the most important lifestyle factors that can strongly influence the maintenance of a healthy, balanced microbiome. Food-based strategies to modulate the composition of the intestinal microbiota include dietary use of prebiotics, probiotics, synbiotics (a combination of pre- and probiotics)^13-16, and a well-balanced, low inflammatory/allergenic diet comprising bioactive and functional foods.^{16, 17} This dietary approach can create an inhospitable environment for the growth of pathogenic bacteria, fungi and parasites.

The restoration of the microbiome ecosystem is largely and detrimentally ignored by most conventional cancer treatment protocols. Rebuilding the microbiome is not only a potential therapy, but also an influence on the success of other treatments, augmenting survival and quality of life.¹⁸ The purpose of this article is to provide you information on how to cleanse, balance and feed your microbiota in order to modulate your immune system and thereby indirectly influence your treatment and quality of life outcomes.

Cleansing your body at the cellular level: the impact of elimination diet as a therapeutic target

Cleansing at the cellular level requires an elimination of proinflammatory foods from your diet that may impact your immune health, stimulate tumor growth, or modulate response to cancer therapies. Proinflammatory foods may alter the integrity of the gut lining and gut-associated lymphoid tissue (GALT) balance leading to hyperreactivity of the immune system, commonly labeled as food sensitivities or intolerances (leaky gut).^19-21 In reality, there is no such thing as “food intolerances.” What we experience is usually a sick gut that has lost its selective permeability, naturally orchestrated by GALT lymphoid cells as a result of chronic inflammation.²² GALT cells limit and monitor inflammatory responses, keep microbes confined to the gut, and recognize and respond to pathogens that can cause tissue injury or disease. Failure to carry out these vital functions may result in a depleted immune system, decreased detox capacity, and a feeble response to cancer therapies.

To avoid triggering false immune responses, lower inflammation, and optimize treatment results, it can be helpful to eliminate the consumption of proinflammatory foods, such as certain oils (particularly safflower, sunflower, grapeseed, corn and soybean), trans fats, monosodium glutamate (MSG)-containing foods, refined sugars, cow-derived dairy products, dried fruit, artificial sweeteners, soft drinks (including carbonated beverages), alcohol, cold cuts, animal meat (except wild-caught fish), gluten (sources include wheat, barley, kamut, rye, and spelt), couscous, unsoaked nuts, peanuts, shellfish, raw fish, and deep-fried or smoked foods.³

Besides proinflammatory foods, we need to eliminate xenobiotics (substances, particularly synthetic chemicals, that are foreign to the body) as completely as possible from our daily lives. The GM plays a critical role in xenobiotic biotransformation through oxidation, reduction, methylation, and demethylation reactions. It also helps bind and sequester toxic heavy metals.^{23, 24}  Long-term and severe exposure to xenobiotics can contribute to disrupting the GM’s ability to protect the body from their potent neurotoxic, immunosuppressive, genotoxic, and carcinogenic effects. Common xenobiotics include drugs, toxic metals, pesticides, cosmetics, flavorings, fragrances, food additives, industrial chemicals, environmental pollutants, and certain plant constituents.

To avoid xenobiotics, choose organic, non-GMO products as much as possible and switch all regular cosmetics and hygiene products to natural formulas, including your toothpaste! Consider having a water filter at home, especially if you use tap water for cooking and/or drinking.

The relationship between microbial infections and cancer is well documented, which means you should consider eliminating them as part of your preventative strategy. For example, Candida albicans, an opportunist yeast-like fungus that resides in the gut, takes advantage of the immunosuppressed state of patients and is known to increase the risk of carcinogenesis and metastasis.²⁵ Since C. albicans feeds mainly on sugar, a diet that eliminates added sugars is an important nutritional intervention. Some of the restrictions could include carrot or beet juices, and fermented beverages such as kombucha. The latter, while considered generally supportive of good GI health, are not recommend during C. albicans treatment because they contain simple sugars (i.e., sugar without associated fiber) that can favor yeast growth.

Balance: The cellular immunity (Th1) vs humoral immunity (Th2) theory

As discussed earlier, Th1/Th2 regulation is essential for proper immune system function.²⁶ Th1 cells produce predominantly interleukin-2 (IL-2) and interferon-gamma (IFN-g) which are known to have an essential role in generating and activating cytotoxic T-lymphocytes and natural killer (NK) cells, which are main effector cells in cellular immunity against cancer tumors. On the other hand, Th2 activation produces IL-4, IL-6 and IL-10, which downregulate Th1 cells.^{11, 27, 28}

Tumor-derived IL-10 has been documented in lymphoma, melanoma, and neuroblastoma, as well as renal cell, ovarian, and colon carcinoma. Recent clinical studies suggest elevated IL-10 is predictive of a poor cancer prognosis.²⁹

Dysbiosis in cancer patients can lead to overactivation of Th2 immunity, which can lead to immunosuppression of Th1 pathways.⁵ So, besides fixing the host dysbiosis and restoring the gut with beneficial bacteria, what are some other ways to target Th1/Th2 imbalance?

Melatonin and DHEA are hormones with proven benefits over this immune homeostasis.^30-33 Melatonin, for example, naturally present in foods like nuts, olive oil, oats, bananas, cherries, and rice, does not have receptors on Th2-type immune B cells and probably does not boost “humoral” immunity. Our body produces both hormones naturally, but their production progressively reduces with age, which can justify the need for supplementation. Progesterone, on the other hand, contributes to the natural suppression of cell-mediated immunity (Th1-type).

Beta-glucans (either in supplement form or bioavailable mushrooms extracts), key minerals selenium or zinc as well as glycosylated plant sterols like beta-sitoesterol (BSS), found in nuts, seeds, legumes, whole grains, fruits, veggies, flax seed oil, and fermented soy are known to be natural Th1-type cellular immunity boosters.^34-38

Omega-3 fatty acids DHA/EPA (from fish), flavonoids quercetin and curcumin, allicin (from garlic), cinnamaldehyde (from cinnamon), piperine (from black pepper), propolis (from honeybees), as well as botanicals such as Boswellia serrata and Petasites hybridus (butterbur), can effectively address the inflammatory component of Th1/Th2 imbalance.^39-44

Feeding the microbiome: Are all probiotics suitable or equally effective?

The answer is no.

Of course, the best natural prebiotics and probiotics in foods should be available in our daily balanced diet that should include a variety of fiber sources and healthy bacteria from fermented foods. However, can this approach really help cancer patients? In general, it does. However, sometimes the cancer phenotype and stage of disease can work against the reassimilation of a healthy microbiome.

As explained in my previous blog article, some amino acids like asparagine and free glutamate need to be dietarily restricted in certain cancer types.⁴⁵ In advanced stages, cancer cells undergo a reprogramming of metabolism to maintain bioenergetics, redox status, cell signaling, and biosynthesis in what is often a poorly vascularized, nutrient-deprived microenvironment. The fermentation process breaks down proteins into their amino acid components. As a result, fermentation of foods high in glutamine (such as cabbage) and glutamic acid bound to proteins such as soy, can free the glutamate in these foods, offering a direct fuel source for cancer cells’ energy cycle. So, even though kimchi, sauerkraut, and fermented soy products are considered pro-microbiome health foods, we would prefer probiotic supplementation in these scenarios.^46-49

On the other hand, prebiotics found in foods as dietary fibers or indigestible carbohydrates are safe to be consumed in most cases and play a fundamental role in maintaining microbiome health.^{50, 51} Bacterial fermentation of dietary fiber that remains undigested or partially digested in the gut produces short chain fatty acids (SCFAs) and polyamines. These substances, considered to be potential anti-carcinogenic agents, play several crucial roles, such as providing energy to intestinal epithelial cells and maintaining gut barrier integrity. They also mediate immune cell phenotypes through epigenetic mechanisms, altering host gene expression, inducing autophagy, and stimulating production of anti-inflammatory cytokines. Inulin and oligofructose are important prebiotics abundantly present in artichokes, bananas, chicory root, garlic, onions, leeks, legumes, and yams, and can work together as synbiotics to synergize their benefits.

An impaired microbiome has been shown to reduce efficacy of chemotherapy and bio-immunotherapy.⁵² Commensal microbiota can improve the efficacy of anticancer therapies by modulating both the host immunity (increased NK cell activity), as well as tumor-associated immunity. In other words, probiotics may provide an avenue to synergize treatment efficacy.

The immunomodulatory effect of probiotics varies according to the strain, diverging in the cytokine expression profile and its effect over the inflammation response. Beneficial effects of probiotic Lactobacillus and Bifidobacterium based on their immunomodulatory properties over Th1/Th2 balance, as well as their capacity to produce bioactive metabolites from dietary phytoestrogens, have been proven. The following bacteria have demonstrated promising benefits based on numerous scientific studies: (Lactobacillus species) L. rhamnosus, L. plantarum, L. lactis, L. acidophilus, L. salivarus, L. paracasei, and L. fermentum; (Bifidobacterium species) B. longum, B. breve and B. bifidum.⁵³

In general, Bifidobacterium and Lactobacillus species have low enzyme activity involved in carcinogen formation and metabolism compared to major anaerobes in the gut such as bacteroides, eubacteria and clostridia. This suggests that increasing the proportion of these two lactic acid-producing bacteria in the gut could improve levels of xenobiotic-metabolizing enzymes and decrease levels of bacterial carcinogen-activating enzymes, genotoxins and tumor promoters. It could also increase tumor-infiltrating CD8+ T cells, thus reducing tumor growth.⁵⁴

Long-term studies with patients supplemented with oligofructose-enriched inulin either alone or as a synbiotic (with L. rhamnosus and B. lactis) showed a reduction in the number of aberrant crypt foci (ACF) in the proximal, distal and total colon.⁵⁵ ACFs are pre-neoplastic lesions found in the etiology of most colon cancers. Similar beneficial effects have been documented for mammary and liver cancers. The growth of both tumor lines was significantly inhibited by supplementing the diet with non-digestible carbohydrates (dietary fiber).⁵⁶

In hormone-driven cancers (ER+ and/or PR+), the selected probiotic strain combinations could represent a potential therapeutic target since these could enhance the antiestrogenic effects from phytoestrogens. Health benefits from phytoestrogen consumption (via curcumin, flaxseeds, whole cereals, sesame seeds, berries, etc.), along with the presence of selected probiotic bacteria, may ensure the production of equol, enterolignans, and urolithin. These are anticarcinogenic, bioactive metabolites produced in the healthy gut.

Much progress has been made over the past two decades in unravelling the interaction between our immune status and microbiome. We can conclude that a clean, low-inflammatory diet, rich in bioactive nutrients, SCFAs derived from prebiotic fermentations, selected probiotics strains, and their synbiotic combinations can improve gut mucosal lining integrity, reduce inflammation, and improve detox capacity. Working on these aspects will help the body improve its autoregulatory response and immune system modulation that is likely improve overall quality of life and lead to effective therapeutic outcomes.

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